MDMA / Ecstasy : Utopian Pharmacology
Mental Health in the Third Millennium
MDMA and Beyond
- A brief history of MDMA
- The MDMA Experience
- MDMA : neurotoxicity
- MDMA : neuroprotection
- Ecstasy for life?
- The molecular machinery of magic
- Post-Darwinian Medicine
- Beyond MDMA : mental superhealth
MDMA/EcstasyCan safe, sustainable analogues of MDMA
be developed? There is an urgent need for non-neurotoxic empathogens
and entactogens suitable
for lifelong use. Alas no single "magic bullet" yet exists that replicates the
subjective effects of MDMA on a long-term basis. Hence most of us are doomed to
display the quasi-psychopathic indifference to each other characteristic of the
A brief history of MDMA
MDMA [3,4-methylenedioxy-methamphetamine: 'Ecstasy'] was first1 synthesized in 1912 by the German pharmaceutical company Merck. MDMA was patented in Darmstadt, Germany on May 16th 1914, issue number 274,350; and promptly forgotten. Merck's researchers had no idea of the significance of what they had done. Merck were searching for a good vasoconstrictor, a styptic to reduce bleeding. In 1912 two of their chemists, G. Mannish and W. Jacobsohn, created MDMA as a by-product while attempting to synthesise hydrastinin. MDMA is listed on Merck's patent-application merely as a chemical intermediate "for products of potential pharmaceutical value".
MDMA surfaced again briefly
as one of a number of agents used in clandestine US military research during the
1950s. The CIA's Project MK-Ultra was investigating
new techniques of brainwashing, espionage and mind-control. MDMA, code-named EA-1475,
was tested at the US Army's Edgewood Arsenal in Maryland. However, unlike LSD
or the ill-named "truth drug" scopolamine,
MDMA was used only on animals: mice, rats, pigs, monkeys and dogs. Thankfully,
MDMA's military potential was not realised. For although MDMA is no infallible truth-serum,
its effects on the human user might indeed be abused for sinister purposes by
skilled interrogators. The heightened emotional responsiveness, lowering of defensive
barriers, openness and sense of closeness to others induced by MDMA can promote
an honesty of self-disclosure that might be manipulated for malign ends. Fortunately,
this hasn't yet happened on an organised scale.
parent and longer-acting metabolite, 3,4-methylenedioxyamphetamine [MDA]
was first synthesized in 1910 by the same two unsung Merck researchers who went
on to create MDMA. MDMA differs structurally from MDA only in its additional
methyl group attached to the nitrogen atom. MDA's own empathy-enhancing effect
at low doses was explored by Chilean anthropologist-psychiatrist Dr
Claudio Naranjo in his private practice. Dr Naranjo discusses MDA-assisted
therapy in his classic The Healing Journey (1973). MDA was patented by
drug company SmithKline French for use as a tranquilliser (1960) and appetite-inhibitor
(1961). SmithKline were interested in MDA's potential as an antidepressant and
a slimming-drug. In 1958 human trials were conducted; unfortunately the compound
was to prove too psychedelic for licensed clinical use. But MDA was popular as
"the love drug" in the counterculture of the 1960s.
identity of the first human being to take MDMA/Ecstasy isn't known. The drug
gained prominence only in the late 1970s. Tipped off by Merrie Kleinman, a graduate
student in the medicinal chemistry group he advised at San Francisco State University,
the legendary Californian psychedelic
chemist Alexander ("Sasha") Shulgin synthesized and taste-tested MDMA at incrementally
ascending doses. Ironically, Dr Shulgin had himself synthesized MDMA in 1965,
but hadn't tried it, an error of omission he later did much to repair. The effects of a 120mg dose of MDMA are recorded in Dr Shulgin's
lab-notes (Sept 1976):
"I feel absolutely clean inside, and there
is nothing but pure euphoria. I have never felt so great or believed this to be
possible. The cleanliness, clarity, and marvelous feeling of solid inner strength
continued throughout the rest of the day and evening. I am overcome by the profundity
of the experience..." In the first published scholarly paper
[Shulgin,A.T. & Nichols,D.E.: Characterization of three new psychotomimetics. In: Stillman,R.C. & Willette,R.E. (Eds.) The Pharmacology of hallucinogens. New York: Pergamon, 1978] on MDMA use in humans, Dr
Shulgin and Dr
David Nichols describe the effects of MDMA on the human psyche as "an easily
controlled altered state of consciousness with emotional and sensual overtones."
The well-connected stepfather of MDMA soon introduced the drug to the wider scientific
community. Some of Dr Shulgin's friends, notably the "Johnny Appleseed of MDMA",
Leo Zeff, were professional therapists. They in turn introduced MDMA to colleagues
as a valuable adjunct to psychotherapy.
Later, in 1991, Dr Shulgin
and his wife Ann
[Phenethylamines I Have Known And Loved]: A Chemical Love Story. PiHKAL
describes the synthesis and systematic testing on human subjects of a range of
novel or neglected phenethylamine research drugs. PiHKAL also offers a
uniquely sophisticated methodology for human psychopharmacology and the scientific
study of mind as an experimental discipline.
the early 1980s, over a thousand private psychotherapists
in the USA were using MDMA in their clinical practice. MDMA was commonly known
as "Adam", an allusion to "being returned to the natural state of innocence before
guilt, shame and unworthiness arose". MDMA was used discreetly; no one wanted
a re-run of the 60s. Dr
Shulgin himself reportedly felt MDMA came closest to fulfilling his ambition
of finding the perfect psychotherapeutic drug.
word leaked out. MDMA was profiled by the San Francisco Chronicle as "The
Yuppie Psychedelic" (10 June 1984). In Newsweek, J Adler ["High on 'Ecstasy",
April 15 1985] likened his MDMA experience to "a year of therapy in two hours".
Harpers Bazaar described MDMA as "the hottest thing in the continuing search
for happiness through chemistry". Unsurprisingly, MDMA use soon spread beyond
the couch and clinic to the wider world. MDMA's now universal brand-name, "Ecstasy",
was coined in 1981 by a member of a Los Angeles distribution network. The unnamed
distributor, quoted in Bruce
Eisner's Ecstasy:The MDMA Story (1989), apparently chose the name "Ecstasy"
because "it would sell better than calling it 'Empathy'. 'Empathy' would be more
appropriate, but how many people know what it means?" Condemned by purists as
a cynical marketing ploy, the brand-name "Ecstasy" isn't wholly misleading [ecstasy:
"an overpowering emotion or exaltation; a state of sudden intense feeling.
Rapturous delight. The frenzy of poetic inspiration. Mental transport or rapture
from the contemplation of divine things"]. Many first-time MDMA users do indeed
become ecstatic. Some people report feeling truly well for the first time in their lives.
In the early 1980s, American production
of MDMA beyond the research laboratory was effectively controlled by chemists
known as the "Boston Group". Somewhat incongruously, MDMA was especially popular
in Texas, where the Southwest distributor for the Boston Group launched his own
commercial operation. Mass-production of MDMA by the so-called "Texas Group" began
in 1983; supply (and demand) soon mushroomed. Ecstasy was distributed openly in
bars and nightclubs in Dallas and Fort Worth. It could be purchased via toll-free
800-numbers by credit card. The drug was even marketed via pyramid-style selling-schemes.
Ecstasy could be bought in little bottles at convenience stores under the label
"Sassyfras", a tongue-in-cheek allusion to the botanical origins of its precursor.
reacted by petitioning to have MDMA banned altogether. In 1985 the drug-warriors
succeeded in having MDMA made Schedule One. Schedule One is the most restricted
of all drug categories i.e. MDMA had allegedly "no legitimate medical use or manufacturer"
in the USA; it lacked safety for use even under medical supervision; and it carried
a "high potential for abuse". But by then MDMA's fame had spread across the Atlantic.
MDMA had metamorphosed from "Adam", the psychotherapeutic tool, to "Ecstasy",
the party drug.
MDMA was first
introduced to Europe via the sannyasins, disciples of the Bhagwan Shree Rajneesh.
"Sannyasa" is a Sanskrit word meaning complete or perfect renunciation.
Cult members slipped MDMA into the drinks of rich sympathisers to open up their
hearts and their wallets.
became associated with the birth of Acid
House music in the Spanish tourist resort of Ibiza. By the summer of '86,
Ibiza was popularly known as "XTC Island". Returning tourists and disc-jockeys
took the message back home. The UK's rave scene was born. Hundreds of thousands
of tablets were consumed each weekend in the famous "Summer of Love" (1988). The
Conservative Government and its allies in the British press were aghast. A moral
panic set in at the threat to the nation's youth. MDA, MDEA, MDMA and assorted
psychedelic amphetamines had been outlawed in the UK since 1977. Yet the Criminal
Justice and Public Order Act 1994 sought to criminalize an entire youth-culture
by suppressing music played publicly with "sounds wholly or predominantly characterised
by the emission of a succession of repetitive beats".
production and distribution of the world's leading empathogen-entactogen fell
into the hands of organised crime. By the turn of the millennium, perhaps 80-90%
of the world's MDMA was manufactured in Belgium and the Netherlands. Russian-Israeli
syndicates and Eastern European chemists are now increasingly active too. The
expertise needed in
MDMA production varies according to the route of synthesis. Over twenty recipes
have been described in the literature. Only seven are common. Clandestine production
is easiest starting with MDP2P. MDP2P (3,4-methylenedioxyphenyl-2-propanone) is
a commercial product used by the flavouring and fragrance industry. Groups with
access to MDP2P can make MDMA via a simple conversion process. Otherwise, MDMA
must be synthesized
from piperonal, isosafrole, or safrole.
These primary precursor chemicals of MDMA are produced in India, China, Poland,
Germany, and increasingly elsewhere. Typically, safrole or isosafrole are first
converted to MDP2P. The essential oil safrole occurs naturally as the primary
constituent of oil of sassafras. Oil of sassafras is found in the root-bark of
US East Coast tree Sassafras albidum and from the above-ground woody parts
of the South American tree Ocotea pretiosa. Safrole is also present in
fragrans), dill, parsley seed, crocus, saffron, vanilla beans, and calamus.
If MDMA were on-patent, then today it might be marketed as "natural" or "naturally-inspired";
but Nature has not been so kind.
in the twenty-first century, an estimated several million people worldwide were
taking Ecstasy and allied research chemicals each month on college campuses, in high schools and on dance-floors.
Purity varies; perhaps 10%-15% of tablets consumed contain MDMA as the sole active
ingredient. Illicit knowledge of the "penicillin of the soul" is spreading
rapidly around the world, but in corrupt and contaminated form.
MDMA ExperiencePure MDMA salt is a white crystalline solid. It looks white
and tastes bitter. The compound is chemically stable. MDMA does not readily decompose
in heat, air or light. The optimal adult dose of racemic MDMA is probably around
120-130mg [around 2mg/kg of body weight i.e. about 125mg] but it ranges from perhaps
75mg to as much as 250mg. Pills sold in clubs often contain less. There are gender
differences in response; proportionately to body-weight, women
are more sensitive than men to MDMA, so their optimal dosage may be lower. The
preferentially metabolised (+)-enantiomer
("mirror image") of MDMA is more active, more stimulating, and more neurotoxic
than the (-)-enantiomer.
MDMA is usually taken orally as a tablet, a capsule, or a powder. MDMA is readily
absorbed from the gastrointestinal tract into the bloodstream. More rarely, the
drug is snorted, smoked or injected.
of action is normally within twenty to sixty minutes or so after administration.
When MDMA is administered by the oral route, "coming up" is naturally faster on
an empty stomach. Taking MDMA causes both an increased neuronal reuptake inhibition
of the neurotransmitter serotonin
(5-hydroxytryptamine, 5-HT) and also, critically, its increased synaptic release.
The MDMA molecule is small enough to be taken up via the membrane-bound serotonin
transporter into the presynaptic serotonin axon terminals. Here MDMA acts to reverse
the normal direction of the so-called serotonin reuptake pump. Inside the nerve
cell, MDMA alters the configuration of the transporter protein so it binds to
cytoplasmic serotonin, after which the transporter dumps serotonin outside the
cell, reversing the normal inward-bound direction of the transporter channel i.e.
MDMA increases the rate of transporter-mediated serotonin outflow. The consequent
additional flood of serotonin in the user's synapses is soon followed by an increased
release of dopamine especially
in the reward centres of the striatum and nucleus
MDMA users occasionally feel confused or anxious before the dose-dependent dopamine-release
kicks in. A transient hint of nausea is common when coming up. Most of the body's
serotonin is found outside the brain, notably in neurons of the enteric nervous
system, our "little brain" inside the smooth muscles of the gut. The user's peak
experience or plateau phase after the exhilarating dopaminergic "rush" doesn't
last much more than ninety minutes to two hours. MDMA's primary effects wear off
after some 3-4 hours. MDMA is more fat-soluble than its structural parent, so
its speed of onset is slightly faster and its duration of action shorter. With oral MDMA dosing, peak concentration in the plasma follows after around two hours. Therapists then
sometimes add(ed) a final 50mg booster-dose. Heavy recreational users are not
always so restrained either in dosage ["stacking"] or top-up schedule ["piggybacking"].
The clarity and unique psychological
effects of MDMA can be impaired by ethyl alcohol. Thus MDMA is best taken while
completely sober, though a modest drink later to ease any comedown may be useful.
MDMA has a complex nonlinear
pharmacokinetics. Taking higher and/or more frequent doses of the drug disproportionately
increases levels of plasma MDMA. Higher levels substantially increase oxidative
stress and magnify the risk of toxicity. MDMA is metabolised
via N-demethylation to the active metabolite MDA; MDA can itself induce a state
of sensual euphoria, though in humans the conversion rate from MDMA in the body
is low. At least four other metabolites have been identified. MDMA is broken down
mainly in the liver, primarily by the polymorphic cytochrome
P450 enzyme CYP2D6. However, other enzymes are involved in its degradation
beside CYP2D6; some of them, like CYP2D6 itself, are saturated at relatively low
MDMA concentrations. MDMA metabolism seems to run up against such a metabolic
saturation-point somewhere between 120 and 150mg. When the high-affinity enzymes
are saturated, a disproportionately large increase in blood- and brain MDMA-concentrations
may occur if the user then takes more of the drug. A large but variable quantity
of the parent compound is excreted unchanged, especially when the drug is taken
at higher doses; but the opportunities for MDMA recycling by the cost-conscious
are normally wasted.
is sometimes described as a cross between a psychostimulant and a mild hallucinogen.
Since it's a methoxylated amphetamine, MDMA is indeed structurally related to
mescaline. MDMA's methylenedioxy
(O-CH2-O-) group is attached to positions 3 and 4 of the aromatic ring
of the amphetamine molecule. But hallucinations on MDMA taken at therapeutic dosages
are extremely rare; and psychostimulants, unlike MDMA, don't typically induce
a profound sense of inner peace. Thus MDMA exhibits a different profile both from
the prototypical "serotonergic" 2,5-dimethoxy-4-methylamphetamine (DOM),
with its psychedelic 5-HT2A-mediated
mechanism of action, and also from the prototypical "dopaminergic" stimulant (+)-amphetamine.
MDMA is perhaps best characterised
as belonging to a functionally unique class of "empathogen-entactogen". These
words don't mean a great deal in the MDMA-naïve state. The term "empathogen"
to describe MDMA and other closely related phenethylamine "empathy drugs" [MDA,
MDEA, MBDB] was proposed by Ralph
Metzner, Dean of the California Institute of Integral Studies, at a 1983 conference
at the University of California at Santa Barbara. The term "entactogen"
was coined in 1986 by Dr David Nichols, Professor of Medicinal Chemistry and Pharmacology
at Purdue University and co-founder of the Heffter
Research Institute, to refer to substances that generate a sense of "touching
within" or "produce a feeling in one's innermost being". Both terms are quite
apt, though neither will win any marketing awards. MDMA can promote an extraordinary
clarity of introspective self-insight, together with a deep love of self and a
no less emotionally intense empathetic love of others. MDMA also acts as a euphoriant.
The euphoria is usually gentle and subtle; but sometimes profound.
set and setting inevitably shape the MDMA experience. Idiosyncratic responses
to MDMA aren't rare. MDMA has even been described as a drug that "could be all
things to all people" (Dr Shulgin). Even so, MDMA's primary effects on the user
are surprisingly consistent, unlike the wilder psychedelics such as LSD,
DMT. MDMA may feel mystical,
magical or sublime; but it doesn't feel weird. The drug's influence feels
highly controllable. MDMA tends to enrich the user's sense of self-identity, not
diminish it. MDMA "provides a centering experience, rather than an ego diffusing
experience" (Dr. Philip Wolfson), though it may also cause a "softening of the
ego-boundaries". Sometimes a degree of derealisation on MDMA may occur, but rarely
depersonalisation in the ordinary
sense of the term. On the contrary,
users feel they can introspectively "touch inside" to their ideal authentic self
with total emotional self-honesty.
well as acting as a "gateway to the soul", MDMA "opens up the heart". Taking MDMA
induces an amazing feeling of closeness and connectedness to one's fellow human
beings. MDMA triggers intense emotional release beyond the bounds of everyday
experience. The drug also enhances the felt intensity of the senses - most exquisitely
perhaps the sense of touch. The body-image looks and feels wonderful. Other people
look and feel wonderful too. Minutes after dropping a pill, a lifetime of Judaeo-Christian
guilt, shame or disgust at the flesh melt away to oblivion.
MDMA is taken outdoors, the natural world seems vibrant and awe-inspiring, perhaps
even enchanted. The experience of colour is gorgeously intensified. On MDMA, Dr
Shulgin reported how mountains he'd observed many times before appeared to be
so beautiful that he could barely stand looking at them. MDMA is not normally
classed as an entheogen. "Entheogen"
is a term proposed in 1979 by the scholars R. Gordon Wasson, Carl A.P. Ruck, Jonathan
Ott, Jeremy Bigwood and Danny Staples for agents "generating the god or the divine
within", shorn of any speculative metaphysics. Yet MDMA is used by a variety of
of widely diverse beliefs as a gateway to the divine. Some MDMA users undergo
life-changing spiritual experiences. Nicholas
Saunders, author of the book E for Ecstasy (1993), cites a Benedictine
monk who finds MDMA "opens up a direct channel to God". MDMA may not be "Christ
in (al)chemical form", but if it had been present in the Eucharist, then we would
all still be devout Christians, possibly for ever. A minority of first-time MDMA
users undergo what the inventor of the Shulgin scale christened a Plus Four...
"PLUS FOUR, n. (++++) A rare and precious transcendental state,
which has been called a "peak experience," a "religious experience," "divine transformation,"
a "state of Samadhi" and many other names in other cultures. It is not connected
to the +1, +2 and +3 of the measuring of a drug's intensity. It is a state of
bliss, a participation mystique, a connectedness with both the interior and exterior
universes, which has come about after the ingestion of a psychedelic drug, but
which is not necessarily repeatable with a subsequent ingestion of the same drug.
If a drug (or technique or process) were ever to be discovered which would consistently
produce a plus four experience in all human beings, it is conceivable that it
would signal the ultimate evolution, and perhaps the end of, the human experiment.
(PiHKAL, pages 964-965)" Plus Fours are rare, today. But on MDMA,
even the most jaded and world-weary soul with a tin-ear for poetry
may "see a world in a grain of sand, And a heaven in a wild flower, Hold infinity
in the palm of your hand, And eternity in an hour."
is sensuous and sensual in its
effects without being distinctively pro-sexual. Although once dubbed "lover's
speed", MDMA is proverbially more of a hugdrug than a lovedrug: "I kissed someone
I was in love with and almost felt as if I was going to pass out from the intensity",
recalls one American clubber. However, MDMA's capacity to dissolve a lifetime's
social inhibitions, prudery and sexual hang-ups means that lovemaking while under
its spell is not uncommon. Superfluous clothes tend to get shed. In men, orgasm
is more intense than normal but delayed: MDMA retains a residual sympathomimetic
activity, triggering a detumescence of the male organ. To ease MDMA-induced performance
difficulties, flagging Romeos increasingly combine Ecstasy with Viagra
('Sexstasy'). Unless carefully premeditated, this is not a recipe for safe sex.
MDMA may sometimes cause "inappropriate bonding". Prudence should be exercised
before taking it with ex-girlfriends, boyfriends or culturally inappropriate love-objects.
The effects of MDMA on bonobos
("pygmy chimpanzees"), our sexually uninhibited primate cousins, are unknown.
On pure MDMA, subjects feel
at peace with themselves and the world. They discover an enhanced sense of self-worth,
self-forgiveness and complete self-acceptance. Cynical thoughts and negative feelings
disappear. Aspects of life normally too sensitive to talk about can be explored
freely. Heightened feeling allows long-forgotten and repressed emotional memories
from childhood can be retrieved with unusual ease. In some settings, painful,
highly-charged and even hitherto unmentionable problems may be discussed with
(rose-tinted) candour. On MDMA, a lifetime of accumulated psychological barriers
and defence-mechanisms go down, somehow magicked out of existence with a pill. Anger, irritability
and ingrained fear dissolve; the hostile amygdala
is subdued, if only for a few hours. Ecstasy users tell each other affectionately
what beautiful people they are; and they do so from the depths of their hearts.
Before the Orwellian-sounding
Drug Enforcement Administration [DEA]
placed MDMA on Schedule 1 of controlled substances, professional therapists
in the USA found MDMA a valuable tool for counselling and marriage-guidance sessions.
MDMA's capacity to induce empathetic bliss, heightened introspection and an increased
ability and desire to communicate feelings can create a rapport with the therapist
and accelerate a successful outcome. MDMA boosts self-esteem and self-confidence,
while paradoxically diminishing egotism. The user's sense of social isolation
vanishes. "I love the world and the world loves me", affirmed one beneficiary
of MDMA-assisted therapy.
a more sceptical note, it's hard scientifically to validate claims of long-lasting
therapeutic success. For MDMA's stunning short-term results make double-blind,
placebo-controlled trials effectively impossible. Such a problem doesn't always
bedevil today's lame
"antidepressants", the results
of whose trials often struggle to reach statistical significance. Investigational
drugs are lab-tested by Big Pharma to discover whether or not non-human animals will self-administer
them. Candidate compounds are normally discarded if the animals do so, arguably a perverse route
to uncovering antidepressants with good clinical efficacy and high patient compliance. By contrast, MDMA is
a warm, fast-acting, non-sedating mood-enricher that banishes social anxiety and
physical pain alike. Unlike opioids or the
MDMA doesn't cloud consciousness even at relatively high doses. This doesn't stop
less cerebrally-inclined ravers from getting "cabbaged" by swallowing pills all weekend.
Explored in a controlled setting,
MDMA can be therapeutic for victims of Post-Traumatic Stress Disorder (PTSD).
A minority of subjects find they enjoy the experience too much to focus on the
emotional baggage of the past. Sessions are most likely to be productive with
an experienced MDMA therapist. In the Prohibitionist era, MDMA-assisted therapy-sessions
Dr David Nichols
suspects that the related phenethylamine entactogen MBDB
("Eden": 2-Methylamino-1-(3,4-Methylenedioxyphenyl)Butane), formed by extending
the 3-carbon chain of MDMA to a 4-carbon chain, might prove superior to MDMA as
an adjunct to psychotherapy. This is because Dr Nichols' creation lacks significant
dopaminergic activity. It's thus less likely to induce a distracting euphoria.
On the other hand, if and when the substrates of blissful self-insight can be
sustained indefinitely, then who'll need therapy? Perhaps some inner demons are better
left to die of neglect, not awakened for exorcism. Either way, a case can be made
that MBDB is indeed a "purer" entactogen than MDMA. Yet as an empathogen, MDMA
is unsurpassed and possibly unmatched. MDMA's residual dopaminergic amphetamine-like
action contributes a euphoric warmth to the user's intensified feelings and also
the desire and ability to express them freely.
formidable odds, the Multidisciplinary Association for Psychedelic Studies (MAPS)
has been seeking funding and FDA-approval for controlled trials
of MDMA-assisted therapy for PTSD. If these trials are successful, then MAPS hopes
that MDMA could eventually become a prescription-medicine. For on MDMA, many traumatized
or seemingly emotionally frigid people who can never otherwise speak about their
innermost fears and feelings find they can spontaneously open up. There is no
compulsion to talk - just a dissipation of the social anxieties that make us normally
analogues of MDMA may one day be employed in other kinds of insight-oriented therapy
as well. Safe, long-acting MDMA analogues may prove therapeutic in the treatment
of social phobia, eating
disorders and obsessive-compulsive disorder (OCD).
In December 2004, the FDA granted permission for Dr John Halpern's proposed study of MDMA-assisted psychotherapy for patients diagnosed with severe anxiety related to advanced cancer. The likelihood of DEA approval of the protocol is unknown. If the magic of MDMA could be replicated safely and sustainably, then the fear of death and dying could in principle be banished in the population at large. This would be a substantial payoff, though the fear of personal mortality is probably the prime mover of scientific progress in anti-aging research.
Dr Julie Holland, editor of the invaluable Ecstasy:The
Complete Guide (2001), tentatively endorses "the judicious, supervised
and single oral doses of MDMA as a psychiatric medicine..." In her introduction
to the guide, Dr Holland notes that "Like any powerful tool, it should be used
by people who are properly trained, educated and supervised. And like any powerful
tool, it should come with an instruction manual. This book, I hope, will serve
as that manual". It may be testimony to the comparative safety of MDMA
that millions of young people use MDMA in the absence of a manual or any training,
education and supervision at all. Alas Prohibitionism puts the
young and vulnerable
at unnecessary risk; and squanders the therapeutic opportunities. In defiance
of scepticism from medical orthodoxy, Dr Holland also provides supporting evidence
to back up anecdotal reports that MDMA can induce temporary remission of symptoms in victims
of otherwise intractable schizophrenia.
Less controversially, it's possible for victims of body dysmorphic disorder (BDD),
or simply anyone with a negative body self-image, to view themselves in the mirror
while euphorically loved-up on MDMA. The transformation can be magical, though
it would be imprudent to repeat the experiment two days later.
can also be used just to have fun. Most commonly today, teenagers and young adults
take Ecstasy to rave. Mozart sounds great
on Ecstasy, but high-energy all-night dance parties celebrated with techno-pop
house music are more standard. Raves
are held in clubs, warehouses or more exotic outdoor settings and open fields.
Often raves last a whole weekend. The music may be techno, hardcore, jungle, trance
or form an improvised, eclectic mix of styles harder to categorise. The atmosphere
is astonishingly friendly, the mood and ethos is well captured by the ravers'
motto P.L.U.R. ["Peace, Love,
Understanding and Respect"]. In darkened clubs, the intoxicating atmosphere of
the rave is enhanced with artificial fog, lasers, strobe lights, glow sticks,
whistles and Vicks inhalers [on MDMA, aromas are fragrantly enriched]. In many
cases, the product now passed off as "Ecstasy" is adulterated with other agents.
Individual pills bought by the end-user typically cost between US$7 and US$25.
The worldwide street price is falling. Tablets can be mass-manufactured for as
little as 50 cents. Professionally-made tablets of MDMA are stamped with distinctive
logos. This is because MDMA manufacturers and merchants seek to promote brand-awareness
and customer loyalty. Alas counterfeit goods are still rife.
"Ecstasy" doesn't contain MDMA at all, but MDA;
"Eve"); 2-CB (4-Bromo-2,5 Dimethoxyphenethylamine:
''Nexus", "Venus", "Bromo"); 2C-I; PMA
("speed"); ephedrine; pseudoephedrine; caffeine;
the dissociative anaesthetic ketamine
("Special K"); DXM
(gamma-hydroxybutyrate: "liquid ecstasy"); or some combination thereof. This list
is far from exhaustive. A minority of psychologically robust or reckless clubbers
purposely mix MDMA with LSD
("candyflipping") to impart a
"warm, loving glow" to their acid trips. Or they "hippieflip" with psilocybin
mushrooms; or "kittyflip" with ketamine.
Cannabis is widely smoked as
well. Ravers who want to dance all night may prefer Ecstasy laced with speed;
a sub-neurotoxic dose of MDMA can be made toxic by adding (+)-amphetamine. To
outsiders, Ecstasy-fuelled raving might seem mindless hedonism;
its devotees have likened it to group-therapy or meditation. But either way, chronic
heavy use of the methoxylated amphetamines or any other "club-drug"
poses risks to the user's health.
compelling evidence exists that taking a single c.125mg dose of MDMA a few times
or so a year is likely to cause any long-term harm to the user's mental or physical
health. Nevertheless, even pharmaceutical-grade MDMA taken at moderate doses in
optimal conditions is not
a wholly benign drug. The problem isn't (just) the toxic adulterants used by dance-floor
pharmacologists or the botched syntheses of bathtub chemists. Deceptively, and
in contrast to most other recreationally used drugs, ingesting pure MDMA can sometimes
leave the user feeling better than normal the next day, albeit tired and slightly
spaced-out. Beyond warm memories, this afterglow may in part be explained by MDMA's
residual amphetamine metabolic by-products: MDMA itself has a long, c.8-9 hour
elimination half-life from the blood; and its main metabolite's longer-acting,
(-)-MDA enantiomer has 5-HT2A
activating effects resembling low-grade LSD. But two days or so after taking MDMA,
most users experience the serotonin
dip. The dip ranges from the almost imperceptible to the markedly unpleasant.
The functional deficit the dip reflects may last ten days or more - in some cases possibly
weeks or months. A biphasic post-E serotonin profile in the user has been reported:
users' serotonin levels - though hard to measure and interpret - apparently fall
3-6 hours after taking the drug, then recover to nearly normal levels after around
24 hours, and then decline again.
Excessive MDMA intake triggers oxidative damage to the user's
serotonergic nerve cell fine axon terminal
lipids and proteins via the production of toxic free radicals.
However, the threshold dose for any lasting MDMA-induced toxicity is unknown;
and the identity and precise mechanism of the chemical(s) causing the oxidative
stress is unclear. The issue is also controversial. Currently the three leading
candidates for guilty agent are:
1] toxic metabolites of MDMAAn
of the published scientific evidence on neurotoxicity is offered by Matthew Baggott
and John Mendelson on the indispensable Erowid.
A role has also been proposed for nitric
oxide; increased Ca2(+); and
a toxic intraneuronal metabolite of serotonin.
Elevation of body temperature
can seriously worsen possible MDMA-induced toxicity; and the thermogenic effect of MDMA is
magnified in a hot environment like an indoor rave. Certainly, hypothermia-inducing agents are (partially) neuroprotective against Ecstasy damage; and the primary role of dopamine in MDMA-induced toxicity may actually be to elevate body temperature via its increased action on the dopamine D1 receptors rather than its uptake into the depleted serotonergic axon terminals. But consensus on the molecular
mechanisms behind MDMA megadose-induced damage remains elusive.
2] toxic metabolites of dopamine
impaired cellular energetics
itself (probably) isn't the culprit. Experimental microinjection of MDMA, MDA or other
amphetamine analogues directly into the cerebrum doesn't produce the toxicity
to the serotonergic axons ascending from the dorsal
raphé nucleus that follows
high and/or frequent doses of the peripherally administered drug. MDMA can be
centrally injected to induce the release of just as much serotonin as the toxic
peripherally-administered dose; but there's still no sign of neurotoxicity. Nor
does experimental central MDMA perfusion trigger the toxicity-enhancing higher
body temperatures likely from the peripheral route. When MDMA is centrally administered
in animal experiments, not even artificially inducing hyperthermia
in the victim is enough to produce serotonergic damage. If systemic metabolism
of MDMA is indeed necessary for neurotoxicity, the nature of any such possible
toxic metabolite(s) is
unknown: thioether conjugates
of alpha-methyl dopamine have been mooted. Since drug metabolites are normally
more hydrophilic than their parent drug, specific transporters are presumably
needed to take up the neurotoxic metabolite into the brain; but their identity
or even existence isn't known either. If they do exist, then presumably they are monoamines; otherwise selegiline wouldn't be protective against MDMA-induced neurotoxicity.
Whatever the mechanism at work, most users eventually stop taking MDMA. They do so after
either they find the E-magic wears off, or the unwanted side-effects of heavy E-use
begin to outweigh its joys. Doctors report that one Englishman consumed an estimated 40,000 tablets of MDMA over a nine year period. Such cases are exceptional. Even so, some heavy MDMA users claim they don't experience
any long-term adverse effects. Prolonged MDMA administration can even cause a
long-lasting increase in
the dopamine content of the nucleus accumbens, possibly indicating its disinhibition
from normal serotonergic control. The persistent elevation of dopamine function
reported in the nucleus accumbens of some MDMA veterans might otherwise be expected
to enhance mood, not darken it. Likewise, MDMA users may be less anxious
or panic-stricken in response to the normally anxiogenic challenge of a 5-HT2C
agonist such as m-chlorophenylpiperazine (m-CPP).
Depending on one's ideological agenda, this diminished response to m-CPP can be described
as evidence either of serotonergic "toxicity", or alternatively as a pointer to
the substrate of a long-lasting "therapeutic" effect. Again, MDMA use increases
sensitisation to the rewarding
effects of euphoriant dopaminergics such as cocaine;
and once more, this is not inherently a sign of "brain damage". However, reports
of real and serious health problems from excess E-use are not all prohibitionist
propaganda or part of a government-inspired conspiracy to stop young people having a good
time. Among heavy "recreational" MDMA users, self-medicating or otherwise, the
incidence of depression
seems to be more common than healed minds or any enduring
The prospect of serotonergic axon terminal degeneration doesn't sound much fun,
even if the axons re-sprout
- one way or another. Worryingly, the MDMA-induced pruning of the serotonergic
axon tree seen at high-dosage regimens leads to altered patterns of reinnervation
by ascending axons projecting especially to forebrain sites. In the process of recovery from
a prolonged MDMA-binge, the hippocampus, a brain structure critical for episodic
memory formation, may actually be hyperinnervated, but reinnervation of the dorsal
cortex is sparser. It has been suggested that the heavy MDMA user who discerns
no long-lasting ill effects, and who displays minimal functional impairment, may
still be subtly damaging his or her serotonergic "functional reserve". The disturbing
parallel drawn here is with neurodegenerative disorders: clinical signs of Parkinson's
disease, a progressive disorder caused by outright dopaminergic cell death
and frequently prefigured by depression, only become apparent after 70-80% of
dopamine cells have been lost. It is fiendishly hard to demonstrate MDMA-induced
dopaminergic cell damage without virtually killing
the victim; in contrived
circumstances it can be done. Yet the most notorious attempt to show MDMA-induced dopaminergic neurotoxicity, Ricaurte's September 2002 paper Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy") in Science, actually demonstrated methamphetamine-induced dopaminergic neurotoxicity instead. This unfortunate study, its publication timed to coincide with debate in US Congress over the "Anti-Rave Act", was retracted in September 2003; but the spectre it raised of a post-E generation of Parkinsonian zombies may prove harder to dispel.
even heroic doses of MDMA are likely to kill off serotonergic brain cells, though
there have been unconfirmed reports of MDMA-induced apoptosis
in mega-dosed rats. Only the most alarmist commentators anticipate a delayed epidemic
of demented depressives as a result of serotonergic carnage caused by MDMA abuse.
But equally, no alien anthropologist in his right mind who merely read the gruesome
scientific literature on MDMA would want
to self-experiment with such a deadly neurotoxin.
Taking weed-killer, glue sniffing or swallowing rat poison sounds marginally less
dangerous. Calling it
dystopian pharmacology might seem more apposite. Even listening
to glowing, first-person accounts of the MDMA experience is curiously uninspiring
when refracted through the lens of our normal Darwinian consciousness. The prospect
of love, peace and empathy seems less exciting than a round of Quake 3.
We are all prone to mood-congruent thoughts.
any case, MDMA users themselves may find the magic of the initial drug-induced
epiphany tends to fade with frequent use. For many but not all users, a magical
drug becomes just a feel-good drug. Adverse side-effects tend to become more troublesome.
Higher doses are needed to gain the same effect. Users lament that "the E isn't
as pure as it used to be"; and that the tablets are weaker. Often indeed this
is true; but a physiological explanation for so-called "cumulative tolerance"
must be sought as well. Enzyme-induction plays a role, though the phenomenon isn't
fully understood. Pharmacodynamic tolerance to a drug is normally reversible,
yet some users of MDMA report they never quite recapture the initial ecstatic
glory even if they abstain for a year or more. Researchers are still unsure if
this fade-off is a symptom of long-term neuroadaptation or serotonergic damage.
Perhaps we shouldn't be so
surprised at the "loss of magic". The liver (and the brain) is adapted to life
on the African savannah. Our vital organs can't know the difference between the
elixir of life and a poison. MDMA has the attributes of both, and in the African
bush, the latter is a more realistic outcome. Yet we won't be trapped in brutish
states of consciousness for ever. In the near future, functional analogues of MDMA promise
to enhance mental health, add perpetual magic to our lives, and beautify our troubled
minds. Empathetic bliss isn't inherently toxic; though its reactive
metabolites may be. In principle, the psychopathologies of everyday life can
all be cured. MDMA offers a foretaste of life in post-Darwinian
paradise; but it delivers, at best, only a fleeting hint of the magic to come.
MDMA: neuroprotection No safe, indefinitely sustainable entactogens-empathogens
yet exist. Drugs that consistently induce the opposite syndrome are legion. Some
such drugs are billion-dollar moneyspinners for Big
Pharma. They are clinically licensed and widely prescribed in the guise of
psychiatric medicines. Other psychoactive drugs are used mainly for "unrecognised"
and non-medical purposes. Psychostimulants like cocaine
and amphetamine notoriously promote egotism
and aggression. Drinking ethyl alcohol tends to make the user relaxed, disinhibited
So is MDMA itself
best reserved as a sacrament for special occasions? Or can it be safely taken
"recreationally" and socially? What dosage, if any, is prudent? Is the MDMA experience
so tantalising that it's best avoided altogether lest the rest of one's life pall
in contrast? Would one want one's sixteen year-old daughter to take it; and with
Currently the risk-benefit
analysis of taking - or missing out on - MDMA is unclear. Probably the gravest
threat to the long-term emotional and physical health of the user is getting caught
up in the criminal justice system. Victims of the law-enforcement agencies frequently
suffer long-term neuropathological changes. Lowered serotonin levels, elevated
cortisol, confusion, depression, sleep problems, severe anxiety, and paranoia
are common. In some cases, the neurological damage may be permanent. Currently
around 500,000 "drug-offenders"
languish in American jails alone; and millions more young people throughout the
world are at risk. Yet repealing ill-conceived drug laws is only part of the answer
in protecting mental health.
Ever more alarming animal studies conducted
over a decade by George Ricaurte, a neurotoxicologist at John Hopkins University
School of Medicine, suggest that taking high and/or frequent doses of MDMA causes
damage to the terminals of serotonin axons in the brain. Cerebrospinal fluid 5-hydroxyindoleacetic
acid (5-HIAA), serotonin's
major metabolite which serves as a marker of central serotonin (5-hydroxytryptamine,
5-HT) neural function, may be lower in human MDMA users than in putatively matched
controls. The number of serotonin transporter sites, structural protein elements
on the presynaptic outer axonal membrane that recycle the released neurotransmitter,
may be reduced too. Long-term MDMA-induced changes in the availability of the serotonin transporter may be reversible; but it is unclear whether recovery is complete. Currently the balance of neurochemical and neuroanatomical
evidence, and functional measures of serotonin neurons, suggests that it is imprudent
to take MDMA or other ring-substituted methamphetamine derivatives without also
taking neuroprotective precautions.
Arguably, it is best to take MDMA infrequently and reverently or not at all -
Dr Shulgin once suggested a maximum of four times a year.
apologists aren't convinced that the neurotoxicity evidence is persuasive - except
for MDMA taken at unrealistically high doses. As Paracelsus
(1493-1541) noted centuries ago, "All substances are poisons: there is none which
is not a poison. The right dose differentiates a poison and a remedy." Most early
studies of the possible long-term adverse effects of MDMA use in humans have been
methodologically flawed - inadequately controlled, retrospective rather than prospective,
and marred by a failure adequately to exclude confounding
variables - e.g. the so-called stereotype threat. Some published toxicity studies include a large percentage of self-reported
"Ecstasy" users who've never even taken MDMA. Other studies rely on a small minority
of users whose drug-taking methodology owes more to Hunter S. Thompson than Sasha
Yet the biggest problem
in evaluating the published evidence isn't so much sloppy science or value-judgements
masquerading as statements of fact. It's rather that just as the strongest predictive
factor in the outcome of a published clinical trial of any psychiatric drug is
the identity of the funding body, likewise the investigation of MDMA isn't a disinterested
search for scientific truth. Published
papers that examine possible confounding variables in MDMA "toxicity studies"
omit to mention the greatest biasing factor of all. Independent funding is critical
to the integrity of biomedical research; but MDMA is now a Schedule One drug.
Studies of MDMA can be lawfully conducted only under government license by ideologically-vetted
researchers. Authors and licensed researchers are implicitly paid to show how
prohibited drugs are harmful, not that they can be potentially therapeutic. Researchers
certainly aren't paid to report that some illegal drugs are potentially
life-enhancing agents. Nor do their paymasters expect them to investigate the
design of safer, more sustainable analogues to improve the user experience.
Intuitively, at least, it might
seem axiomatic that in a democratic free society every person should have "the
license to explore the nature of his own soul" (Dr Shulgin). Yet this license
has lately been revoked in the name of the War
Against Drugs. Every law-abiding citizen is now locked into traditional modes
of consciousness on pain of criminal prosecution and imprisonment. The chemical
keys to the locks themselves have been outlawed. Most natural scientists are scornful
of social constructivists who think that power structures underwrite the way we see
the world. But in a daring extension of the Papacy's Index Librorum Prohibitorum,
knowledge of entire state-spaces of potential experience has been outlawed following
passage of the USA's Controlled Substance Analogue Enforcement Act of 1986. The
UN's World Health Organization and foreign governments have been leaned on, bribed
or dragooned into the War On Drugs too. In the USA itself, the world's most celebrated
psychedelic chemist and leading authority on MDMA has been stymied from conducting
human research on Schedule One compounds after publishing his trailblazing autobiography-cum-cookery
book. Worried that his life's work might be quite literally destroyed by the drug-warriors,
Dr Shulgin acted to thwart the obscurantists before it was too late. "I can see
having maybe two or three people in the higher echelons of the government who
may not like what I do, and I did not want particularly to have all of this be
seizable and burnable, So I published it. Now you cannot get rid of it." Dr Shulgin
had a DEA analytical license - a "Faustian bargain" according to MAPS's Rick
Doblin. But in 1994, Dr Shulgin fell victim to a DEA raid
on his research lab. Under the transparent pretext of "health-and-safety" infractions,
Dr Shulgin's license to work with scheduled drugs was withdrawn.
of "illicit" knowledge in academia and the overground research community isn't
normally so melodramatic or heavy-handed. But systemic bias and the habit of internalised
self-censorship extends throughout the apparatus of peer-reviewed journals, sponsored
conferences, and mainstream clinical medicine. On the one hand, negative results and non-results
from toxicity studies are difficult to publish or publicise. Conversely, "positive" toxicity
results from studies run by primate vivisectionists using chronic or near-fatal
MDMA doses are newsworthy and fundable. Such publication bias is insidious and
endemic; it's underestimated because prospective authors are broadly aware of
what can - and can't - get published; and so they don't bother to submit what
they know can't be accepted. Even this biasing factor massively understates the
problem. This is because most potential psychedelic research projects can't get
official permission or funding in the first place. As noted
by New Scientist in Ecstasy on the Brain (April 2002): "'It's an open secret
that some teams have failed to find deficits in ecstasy users and had trouble
publishing the findings...The journals are very conservative,' says [Andrew] Parrott.
'It's a source of bias.' Parrott himself has had two papers of this sort turned
Of course bias cuts
both ways. MDMA enthusiasts find it hard to write even-handedly too. Among MDMA's
"unlicensed" and independent researchers, there is a natural tendency to believe
any agent that triggers such sublime states must essentially be good for you.
MDMA can indeed be life-transforming; but unless it's used sparingly and at conservative
doses, it is still a potentially
toxic drug. MDMA's defenders would say that the
same is true of lithium, penicillin or paracetamol, none of which are banned.
Some studies suggest that
possible MDMA-induced neurotoxicity to the serotonin system can be largely prevented
by taking a double dose of fluoxetine
(Prozac) or another SSRI
shortly after starting to "come down". Post-E Prozac in particular mitigates the
oxidative stress and consequent risk of serotonergic axon damage caused by reactive
products of dopamine deamination. The long-acting SSRI Prozac/fluoxetine, and
its even longer-acting metabolite norfluoxetine, apparently prevents the uptake
of dopamine (and any toxic metabolite(s)?) into the serotonergic nerve terminals
by binding to the serotonin reuptake transporter with higher affinity than MDMA
or serotonin. Unfortunately, although liquid refreshment is now freely available
at most MDMA-propelled raves, most chill-out rooms don't offer Prozac. Two days
and more after taking MDMA, heavy recreational users are typically more irritable,
subdued, unsociable and subtly less empathetic than before their weekend
binge: the "Terrible Tuesday's" syndrome of midweek blues. So with cruel irony, two or three days after communing on Ecstasy and declaring their undying
love, couples are more likely to have rows and split up. Other heavy regular MDMA
users, even those who aren't self-medicating for a pre-existing malaise,
may experience depression, anxiety,
emotional burnout, rejection-sensitivity, fatigue, insomnia, aching limbs, subtle
cognitive deficits, immune
system dysfunction, body temperature
dysregulation, and a sense of derealisation or depersonalisation for several weeks
or months afterwards. This litany of woe sounds a high price to pay even for the
peak experience of a lifetime.
adopting a prophylactic SSRI regimen isn't a realistic long-term option for frequent
MDMA users either, or at least not if they intend to continue using their hugdrug
of choice. This is because a sustained regimen of SSRIs largely blunts
MDMA's empathogenic and entactogenic effects. SSRIs inhibit the binding of MDMA
to the serotonin transporter. Thus pre-treatment with SSRIs prevents MDMA-triggered
serotonin-release; and this in turn reduces dopamine-release in the striatum.
Some SSRI users who like to rave nonetheless continue to take MDMA. They consume abnormally
high quantities of pills to gain the desired E-like effect. At this dosage range,
the persistence of metabolite-induced
MDA-like states of consciousness the next
day is not unexpected. In practice, the after-effects are often modulated by cannabis
MDMA itself develops quite rapidly with steady use. If MDMA is taken several days
in a row, amphetamine-like and eventually dysphoric effects start to predominate.
most drastically serotonin, are depleted from the axon terminals; serotonin synthesis
is choked off following oxidative inactivation of tryptophan
hydroxylase; and the nerve-cell receptors re-regulate. Thus MDMA is not addictive
in the conventional sense. Taken chronically, it soon ceases to be rewarding.
Even dedicated ravers typically don't binge more than once a week. Wiser heads
save the drug for "special occasions". Yet MDMA's non-addictive profile is no
guarantee that (as was once fondly hoped), "once you get the message you hang
up the phone." The mind/brain isn't built like that. If you really like a drug-delivered
message, you want to hear it again and again. But with MDMA, the message can subtly
change with time; and its primal magic gets sullied or forgotten.
are other options for neuroprotection besides taking post-Ecstasy Prozac. On one
hypothesis of MDMA-induced serotonergic neurotoxicity, the extra dopamine
released into the synapses is transported into the depleted serotonin axonal terminals
where it is deaminated by the enzyme monoamine oxidase type-B present in the terminal.
MAO has two isoforms, MAO-A
and MAO-B. These differ
in their substrate affinities and inhibitor sensitivities: the MAO-A isoenzyme
has a greater affinity than the MAO-B isoenzyme for serotonin, but mainly MAO-B
is present in the serotonergic axonal terminals, where it breaks down "foreign"
neurotransmitters. However, after a subject has taken a high dose of MDMA, excess
dopamine is taken up by the so-called serotonin transporters into the depleted
serotonin terminals. Here its oxidation produces a glut of toxic free
radicals - highly reactive chemicals with one or more unpaired electrons -
such as hydrogen peroxide (H2O2). These toxic free radicals
are liable to exhaust or overwhelm the free radical scavenging systems of the
cell. In consequence, the serotonin fine axonal terminals are broken down by lipid
peroxidation. Why exactly the serotonin reuptake transporters lose their normal
selectivity for serotonin and take up dopamine isn't known for certain. Possibly
it's because by this time there's far less serotonin around for the reuptake pump
to use. After the directionality of the reuptake pump is reversed by MDMA, serotonin
released into the synapse can't be recycled back into the cell; and so it diffuses
away. In any event, the monoamine oxidase inhibitor selegiline
[l-deprenyl/Eldepryl] appears to be neuroprotective
at monoamine oxidase type-B-selective dosages i.e. 2 x 5mg daily or less. Selegiline
also protects against MDMA-induced inhibition of tryptophan hydroxylase. Interestingly,
Prozac too has MAO-B inhibiting properties; and these may contribute to its neuroprotective
effect. Selegiline itself has additional free radical scavenging properties that
may exert a neuroprotective action. It will be instructive to compare the neuroprotective
efficacy of selegiline with rasagiline (Azilect, Agilect) for E-users. Rasagiline is a selective
MAO-B inhibitor licensed from mid-2005 in the EC for the treatment of Parkinson's disease;
rasagiline lacks selegiline's trace amphetamine metabolic by-products. Whatever
the older compound's neuroprotective efficacy compared to rasagiline,
selegiline is potentially valuable too because, unlike taking a SSRI, adopting a long-term
selegiline regimen doesn't impair MDMA's subjective effects. Even so, no controlled
clinical trials of their co-administration are currently planned.
reason for such caution beyond a reflex Just-Say-No dogmatism is that it's potentially
dangerous to tamper with the MAO enzyme. Selegiline has lifespan-extending properties
in "animal models", and possibly in humans too; but if used recklessly, then it
could abruptly shorten life instead: selegiline is an irreversible MAO-B inhibitor.
Prohibitionism and a consequent absence of quality-control means that the "Ecstasy"
sold in clubs often contains liberal quantities of amphetamine. Amphetamine and
MAO inhibitors should not be combined. Both enantiomers of MDMA itself have MAO-inhibiting
effects, preferentially for isoenzyme type-A. Taken at dosages of above 2 x 5mg
per day, selegiline loses its selectivity for MAO-B. Individual variation in MAO
status makes it imprudent for the MDMA user to take selegiline even at 10mg daily;
and selegiline itself, like MDMA, is a weak inhibitor of MAO-A. MAO-A deaminates
serotonin; and the serotonin
syndrome, characterised inter alia by hyperthermia, autonomic instability
and altered muscle tone, is potentially lethal. Serotonin 5-HT2A antagonists like
can inhibit the syndrome; but they aren't widely available on the street or average
of the serotonin syndrome are not uncommon among the hard-rolling stackers
and piggybackers dancing all night at crowded ill-ventilated
raves. Dehydration and overcrowding tend to worsen drug-induced toxicity. Heat
exhaustion and severe hyperthermia are probably the gravest risk to the raver's
health. MDMA tends to raise
body temperature by a degree or so, sometimes by quite a bit more if the user dances
all night without rest ["Saturday night fever"]. MDMA also increases the body's
secretion of antidiuretic hormone, arginine-vasopressin.
Ravers sometimes overcompensate for the risk of dehydration by gulping down too
much pure water. This can cause hyponatraemia
(literally "low salt": "water intoxication"). Sipping a couple of sports-drinks
every hour or so instead is a prudent way to maintain electrolyte balance. Indeed it
would be safer if sports drinks were distributed with each E-tablet sold as a matter
of course, perhaps accompanied with a neuroprotectant mix and a health-tips sheet thrown in
for good measure.
tips found on the Net are no substitute for systematic, well-planned health-education
programs. Organisations like the Berkeley-based Dancesafe, funded by Microsoft
millionaire the late Bob Wallace and founded to promote safe raving, are rare;
their activities are also controversial.
becomes part of the educational core curriculum, any responsibly designed drug
cocktail, and any harm-reduction program, must be formulated with the recklessness
of a minority of sensation-seekers in mind, not just risk-averse research scientists.
Such a revolution in mental healthcare for young people is sorely needed. An examination
system akin to ritualised child-abuse wreaks terrible damage on the young minds
incarcerated in our educational institutions. Critics of exam-culture claim an
"education" based around competitive testing screws kids up far more than empathetic
drugs. Unfortunately, what's tested in these rituals of abuse isn't our children's
emotional well-being, levels of reflective self-insight, capacity for loving empathy
or social intelligence. Nor do schools and colleges offer courses in effective
technologies to promote them.
healthcare revolution of this magnitude isn't going to happen tomorrow. So more
realistically for now, clubbers seeking neuroprotection against MDMA-induced toxicity
may do well to use humble antioxidants such as ascorbic
acid (Vitamin C), alpha-tocopheryl-acetate
(Vitamin E), zinc, alpha-lipoic
acid, and L-cysteine.
The optimal mix and dosage before, during, and after dropping an E to maximise
their respective neuroprotective action, and minimise any post-ecstatic hangover,
hasn't yet been established. Even at high dosage, the neuroprotection such antioxidants
offer may be inadequate for heavy MDMA users. More encouragingly, antioxidants
also reduce tolerance between exposures. Clearly a lot more research is needed,
hopefully without the usual animal holocaust that accompanies drug testing today.
serotonin precursors L-tryptophan
and 5-hydroxytryptophan (5-HTP)
are also neuroprotective against MDMA-induced toxicity, possibly in part because
of their antioxidant effect but mainly because of their precursor role. 5-HTP
is the metabolite of L-tryptophan.
It's the direct metabolic precursor to serotonin (5-HT). In contrast to the catecholamine neurotransmitters dopamine and noradrenaline, the synthesis of serotonin
isn't subject to strong end-product inhibition. Like L-tryptophan, 5-HTP is sometimes used as an antidepressant
and antianxiety agent; it seems to have a relatively narrow therapeutic window.
Unlike SSRIs, L-tryptophan and 5-HTP can be taken chronically without
blunting MDMA's effects. Indeed some clubbers pre-load with L-tryptophan or 5-HTP to intensify
and enrich the MDMA experience and prevent serotonin depletion. Serotonin depletion
increases the vulnerability of the axon terminals to damage. Though such a tactic
is sensible enough in theory, excess preloading with 5-HTP may potentially precipitate
or exacerbate the serotonin syndrome. So care is in order.
or without 5-HTP supplementation, an idealised stone-age diet
can be especially valuable for heavy MDMA users. Contrary to a once widely-propagated
but now discredited myth, Merck
never planned to develop MDMA as an appetite-suppressant. Yet the company might
well have done so: MDMA's appetite-suppressing effect is quite strong. Drugs that
directly or indirectly activate the serotonin 5-HT1B and 5-HT2 receptors tend to
be anorexiants. Lazy and reluctant eaters who regularly take Ecstasy are at greater
risk of vitamin and mineral deficiencies, and more vulnerable to MDMA-induced
serotonergic damage, than matched controls.
One novel and unlikely-sounding proposal to minimise MDMA-induced neurotoxicity is pretreatment with aspirin. Aspirin inhibits the enzyme prostaglandin H synthase (PHS). PHS catalyses the transformation of amphetamines into toxic free radical products. Therefore taking aspirin before MDMA use may also indirectly block the conversion of amphetamines into reactive oxygen species responsible for long-term neurotoxicity. As of 2006, no controlled trials of aspirin have yet been conducted with MDMA-using humans. But if aspirin pretreatment does prove an effective harm-reduction strategy, then this is potentially a godsend - not least because other candidate neuroprotectants (SSRIs, selegiline, etc) carry hazards of their own in conjunction with E-use. Aspirin itself cannot strictly be described as risk-free; but the risk/benefit ratio of its use is both favourable and well-known.
the biggest long-term obstacles to preventing neurotoxicity and
health problems are ideological, not pharmacological. The discovery that MDMA
is not always the harmless fun-drug that a number of its recreational users (understandably)
first supposed has caused the medical establishment to demonise MDMA or dismiss
its psychotherapeutic potential completely. Critics of the drug-warrior mentality
claim that MDMA's possible neurotoxicity served only as a pretext for banning
it. The case for making, say, tobacco
a schedule-one drug isn't notably less compelling, nor would any rush to judgement
on the safety, medical use or addictive potential of tobacco-products seem so
premature. The size of the cumulative death toll in the tobacco epidemic almost
defies comprehension: yet we continue energetically to market a lethal drug to
hundreds of millions of youngsters in the Third World. The contrast between the
treatment of dealers in tobacco products and MDMA distributors couldn't be much
starker. Instead of aiming to prevent possible MDMA-induced neurotoxicity by tweaking
or enhancing the agent in question, or designing better functional analogues,
or seeking ways to antagonise possible toxic metabolites, or running health campaigns promoting
the co-administration of free radical scavengers or other neuroprotectants, the
authorities opted simply to outlaw MDMA altogether. Users and independent researchers
alike were criminalised. Scientific investigation was crippled. MDMA was driven
underground, where it could mix with innumerable contaminants and organised crime.
Fortunately, scientific research
on MDMA has lately revived,
albeit under license and mainly on non-humans. Rats and monkeys
are in some ways uncannily similar - genetically, behaviourally and biochemically
- to human beings. Both the electrical-signalling properties and molecular machinery
of neurons are widely conserved across the animal kingdom. There are interspecies
differences e.g. MDMA is anxiogenic
rather than anxiolytic in some mouse strains at low doses; MDMA administered to rats in cold ambient temperatures induces hypothermia; and MDMA causes opposing
effects in rats and humans. Yet the fundamental similarity of "animal models"
to human beings is precisely why we use, vivisect and then "sacrifice" our fellow creatures
in drug discrimination studies and medical research. Using principles of interspecies
scaling, it is possible to estimate the crude physical effects of comparable MDMA
doses on people after conducting animal experiments, although species differences
in MDMA's pharmacokinetics and active metabolites make the details of such scaling
controversial. If oxidative metabolites, not MDMA itself, are responsible for
neurotoxicity, then investigation of the particular ways MDMA is metabolised in
humans will be critical in determining safe dosages. But beyond the narrow physical
effects of MDMA on the brain, it's hard enough for articulate humans who take
insight-and-empathy drugs to verbalise their processes of introspection. What
can we learn about entactogenesis by
mega-dosing a rhesus monkey? All sorts of intellectually fascinating physiological
data can be gleaned from experimenting on live animals - and even more data from
experiments on live humans. Yet ethically, how can we humanely experiment on members
of other species when we can't "predict whether a particular molecule will open
the gates of heaven or stoke up the fires of hell" (Dr David Nichols). Clearly
non-humans can't describe the effects
on their consciousness of psychoactives, even though they can be taught to "discriminate"
them - the so-called "animal model" of subjective drug effects. So members of
other species can't describe the illegal knowledge drug-naïve humans are
missing out on - or the horrors we inflict on their minds and bodies.
if animal research throws up a true wonderdrug ideal for human use - a safe, sustainable
miracle-pill with a well-defined therapeutic window, life-enriching subjective
profile, and no significant adverse side-effects - then under today's regulatory
regime, the potential wonderdrug couldn't get a product-license. In law, only
medicines to treat well-defined clinical disorders can be licensed, not investigational
agents designed to enhance our quality of life or enrich "normal" human mental
(ill-)health. Short of labelling the agent as a "food supplement" - which might
be stretching it a bit for MDMA and its analogues - true pharmacological life-enrichers
will be condemned to legal limbo. Even if this perverse restriction on legal drug
availability were lifted, then any prospective blockbuster most likely still wouldn't
get regulatory approval in practice. Human clinical trials cost tens of millions
of dollars to run. MDMA itself has long been off-patent. So profit-driven
pharmaceutical companies aren't interested in funding pilot studies. Empathy-And-Insight
Deficiency-Disorder isn't covered in DSM-IV,
the psychiatrists' bible. A condition that isn't medically acknowledged can't
be treated by state-licensed pharmacotherapy.
gloom-and-doom shouldn't be overdone. Eventually, safe long-lasting E-like super-cocktails
and enhanced functional analogues of MDMA may indeed be both patentable and judged
therapeutic for "officially" sanctioned medical conditions such as anti-social
personality disorder, refractory depression, PTSD, Asperger
syndrome and autism. These super-cocktails and sustainable MDMA analogues
should prove life-enhancing for "normal" self-regarding people who would like
to improve themselves too. Such usage may or may not stay "off-label"; but it
needn't be illegal.
meantime, bitter experience of the hedonic treadmill of Darwinian life instils
a reluctance to believe anything so magical as the MDMA experience could be sustained
and enriched indefinitely. ["You can't have the sweet without the sour"; "You
need pain to appreciate pleasure", etc.] But such superstition is pre-scientific;
it may soon seem quaint. As intracranial self-stimulation
studies attest, pure pleasure
induced by electrical stimulation of the ancient mesolimbic pleasure
centres of the brain shows no tolerance.
Response- and remission-rates are 100%. In the present era, depression, self-ignorance
and sociopathy are demonstrably sustainable over a lifetime; but so, in theory,
are the biochemical substrates of happiness, lucid self-insight and even saintly
empathetic bliss. The hedonic treadmill can be dismantled, its inhibitory feedback
mechanisms redesigned, and its neurogenetics rewritten. In principle, and perhaps
one day in practice, we can be nicer, happier
and smarter indefinitely. Unfortunately this
utopian outcome won't result from a
chronic regimen of MDMA.
Ecstasy for life? What
are the presently available options for enhancing and extending the MDMA experience?
Two separate questions need to be distinguished. First, what if any drug or drug-cocktail
can safely replicate the acute subjective effects of MDMA? Second, what if any
drug or drug-cocktail or gene-therapy can best induce E-like consciousness over
The holy grail
of safe, sustainable entactogen-empathogens almost certainly won't be found in
the guise of structurally-tweaked chemical homologues
of MDMA. A long-term regimen doesn't seem feasible even if the exact structural
requirements needed to reproduce MDMA's acute stimulus effects were understood.
To make the magic last for ever, or at least to induce it at will over several
decades, only a long-lasting homeostatic
re-regulation of the central nervous system will work. Thus the substrates of
a lifelong capacity for E-like consciousness can't be engineered via, say, a mechanism
akin to the MDMA-induced reversal of the serotonin reuptake pump. Depleting the
brain's serotonin or, even worse, inhibiting the molecular machinery needed for
its renewed synthesis, is a recipe for clinical depression, not Heaven-on-Earth.
Nor can the substrates of perpetual empathetic bliss be delivered by tonic stimulation
of the same pre- and post-synaptic receptors
activated by an acute flood of extra serotonin/dopamine in the synapses - or at
least not in the same way. Prolonged receptor activation typically leads to receptor
desensitisation and/or down-regulation. The inhibitory feedback mechanisms that
keep our Darwinian brains so mean-spirited need to be sabotaged, not kicked into
Such a profound homeostatic
shift in normal waking consciousness might conceivably be delivered by functional
analogues of MDMA. The idea here would be to reproduce E-like euphoric and empathogenic-entactogenic
effects, not acutely, but via delayed receptor subtype-specific re-regulation.
MDMA itself rapidly depletes serotonin from the axon terminals and inactivates
the enzyme tryptophan hydroxylase
needed for its renewed biosynthesis. By contrast, altering the density and signal-transduction
efficiencies of the mission-critical receptor subtypes [5-HT1B(?),
D2(?)], could, ideally,
deliver sustained ecstasy without emotional burnout. Such receptor re-regulation
might involve a time-lag
of one-to-three weeks, as is normal with conventional "antidepressants". Delayed-onset
magic, if achievable, would offer an immense social and therapeutic advantage.
This is not just because the magic should be sustainable without limit, but because
postponing the onset of drug-induced reward minimises a medicine's "abuse-potential"
without compromising its efficacy. The practice of tobacco-smoking, for instance,
is so addictive not because
of the surpassing joys of inhaling a cigarette, but because a tobacco abuser need
wait only seven seconds or so between taking a puff and the miniscule hit. The
reward from oral MDMA takes somewhat longer; but the delight of E-like consciousness
needs to be divorced from its intimate association with pill-popping.
Alas the brain's post-synaptic
signal-transduction mechanisms aren't yet sufficiently understood to bring about
a magical E-like re-regulation of waking consciousness indefinitely. Inducing
lifelong egoistic bliss is less of a technical challenge. Wireheading
is uniquely effective, though most of us might prefer the services of a molecular
psychiatrist to a neurosurgeon. Fortunately, our options may soon extend beyond
the crudely hedonistic. Indeed within a few decades, taking a controlled-release
maintenance dose of functional
analogues of MDMA may seem as natural as swallowing a multivitamin pill; and just
what the doctor ordered.
the neurochemical substrates of MDMA-like magic may be preserved, or continually
re-created as desired, via a cocktail of agents rather than monotherapy. On this
approach, each individually designed ligand would be targeted selectively at the
potentially magic-signalling receptor subtypes [or at second-messenger pathways
coupled to the G-protein-linked signal-transduction system, or in theory direct
mechanisms of gene regulation and expression]. This may be feasible; but its orchestration
will be much harder than it sounds. As the catalogue of serotonin receptor subtypes
has grown, so has our library of serotonergic molecular probes; yet so too has
a realisation that agents previously reckoned to be selective for a particular
class of serotonin receptor are less selective than originally claimed. Hence
there is a need for novel agonists, antagonists and inverse agonists with far
greater selectivity for each receptor subpopulation. This multiple targeting strategy
is technically challenging, but it's probably more promising than relying on a
single "dirty" non-specific indirect serotonin agonist like MDMA. Although there
are indeed other, non-neurotoxic
amphetamine derivatives that acutely induce transporter-mediated serotonin release,
achieving the all-important goal of sustainability may entail the use of drug
cocktails. Thus one might explore combining e.g. 1] new synthetic allosteric
modulators of the serotonin 5-HT1B autoreceptors that regulate the evoked release
and synthesis of serotonin; 2] agents acting selectively on the 5-HT1B-autoreceptors
and heteroreceptors; 3] the right 5-HT2C receptor antagonist or inverse agonist to make the E-like state more ecstatic; 4] the right dopaminergic(s)
or, ideally, agents targeting the medium spiny GABAergic projection neurons
in the rostromedial shell of the nucleus accumbens directly. This is all still very speculative and unfunded.
and perhaps more plausibly, locking in the neural substrates of empathetic bliss
as a default-state of consciousness may be achievable only via gene therapy, or
perhaps a hybrid gene-and-drug combination treatment. One option here would be
inserting "good" variants of the tryptophan
hydroxylase gene, which codes for the rate-limiting enzyme of serotonin biosynthesis,
and then once again co-administering receptor subtype-selective ligands and/or
serotonin releasers. Our immediate options are limited. Pharmaceutical interventions
aimed at extending, for example, profound emotional depth over many decades rather
than a few hours may entail, not flooding the synapses with extra serotonin followed
by extra dopamine release as in acute dosing with MDMA, but instead using e.g.
serotonin reuptake accelerators analogous to the memory-enhancing antidepressant
or perhaps enhancing the love-and-nurturance-promoting oxytocin
system; or perhaps using better designed analogues of the emotion-deepening
agent Gamma-HydroxyButyrate (GHB).
A brief comparison of GHB and MDMA may be instructive because one therapeutic
challenge ahead will be to design agents that reverse SSRI-like flattening
of affect without inducing mawkish sentimentalism (cf. ethyl alcohol). In contrast
to mainstream psychiatric drug therapies, both GHB and MDMA deliver a rare emotional
intensity of experience, albeit an intensity different both in texture and molecular
mechanism. GHB is known by clubbers if not structural chemists as "liquid ecstasy".
GHB and MDMA are indeed sometimes mixed at raves; but the two drugs are chemically
unrelated. GHB is an endogenous
neuromodulator derived from GABA,
the main inhibitory neurotransmitter of the brain. A naturally-occurring fatty
acid derivative, GHB is a metabolite of normal human metabolism. GHB has its own
G protein-coupled presynaptic receptor
in the brain. Sold as a medicine, GHB is licensed as an oral solution under the
brand name Xyrem
for the treatment of cataplexy associated with narcolepsy.
Unlike MDMA, GHB stimulates tissue serotonin turnover. GHB increases both the
transport of tryptophan to the brain and its uptake
by serotonergic cells. Taking GHB stimulates growth
hormone secretion; hence its popularity with bodybuilders. GHB offers cellular
protection against cerebral hypoxia, and deep sleep without inducing a hangover.
GHB also stimulates tyrosine hydroxylase. Tyrosine hydroxylase converts L-tyrosine
to L-dopa, subsequently
metabolised to dopamine. Unlike MDMA, the acute effects of GHB involve first inhibiting
the dopamine system, followed the next day by a refreshing dopamine rebound. GHB
induces mild euphoria in many users. In general, the neurotransmitter GABA acts
to reduce the firing of the dopaminergic neurons in the tegmentum and substantia
nigra. The sedative/hypnotic effect of GHB is mediated by its stimulation of GABA(B)
receptors, though GHB also modulates the GABA(A)
receptor complex too. The main effect of GABA(B) agonism is normally muscle relaxation, though interestingly, pretreatment with the GABA(B) agonist baclofen also prevents an MDMA-induced rise in core body temperature.
Whatever the exact GABA(A), GABA(B), and GHB-specific mechanisms by which GHB works,
when taken at optimal dosage GHB typically acts as a "sociabiliser". This is a term
popularised by the late Claude Rifat (Claude de Contrecoeur), author of GHB:
The First Authentic Antidepressant (1999). Rifat was GHB's most celebrated
advocate and an outspoken critic of Anglo-American psychiatry. Similar therapeutic
claims have been made for GHB as for MDMA, despite their pharmacological differences.
GHB swiftly banishes depression and replaces low mood with an exhilarating feeling
of joy; GHB has anxiolytic properties; it's useful against panic attacks; it suppresses
suicidal ideation; it inhibits hostility, paranoia and aggression; it enhances
the recall of long-forgotten memories and dreams; and it promotes enhanced feelings
of love. Like MDMA, and on slightly firmer grounds, GHB has been touted as an
aphrodisiac: GHB heightens and prolongs the experience of orgasm. GHB disinhibits
the user, and deeply relaxes his or her body. Inevitably, GHB has been demonised
as a date-rape drug ["I was at this party, and this guy gave me a drink. Next
thing I know, it's morning and I'm in someone's bed. I've no idea what happened
in between..."] GHB has a steep dose-response curve. Higher doses will cause
anterograde amnesia i.e. users forget what they did under the influence of the
drug. It's dangerous to combine GHB with other depressants. So despite GHB's therapeutic
and pro-social potential, GHB is probably unsafe
to commend to clubbers. This is because a significant percentage of the population
will combine any drug whatsoever with alcohol
regardless of the consequences to health. If used wisely, sparingly, and in a
different cultural milieu, then GHB could be a valuable addition to the bathroom
pharmacopoeia. But even then, it's still flawed. GHB may intensify emotion and
affection, but not introspective depth or intellectual acuity. Unlike taking too
much MDMA, overdoing GHB makes the user fall profoundly asleep. If our consciousness
is to be durably enhanced, then sedative-hypnotics have only a limited role to
play in the transition ahead.
what are the prospects for richer, intenser, sustainable insight-and-empathy drugs
from MDMA's phenethylamine sisters and cousins?
the quantified structure-activity relationships of MDMA and related compounds
(MDEA, MDA, MBDB, MMDA,, etc) have been investigated, even though systematic overground
exploration of their effects on the human psyche has been strangled at birth.
Research chemists have designed a host of ring-substituted amphetamine derivatives
with one or more substituents attached at different positions to the phenyl ring
of the amphetamine or methamphetamine
structure. Other such derivatives have been devised by entrepreneurs whose synthesis
of designer drugs aims more at circumventing
legal restrictions than pushing back the frontiers of knowledge.
their parentage, the phenethylamines as a whole exert a spectrum
of action from the purely stimulant activity shown by "noradrenergic/dopaminergic"
amphetamine to the almost entirely psychedelic activity of the "serotonergic"
DOM - distributed at ultra-high doses in Haight-Ashbury San Francisco 1967 under
the name of 'STP': Serenity, Tranquillity, and Peace. In drug
discrimination studies, MDMA's subjective effects only partially cross-generalise
to DOM and amphetamine. Indeed MDMA only partially cross-generalises to the other
two hypothetical family prototypes currently identified, PMMA
[N-methyl-1-(4-methoxyphenyl)-2-aminopropane] and TDIQ
[5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline] from the "fourth dimension".
MDMA itself is truly "one of kind" (Dr Shulgin), both structurally (i.e. the effects
of the N-methylation of its primary amine, exclusive 3-4 di-substitution on the
aromatic ring, its anomalously potent (+)-enantiomer) and subjectively. There's
no obvious new tweak of its molecular structure, or to structurally related agents,
that promises to deliver SuperEcstasy Mark 2, or even if there were, to suppose
the supermagic would be truly sustainable. Thus MDMA's immediate homologue and
closest relative, MDEA (3,4-methylenedioxyethylamphetamine:
"Eve"), formed by swapping the 1 carbon methyl group for a 2 carbon ethyl group,
is an interesting agent in its own right, but it's not going to deliver lifelong
empathetic bliss. Indeed MDEA is actually less warm and empathetic, and more introverted
in its typical subjective effects, than its sister molecule. Instead of taking
MDEA as the racemate, one option is administering only (+)-MDEA,
the optical isomer responsible for racemic MDEA's entactogenic
quality. Yet pure preparations of individual enantiomers are not always readily
to hand, nor a route to lifelong wisdom if they were.
Curiously, the beta-ketone analogue of MDMA, methylone (3,4- methylenedioxymethcathinone, MDMCAT), is poorly researched. Only a handful of papers appear in the published scientific literature. Methylone is another creation of Dr Shulgin. The drug is sold (expensively) as a "research chemical" over the Net. Branded rather unsubtly as "Explosion", methylone is also available in several Dutch smartshops. Recently it has become very popular in the scientific counterculture. Methylone is not specifically scheduled (as of late 2005); it may nonetheless fall within the scope of analogue drug laws. It is not as potent as MDMA; and it has a higher dosage range. Methylone causes less inhibition of serotonin reuptake and triggers less serotonin release than MDMA; but its potency in promoting the synaptic accumulation of the catecholamine neurotranmitters noradrenaline and dopamine is similar. Thus methylone has activating and empathetic effects while inducing less emotional outpouring. Many subjects experience an E-like "magic", though the two drugs can readily be distinguished by experienced users. It should be stressed that the comparative safety of methylone has not yet been well established, even at relatively low dosage levels of 120-150mg. This is still a new drug. Methylone is mood-elevating; higher doses induce a clear-minded and serene euphoria. Reputedly there is less serotonergic toxicity than MDMA; but there can still be a very noticeable comedown. If methylone is taken chronically, its stimulant effects become more pronounced. Empathetic qualities diminish. Tolerance soon sets in: a sad and familiar story.
From a theoretical perspective, PMMA
[N-methyl-1-(4-methoxyphenyl)-2-aminopropane] a structural hybrid of paramethoxyamphetamine
and methamphetamine, is interesting. PMMA arguably better represents a pure entactogenic
[inward-looking, self-accepting, peaceful] family prototype than MDMA. However,
the warm self-acceptance and empathetic love of others experienced on MDMA feels
so clean and pure precisely because its mechanism is so messy. PMMA, on the other
hand, lacks MDMA's residual psychedelic or speedy effects: PMMA is thus clearly
distinct from the other hypothetical family prototypes,
DOM or amphetamine, and also from TDIQ, about whose psychotropic effects rats
currently know more than Homo sapiens. Unfortunately PMMA, like most methoxylated
amphetamines, is potentially neurotoxic. In any case, it's completely unsustainable
in regular use, though its ortho-isomer, methoxyphenamine, was once UK-licensed
in tablet form as the bronchodilator Othoxine. PMMA itself is a potent drug with
a very low therapeutic index: the combination of serotonin-release and MAO-A inhibition
integral to its entactogenic profile makes it hazardous in overdose. In general,
taking MAO-inhibiting agents with anything serotonergic is normally contraindicated
because of the risk of the serotonin
dopamine-releasing action makes it less "abusable" than other family members with
overlapping psychostimulant effects. Yet rather than scorning the pleasure
principle by seeking to minimise drug-induced reward, it might instead be
more rational to design safer, benignly addictive lead compounds that maximise
the user's well-being in lastingly empathetic, entactogenic and socially responsible
ways. Well-designed (or serendipitously rediscovered) empathetic euphoriants can
trigger socially responsible happiness. This is the distinctively E-like happiness
that inspires love, nurturance and understanding rather than egotism and dominance
behaviour. It's hard to imagine that any such futuristic love-drugs won't be "abusable"
too. But if a drug isn't remotely rewarding or habit-forming, then it probably
isn't any good. In the immortal words of Jeremy
"Nature has placed mankind under the government
of two sovereign masters, pain and pleasure...they govern us in all we do, in
all we say, in all we think: every effort we can make to throw off our subjection,
will serve but to demonstrate and confirm it."Alas application
of means-ends rationality is rarely the norm in drug-policy debate or in psychiatric
medicine. Nor is the pursuit of happiness undertaken much more rationally elsewhere.
Thus we continue with Rube-Goldbergish efforts to improve our well-being via environmental
scene-shifting - with mixed success.
course the biological route to nirvana has its share of pitfalls too; and MDMA
is merely one of its most alluring seductions. Seekers of sustainable ecstasy
would be rash to fetishise any particular drug or family of pharmacological tools
- however magnificent their acute action on the user. For what matters, presumably,
is the otherwise inaccessible modes of experience such agents can unlock in the
mind/brain - and ways to sustain them - not the chemical structure of the agent
that happens first to disclose their existence. "All science is either physics
or stamp-collecting", Rutherford provocatively once proclaimed; and if some organic
compounds didn't have the potential to unlock the doors to the kingdom of heaven,
then Rutherford might have been right. As it is, school chemistry-lessons and
standard textbooks rarely set young imaginations ablaze. They might conceivably
do so if the PiHKAL-inspired compounds they ought to contain evoked the
magical experiences their structures should ignite. Yet even the most astonishing
centrally active compounds are only research tools or therapies, not sacraments.
At least until we can genetically enrich the human mind/brain, no drug or research
chemical, nor indeed any irritation of the body's surface sensory transducers
by the environment, can do more than select
from a pre-existing menu of brain-states composing the subject's mind/virtual
world. In this sense, we're trapped.
there is an escape-route; the false prison can be transcended. Within a few decades,
the insertion of entirely new genes and variant alleles into our genome promises
to revolutionise our stunted Darwinian minds. Novel neurally-expressed polypeptide
sequences should disclose modes of experience hitherto unknown. The creation of
genetically enriched neurons should allow the exploration of multidimensional
search-spaces of consciousness which we presently lack the molecular wetware to
imagine or even name. No psychoactive drug currently gives access to these hypothetical
state-spaces. Such modes of consciousness have been barred to us by natural selection.
They either diminished their user's Darwinian fitness or would have entailed crossing
gaps in the evolutionary fitness landscape to get there. Whereas merely E-like
states are normally inaccessible because their owners would get eaten or outbred,
these unDarwinian modes of consciousness are quite possibly orthogonal to anything
accessible today within our existing mental architecture. Each new state-space
may be as different from the others as is sound from vision, or volition from
cognition or emotion. The differences in gene-expression profile between neurons
mediating the experience of, say, colour, or disgust, or humour (or being loved-up)
may strike us as subtle. Yet the subjective differences in texture ("what it feels
like") that their respective post-synaptic intracellular cascades generate are
clearly spectacular. Who knows what else is accessible from Nature's psychoactive
library by means of even "trivial" molecular genetic tweaks to our nerve cells?
Disparate new categories of experience, and hopefully revolutionary conceptual
schemes to navigate them, are presumably waiting to be unlocked just by inserting
new sets of neurological instructions. Unfortunately we lack any God's-eye taxonomy
of consciousness that might let us act like physicists and "carve Nature at the
joints". The lack of an overall map, or even the ghost of a theory of consciousness
to guide us, makes it impossible to place MDMA, or the spectrum of altered experience
disclosed by psychedelic amphetamines, within any adequate scheme of classification.
"Empathogen", "entactogen", "entheogen", and "psychedelic" are provisional and
theoretically ill-motivated terms. A mature psychoactive taxonomy will need to
be formulated relative to the architecture of particular phenotypes of mind, not
the structure and pharmacology of the molecular probe alone. Alas the results
of animal "drug discrimination studies" are no substitute for explanatory depth.
In practice, today's psychonauts are reduced to describing the subjective effects
of psychoactive drugs by contrasting them with their "normal" states of being.
Inevitably this is all a bit lame. In retrospect, today's entire dreaming and
waking consciousness may prove to be only minor variants on a theme whose motif
can't be grasped from within.
to say, the genetic choices, varieties of drug habit and modes of consciousness
of our post-human descendants are
a matter for conjecture.
We've barely begun to ring the changes within the state-space of consciousness
we've got. In order to replicate and sustain the family of MDMA-like magical states
safely and reliably, it's necessary first to find the specific neurochemical signature
of the family of enchanted states we're targeting. Thus by using, for example,
transgenic receptor-knockout "animal models", SPECT (Single-Photon Computed Tomography),
PET (Positron Emission Tomography)
and MRI (Magnetic Resonance Imaging) scans, quantitative EEG with dense-mapping
electrode arrays, antisense regulation of protein expression, and pre-treatment
with other pharmacological ligands that activate or antagonise or act as inverse
agonists at particular subtypes of receptor in the brain, it should be possible
for ideologically committed bioscientists to discover
what is crucial - and what's unwanted or inessential - to MDMA's psychological
and physiological effects. Once the E-like signature is established, neuroscientists
can then work how to mimic, refine and extend its magic, even if sustainable ecstasy
is only a staging-post on the route to a richer biochemistry ahead.
however, MDMA's acute adverse side-effects i.e. teeth-grinding ["bruxism"], jaw-tension
["trismus"], loss of coordination ["ataxia"], eye-wiggling ["nystagmus"], profuse
sweating ["diaphoresis"], nausea, appetite-suppression, tachycardia, dry mouth,
idiosyncratic reactions to MDMA need to be eliminated and not just minimised.
The really nasty stuff - hepatotoxicity,
cerebral and pulmonary edema (caused by drinking too much water), rhabdomyolysis
(the breakdown of skeletal muscle), and disseminated intravascular coagulation
(inappropriate blood-coagulation leading to severe bleeding) are statistically
very rare. MDMA-induced incidence of these syndromes was apparently unknown in clinical practice prior to the drug's legal proscription. However, not all the problems of MDMA use can be blamed
on Prohibition and the lethal mix of ignorance and criminality
it spawns. Even pure, low-dose MDMA does not suit everybody. In the era of pre-genomic
medicine, atypical reactions to any drug at all should be expected. Conversely,
with adequate medical research the mildest bad experience on MDMA should be preventable.
Much more speculatively,
the use of personalized somatic gene-therapy may enable future scientists of the
mind, or unabashed hedonists, to sustain an otherwise neurotoxic drug regimen
in safety. For instance, transgenic
mice carrying the sequence of the human CuZn superoxide dismutase enzyme are resistant
to MDMA-induced serotonergic damage. Ideology aside, humans can benefit from genetically
enhanced neuroprotection no less than intoxicated rodents. If ever we wish to
adopt a potentially life-enhancing but otherwise hazardous drug-regimen indefinitely,
then one option may be to protect ourselves by inserting new genes or new alleles
into our legacy genome. Or we may simply induce the overexpression of endogenous
antioxidant enzymes already coded for. We're already on the brink of tailoring
our drugs to our
genes, but in principle we can tailor our genes to our drugs. Or we may choose
to design, insert, and switch on and off as desired a suite of structural and
regulatory genes for whatever life-enriching chemical exotica (or old
favourites) we seek to enjoy. The modes of experience they generate may thereby
become available, as it were, on tap. Nature uses lateral gene transfer; and rationally,
so can we. Or by contrast, it's possible some or all genetically enriched post-humans
may shun adulterants of their beautiful forms of consciousness altogether. If
one's soul has been purified, why defile it?
suppose that we might opt deliberately to micromanage even a subset of the thousands
of neurally active genes of one's genome, and intervene to regulate their complex
post-transcriptional editing, sounds far-fetched, even as the biotech revolution
gathers pace. The prospect that we might personally choose to enrich our genetic
repertoire from an ever-expanding library of newly-created DNA sequences, and
an ever vaster neuroactive proteome, sounds still more remote. Could we really
cope with such an enlarged freedom of choice? In practical terms, and perhaps
surprisingly, yes. Sustainable E-like consciousness is just one option among myriad flavours of sentient existence. Radical enhancements of, say, the sorts of user-friendly visual interface
we rely upon to interact with our PCs today can potentially be exploited to manage
the neuroactive expression and regulation of one's individual genotype. End-user
ignorance of the low-level molecular machinery is fully compatible with everyday
expertise acquired in managing the kinds of consciousness one's genes code for
- and mastering the types of mind/virtual-world these genes express. Thus the
non-specialist user of genetic management software could, in principle, be shielded
from the complex chemical minutiae of what is happening many virtual layers of
complexity below, just as most PC users today wouldn't recognise machine code
if it bit them on the nose.
might argue that the opportunity for such life-transforming manipulations will
be solely the privilege of a rich elite. This anxiety is (probably) misplaced. For the
time-lag between the introduction of a new technology and its diffusion to the
population at large has been progressively shrinking. It took perhaps 50 years
to democratise the radio; some 20 years for the TV; around 10 years in the case
of the PC; and even less for the mobile phone. With information-based products,
the time-lag effectively collapses. Thus the gap between an expensive software
release in Redmond and its availability
to the population of Thailand is perhaps a few hours. Irritating bottlenecks notwithstanding,
information is cheap. Technically, the "counterfeit" generic version is in no way inferior
to the brand-name product. In a mature information-based society, "scarcity" is
a far more elusive concept than in the era of material commodities. On this analysis,
the resources of, for instance, tomorrow's domestic quantum computers may be harnessed
anywhere and everywhere to more humanly empowering pursuits than the factoring
of thousand-digit numbers that so excites contemporary cryptographic theorists.
A good place to start will be simultaneously screening an unimaginable multitude
of alternate histories of gene- and drug-combos in search of promising leads for
one's personal development program. The friendliest, voice-activated, most visually
compelling user-interfaces that creative designers can build may make seizing
control of one's destiny from a legacy genome a less daunting challenge than it
seems today. This doesn't mean we won't need all the help we can get in mastering
the awesome software tools soon available to personalise our own genome and drug-regimen
of choice. But choosing who and what we want to be should feel exhilarating
rather than intimidating.
this optimistic scenario, a product-pipeline of better, faster, cheaper and safer
designer-drugs and drug-and-gene-combos should in principle be accessible to everyone
within 15-20 years. Sustainable E-like empathogen-entactogens may become as familiar
as aspirin; much safer
in overdose; and far more ubiquitous. The design of E-like hugdrugs, lovedrugs
and euphoriants, and perhaps later the genetic programming of E-like waking consciousness,
could be just the beginning of a whole new genetic and chemical cornucopia for
mature post-Darwinian life. For now, certainly, the prospect of a loved-up world
reads like overheated science-fantasy. In practice, such predictions may prove
too tame to be realistic.
The molecular machinery of magic
Lifelong ecstatic wonderpills
and genetic self-mastery are at best some way off. So which ingredients of MDMA's
primal magic are most worth mimicking pharmacologically in the near-term future? Preventing
tolerance, promoting safety, and indefinitely extending duration are vital. Yet
how desirable is inducing more or less euphoria, more or less calmness or behavioural
activation, purer empathogenic or entactogenic action, and a greater or lesser
hint of trippiness?
studies with receptor antagonists indicate that dopamine D2 antagonists such as
haloperidol (Haldol) attenuate
MDMA's positive hedonic effects; 5-HT2A
antagonists like ketanserin
suppress MDMA's residual psychedelic activity; and SSRIs like citalopram (Celexa / Cipramil,
the most selective of the SSRIs) diminish if not abolish the full spectrum of
MDMA's psychoactivity. Drug discrimination studies performed on captive rodents
may overlook certain subtleties of the MDMA experience. Intriguingly, in mice at least, the behavioural and physiological effects of MDMA are selectively antagonised by
the plant alkaloid nantenine (9,10-methylenedioxy-1,2 dimethoxyaporphine). Nantenine is "antiserotonergic" and an alpha1-adrenoceptor antagonist; the effects of nantenine on ecstatic human subjects are unknown. But on present evidence,
it's primarily the interplay between the serotonergic and dopaminergic systems that underlies MDMA's discriminative stimulus effects/sublime magic.
full story is complex and still poorly understood. As the user "comes up", serotonin
released into the synaptic cleft activates multiple serotonin receptor subtypes
(5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7), and subpopulations (most
notably, 5-HT1B, 5-HT2A and 5-HT2C). The hierarchy of their relative contributions
to the subjective and behavioural effects of MDMA use may shift with increasing
dosage and the course of the trip. Several of these serotonin receptor subtypes
have functionally opposing roles, notably the effects of 5-HT1A
and 5-HT2C receptor agonism
on anxiety. As well as inducing a synaptic flood of serotonin, taking MDMA indirectly
induces the release of extra dopamine in the mesolimbic reward centres. Activation
of the serotonin 5-HT1B and 5-HT2A receptors leads to an increase in the vesicular
release of dopamine. Dopamine levels are also increased by reuptake inhibition.
In addition, dopamine synthesis is increased and turnover reduced. Increased synaptic
availability of dopamine in turn inhibits glutamate-evoked firing in the nucleus
accumbens. Dopamine released in the shell of the nucleus accumbens inhibits the
firing of GABAergic
medium spiny projection
neurons. Inhibited excitability of the spiny projection neurons in the rostral shell of the nucleus accumbens - whether it's mediated by dopamine, glutamate antagonists or mu opioid agonists - is the neurological signature of euphoric bliss, whatever its guise.
On MDMA, there's
much more going on as well. MDMA induces the release of noradrenaline (norepinephrine),
and inhibits its reuptake. MDMA also triggers the enhanced release of acetylcholine in the striatum and prefrontal cortex via serotonin 5-HT4 and dopamine D(1) receptor mechanisms. MDMA exerts (weak) binding to the alpha-2 adrenergic and histamine H1 receptors;
this binding contributes in unknown
degree to behavioural stimulation. Activation of the noradrenaline system causes
an acute elevation of blood
pressure. Additionally, taking MDMA increases plasma cortisol, prolactin,
and dehydroepiandrosterone (DHEA) and aldosterone secretion. MDMA use alters the expression of several proteins involved in GABA transmission.
To thicken the plot further, MDMA triggers the release of hypothalamic arginine-vasopressin
and, to a lesser degree, oxytocin
(the "cuddle hormone"). These hormonal changes may influence some of MDMA's psychological
effects. But the current consensus is that enhanced serotonin and dopamine release
are crucial to the magic, even though they don't explain it.
The serotonin system is uniquely complex. A whistlestop tour can't do it justice.
The existence of the serotonin molecule
in Nature long predates the brain; serotonin is found in both the plant and animal kingdoms.
However, the effects exerted by a neurotransmitter on the post-synaptic membrane
aren't determined by the chemical itself, but rather by the structure of the post-synaptic
receptor subtypes to which it binds. Our serotonin-producing neurons belong to
a phylogenetically ancient neurotransmitter system. In the vertebrate CNS, serotonin-producing
neurons regulate aggression, impulse-control, mood, anxiety, cognition, temperature, appetite,
circadian rhythms, sexual activity, sleep, sensorimotor integration, sensitivity
to pain, emotional resilience and romantic
love. Serotonin entering the axonal vesicles is released over time in response to action potentials by exocytosis into the
synaptic cleft, the narrow gap 10-20 nm across between pre- and post-synaptic
neurons. Seven distinct
families of serotonin neuronal receptors have been isolated; 14 sub-populations
of G-protein-coupled receptors and one family of ligand-gated ion channels (the
5-HT3 receptor) have been cloned.
Distribution, density and regulation of the serotonin receptors vary in different
areas of the brain. So does both the affinity of serotonin for its different receptor
subtypes and the effects of serotonin agonists on second-messenger systems. Only
a few hundred thousand of the 100 billion or so neurons
in the brain manufacture serotonin. The serotonergic cell bodies are confined
to the raphé area in the brainstem, but their projections extend to almost all
areas of the brain and spinal cord. Most notably for E-users, serotonergic projections
innervate the dopaminergic nigrostriatal and mesocorticolimbic circuits. The serotonin
system has co-evolved with dopaminergic projections in the course of primate
evolution. Amongst many other roles, the serotonin system helps to regulate
a lifetime spent in complex social hierarchies where more ancient fight-or-flight
reactions have been offset by the need for an increasingly complex cognitive,
emotional and behavioural response. This unique signalling complexity of the serotonin
pathways and their multiple receptors ensures we can now be (un)happy in more
ways than ever before.
serotonin/5-hydroxytryptamine molecule itself is an indole amine synthesized from
the essential amino acid L-tryptophan through the intermediate 5-hydroxytryptophan.
Although some serotonin is present in the cytoplasm of serotonergic cell bodies
and nerve terminals, most serotonin in the axonal terminals is sequestered in
small membrane-bound sacs, i.e. the synaptic vesicles. This prevents the neurotransmitter
from being metabolised by the enzyme MAO. Serotonin is metabolised, mainly by MAO-type A,
into the inactive metabolite 5-hydroxyindoleacetic acid (5-HIAA). Numerous studies
have shown self-destructive violence,
aggression, poor impulse-control, reduced social status, suicide,
and some types of depression are associated with low concentrations of cerebrospinal
fluid 5-HIAA. Consequently, these conditions are often conceived as disorders
of "low serotonin function". Firing of the serotonin neurons causes exocytosis,
a rapid calcium-dependent process of neurotransmitter release. Depolarisation
of the axon induces opening of voltage-sensitive calcium channels; the resultant
calcium influx causes synaptic vesicles to fuse with the plasma membrane, where
they empty their load of serotonin into the synaptic cleft. In the synapse, serotonin
exerts an action on both pre- and post-synaptic receptor sites. Extracellular
serotonin is then normally taken back up into the serotonergic neuron via the
highly efficient presynaptic transport pump. The structure of the transporter
protein determines how it couples ion gradients to substrate transport in ways
that still need to be clarified.
Whatever the precise details, taking MDMA causes a remarkable role-reversal of
normal transporter function. The MDMA molecule binds with high affinity to the
serotonin transporter and enters the presynaptic axon terminal. Current theory
suggests that MDMA causes serotonin release via a diffusion exchange mechanism
involving the serotonin transporter, not by calcium-dependent exocytosis of the
serotonin-containing secretory vesicles. MDMA taken up into the presynaptic terminal
unbinds from the uptake transporter, triggering a reconfiguration of the transporter
so it binds to serotonin inside the cytoplasm of the nerve terminal. The
reconfigured transporter then reverse-pumps the newly-bound intracellular
serotonin out of the cell, changes configuration again, dumps the serotonin
into the extracellular space, and then takes up MDMA once more, repeating the
process of depletion rather than recycling the neurotransmitter.
ensuing flood of serotonin in the user's synapses sets the MDMA magic rolling.
The neurotransmitter binds to multiple serotonin receptor subtypes. The subtypes
play different excitatory and inhibitory roles. So which receptor subtypes are
of most long-term therapeutic and social-recreational interest to a notional paradise-engineer?
Like the proverbial drunkard who searches for his lost keys only under a lamp-post
"because that's where the light is", investigators focus first on wherever they
can probe most easily. The receptor-based account below will soon be superseded
by something deeper. But it probably at least offers clues to the full story.
Serotonin 5-HT1 agonists, sometimes
termed serenics, show
pronounced anti-aggressive properties. Aggressive behaviour is modulated in by
the 5-HT1B receptors in particular. The presynaptic 5-HT1B terminal autoreceptors
form a vital part of a feedback mechanism regulating serotonin synthesis and release.
Receptor knock-out mice
lacking the 5-HT1B receptor are superficially normal in appearance, feeding patterns
and breeding behaviour; but they are ferocious, and highly reactive. Such knockout
mice are also unusually partial to alcohol and supersensitive to the effects of
cocaine, though these traits may reflect a compensatory enhancement of the dopamine
system rather than offer a direct pharmacological model of 5-HT1B receptor function.
By contrast, 5-HT1B receptor agonists such as the drug anpirtoline
exert "serenic" effects. In "animal models", 5-HT1B receptor agonists diminish
alcohol-heightened aggression. Surprisingly, perhaps, there is substantial evidence
to indicate that some endogenous serotonergic pathways normally activate rather
than suppress motor output. Acute activation of 5-HT1B receptors is known to play
a role in MDMA-induced locomotor
activity: 5-HT1B agonists and MDMA show cross-tolerance, suggestive of a common
mechanism of action. 5-HT1B antagonists restrain the hyperlocomotion that rodents and clubbers
typically undergo on serotonin-releasers like MDMA. Perhaps with this crude
behavioural measure in mind, some "unlicensed" psychonauts try combining a supposedly
5-HT1B-selective agonist such as the piperazine derivative TFMPP
[1(3-trifluoromethylphenyl)piperazine monohydrochloride] with dopaminergic psychostimulants like 1-benzylpiperazine (BZP)
to try and replicate the acute effects of taking MDMA. The effect can indeed be E-like; but results are mixed. It is now
known that TFMPP binds at multiple serotonin receptors with only limited selectivity.
Taken on its own in the absence of a dopaminergic psychostimulant, TFMPP does
not feel MDMA-like. Even combined with a dopaminergic, TFMPP's activation of the
5-HT2C receptors makes some users feel anxious. The MDMA effect is hard to emulate:
MDMA is "a multifaceted jewel", not a cheap-and-cheerful euphoriant.
are further subtleties in the way of replicating MDMA's acute effects; and even
more obstacles to sustaining the magic indefinitely. The serotonergic system has
both 5-HT1B autoreceptors
and post-synaptic 5-HT1B
heteroreceptors; they play different functional
roles. 5-HT1B receptors acting as autoreceptors regulate serotonin release via
inhibitory feedback at the presynaptic terminals of serotonergic neurons; turnover
and release of serotonin are typically increased under conditions of acute stress.
5-HT1B heteroreceptors are located on the terminals of nonserotonergic
neurons. Thus 5-HT1B heteroreceptors regulate the release of other neurotransmitters.
A single serotonin neuron can modulate different brain functions and multiple
cellular targets in virtue of the thousands of non-synaptic varicosities on its
axonal branches that project to multiple areas and neurotransmitter systems. 5-HT1B
receptors within the ventral tegmental areas (VTA), for instance, function as
heteroreceptors to inhibit GABA release. Since the GABA terminals in the VTA and
substantia nigra exert a tonic inhibitory influence on dopamine function, inhibition
of GABA by inhibitory 5-HT1B heteroreceptors leads to the disinhibition of dopamine
activity. Thus agents acting directly or indirectly as 5-HT1B agonists can cause
the release of dopamine in the striatum and nucleus accumbens. Indirectly again,
dopamine release is also regulated by 5-HT1B heteroreceptors within the glutamatergic
hippocampo-accumbens pathways. Regulation of 5-HT1B receptor function itself is
under the control of 5-HT-moduline,
an endogenous tetrapeptide that controls 5-HT1B receptor efficacy. 5-HT-moduline
is a so-called allosteric modulator. Allosteric modulators bind to a different
binding site from the natural agonist and can, potentially, circumvent the development
of tolerance. 5-HT-moduline is released from adrenal medulla in response to acute
stress. 5-HT-moduline plays a pivotal role in synchronising the serotonergic signalling
activity of the different terminals of individual neurons, coordinating their
effects on a variety of different cerebral functions. Rationally designed synthetic
drugs that recognize the 5-HT-moduline binding-site on the 5-HT1B receptors, and
act on the 5-HT1B receptors as allosteric modulators themselves, may potentially
exert long-term serenic, anxiolytic
and mood-brightening effects by increasing serotonin release.
general, however, care must be taken in describing serotonin 5-HT1 agonists as
"serenics", even if such agents induce a syndrome outwardly suggestive of inner
tranquillity. The demeanour that an animal exhibits after "serenic" administration
may indeed be submissive, passive and timid - in contrast to the fierce, assertive
and aggressive behaviour of 5-HT1B knockouts. Yet "serenity" tends to connote
an inner E-like peace that may be lacking - and not just in the unfortunate laboratory
rodent. In fact some so-called "serenics" may enhance fear/anxiety
reactions: it's only their use in combination with dopamine-releasing euphoriants
that makes such agents especially interesting to the psychonaut. Indeed supersensitive
5-HT1B autoreceptors are implicated in depression and obsessive compulsive disorder.
By introducing extra
copies of the gene for 5-HT1B receptors into serotonin neurons, researchers
can breed passive and depressive rats that show signs of abject misery [i.e. "learned
helplessness" and "behavioural
despair"]. The syndrome of learned helplessness is associated with excess
production of 5-HT1B receptors that are churned out in greater profusion by the depressive
brain. This isn't to deny that 5-HT1B
agonists may have therapeutic potential, whether in bipolar
disorder, autism, alcoholism or disorders of impulse-control and aggression.
Thus the triptans, serotonin
5-HT1B/1D receptor agonists, are clinically effective for treating migraines;
they can also curb aggression.
But 5-HT1B antagonists and inverse agonists such as SB-236057-A
are under investigation for possible clinical use as long-term and relatively
fast-acting antidepressants. Acute 5-HT1B autoreceptor blockade can increase serotonin
release. Cognitive function is affected by their use too. Whereas 5-HT1B agonists
may adversely affect memory via inhibition of acetylcholine release in the hippocampus,
antagonists and inverse agonists
of the 5-HT1B receptor can improve the consolidation of learning. This simplified
outline of the neurobehavioural role of a single family of serotonin receptor subtype illustrates
how inducing lifelong E-like states - as distinct from "mere" raw bliss - is going
to pose a formidable technical challenge. In this case, the possible existence of
multiple subpopulations of 5-HT1B autoreceptors and heteroreceptors makes inadequate
selectivity of ligands even more of a problem, especially for seekers of precision-tools
rather than chemical coshes.
serotonin 5-HT1B receptor knockout animals are aggressive by nature,
5-HT1A knockouts are timid, anxiety-ridden creatures. Whereas serotonin 5-HT1B
receptors are found mainly on terminal processes, 5-HT1A
receptors are located solely on serotonergic nerve cell bodies within the dorsal
raphé nucleus. Intriguingly, 5-HT1A receptor density is reported to be inversely correlated with susceptibility to spiritual experience,
opening up the possibility of genetically amplifying our capacity for spirituality beyond anything humanly accessible today: it may be premature to assume our descendants will be secular rationalists. However, the role of the 5-HT1A receptors in MDMA's acute subjective effects
still isn't clear. Pretreatment with a serotonin (5-HT1A) receptor antagonist apparently reduces MDMA's pro-social effect, in rats at least. Taken over a prolonged period, selective 5-HT1A receptor agonists
typically exert a delayed-onset anxiolytic as well as (sometimes) a mood-brightening activity.
Their (modest) therapeutic efficacy relies on an adaptive neuronal response. Acute
activation of the presynaptic 5-HT1A receptor on the raphé nuclei tends to reduce
both the rate of firing of serotonin neurons and the corresponding release of
serotonin from the nerve terminals; chronic activation causes the receptors to
desensitise, leading serotonergic neuronal activity to rebound. Clinically, buspirone
(Buspar), a 5-HT1A partial agonist, is licensed for generalised anxiety disorder.
Similar agents like gepirone
tandospirone and ipsapirone
are under investigation. Alas taking them doesn't remotely engender the extraordinary
sense of inner peace induced by MDMA. In rats at least, 5-HT1A agonists facilitate
male sexual behaviour, hypotension, increased food intake and produce hypothermia,
none of which are prominent sequelae of MDMA use. In general, 5-HT1A agonists
are well tolerated. But they may also on occasion induce dizziness, nausea, and
headaches, probably linked to their postsynaptic receptor action rather than presynaptic
anxiolytic effect. Buspirone itself is also a dopamine D2 antagonist, albeit a
weak one. This may explain why it's never been wildly popular with patients. It's
also very slow to work. Gepirone, on the other hand, allegedly lacks significant
activity at the dopamine D2 receptors. Gepirone acts as an agonist at the presynaptic
5-HT1A receptors and a partial agonist at the post-synaptic 5-HT1A receptors.
Hopefully, gepirone will prove a clinically useful anxiolytic and antidepressant.
However, though 5-HT1A antagonists
reduce discrimination of MDMA in animal models, the role of 5-HT1A receptor activation
in MDMA's effects needs elucidation via more first-person experimental studies.
The MDMA molecule, especially
the dextrorotatory "+" isomer, has only a low affinity for the 5-HT2 receptor.
This is why taking the drug within the normal dose-range typically induces only
minor perceptual changes. If prompted, many Ecstasy users report altered time
perception, but any visual distortions are usually mild: the N-methyl group of
the MDMA molecule prevents it from fitting as comfortably into the 5-HT2A receptor
as does the trippier (-)-MDA enantiomer of its structural parent. Experiments
with human as well as non-human animals show a correlation between a drug's psychedelic
potency and 5-HT2A receptor binding affinity. Activation of the 5-HT2A receptors
is a prerequisite of the "classic"
hallucinogenic effects exerted by tryptamine psychedelics such as LSD and phenethylamine
psychedelics like DOM. Conversely, 5-HT2A receptor inverse agonists act
None of this neurobabble should
disguise the fact that psychedelia is still scientifically uncharted. It's often
too weirdly exotic for words. Materialistic neuroscience has failed to close the
ontological gulf between neural porridge and consciousness - whether "ordinary"
or "altered" states. Some psychonauts, understandably enough, feel the neurobabblers
have lost the plot. Most of today's storytelling about altered states and the
chemistry of mind will doubtless seem no less archaic to our descendants than
the Greek humoral psychology of classical antiquity strikes the contemporary molecular
biologist. Yet fortunately for the engineering purposes of inducing sustainable
E-like bliss, we need manufacture only the sufficient neural conditions
for beautiful states of consciousness. We don't need a deep understanding of how
and why consciousness is generated (or alternatively, some philosophers
allege, its fundamental immanence in the world). We can guess even less about
the possible altered states of consciousness of our redesigned successors. We
don't know whether the "explanatory
gap" between the physical facts and phenomenal mind can ever be closed. But
either way, our emotionally invincible descendants should be able to explore entheogens,
and map out even the most outlandish reaches of psychedelia, in safety. Unlike
us, our genetically enriched descendants may revel in the assurance that bad trips
are inconceivable, and psychological damage is impossible. This is because their
obnoxious molecular substrates will have been edited out.
our own less robust minds are psychologically vulnerable to even "physically"
harmless psychedelics that aren't also euphoriants. Dual-action dopamine- and
serotonin-releasers like MDMA are the latter, though they aren't always harmless.
With MDMA, as with so many psychoactive drugs, very often "less is more". This
piety is easy to intone but hard to practise, especially when taking fast-onset
euphoriants. The lucidity of the entactogenic effect of MDMA may be especially
pronounced at low-to-moderate dosages. "Optimal" dosage of psychotropic agents
taken for "non-approved" purposes is most often empirically determined by the user
investigating what level induces maximal enjoyment. Yet the effects of lower,
"sub-optimal" dosages that more subtly modulate consciousness may be of greater
value for facilitating personal growth. Low-to-moderate dosage E-experience may be easier to
integrate into the rest of one's E-less life. Nonetheless at higher, quite possibly
neurotoxic doses of 200mg or so, MDMA can itself sometimes deliver psychedelic
euphoria, entheogenic rapture, and some very interesting exotica indeed. Alas
the unique effects of such doses [and likewise higher doses of other stellar phenethylamines]
cannot safely be investigated in depth until the neurotoxicity of MDMA's metabolites
and/or toxic free radicals can be prevented.
the meantime, if the user desires a completely clear sensorium, then perceptual
alterations might seem eliminable altogether, in principle, by taking only the
(+)-MDMA enantiomer rather than the standard racemate. Sadly, pure (+)-MDMA is
scarce; it's also hard to prepare at home. Thus one unintended consequence of
scheduling MDMA has been to widen youthful exposure to psychedelia, albeit psychedelia
in its warmest and most gentle introductory guise. (-)-MDMA at normal doses is
only minimally active at the "psychedelic" 5-HT2A receptor owing to its (comparatively)
bulky methyl group. By contrast, MDA (which lacks it) is an all-in-one cocktail
that can be hallucinogenic as well as empathetic and slightly speedy.
if uncomplicated perceptual clarity is sought then a 5-HT2 antagonist such as
ketanserin or the 5-HT2A
selective MDL-11939 might
help preserve total lucidity. 5-HT2A antagonists have the additional advantage
of preventing MDMA-induced hyperthermia
that exacerbates toxicity. Neurotoxic hydroxyl radical formation is temperature-mediated;
conversely, hypothermia-inducing agents enhance neuroprotection.
there are complications. Stimulation of the serotonin 5-HT2A receptors contributes
to the rewarding effects of MDMA, or at least plays a permissive role in dopamine
release. So trying to eliminate perceptual alterations completely while retaining
the full-blooded E-magic may be difficult. MDMA is often reckoned a "serotonergic"
drug. Compared to amphetamine this is true: MDMA's affinity for the serotonin
transporter is greater, and its ratio of serotonin to dopamine release is higher,
than amphetamine. Even MDMA's extra release of dopamine partly depends on its
activation of the 5-HT2A receptors. But serotonin-releasing
agents [e.g. the halogenated amphetamine appetite-suppressant fenfluramine
(Pondimin)], taken on their own, aren't notably rewarding or entactogenic/empathetic,
at least at ordinary dosages. The enhanced release and reuptake inhibition of
dopamine is essential to MDMA's tendency to promote blissful well-being and to
colour its entactogenic-empathetic effect.
strands of evidence indicate that dopamine release is critical to the MDMA magic.
Dopaminergic activity in the brain and motor behaviour may be crudely interpreted
as under the inhibitory control of the serotonin system. Yet the multiple serotonin
pathways play functionally different roles. According to one hypothesis, the extra
serotonin released by MDMA stimulates 5-HT2A receptors located on inhibitory gamma-aminobutyric
acid (GABA) striatonigral neurons.
VTA dopaminergic neurons in the brain's reward centres are under continuous inhibition
by GABA. Stimulation of the 5-HT2A receptors inhibits these GABA neurons, thereby
allowing the disinhibition
of dopamine biosynthesis. Post-E levels of dopamine in the mesolimbic reward circuitry
are far higher than would be explained by MDMA's relatively weak additional release
of dopamine via the uptake carrier.
drug discrimination studies, and the human behavioural evidence, tend to support
this dopaminergic account. Although some MDMA users prefer reflective tranquillity
and intimate group hug-ins, many loved-up clubbers opt to dance for hours at raves
- a form of hyperlocomotion one would expect from Peruvian marching-powder rather
than a serotonergic agent.
this account is still simplistic. The release of serotonin following an MDMA-induced
reversal of the reuptake pump results in a stimulation of the 5-HT1B receptors
and, at higher doses, increasingly of the 5-HT2A receptors as well. Such receptor
stimulation can trigger marked hyperactivity, especially in young MDMA users who
rave. At lower doses, MDMA-induced locomotor activity is caused mainly by the
released serotonin's preferential activation of the 5-HT1B receptor. This is because
serotonin has a somewhat higher affinity for the 5-HT1 receptors than the 5-HT2
receptors. The greater flood of serotonin in the synapses triggered by higher
doses of MDMA promotes locomotor activity via 5-HT2A receptor-mediated dopamine
stimulation as well. To complicate matters, MDMA may itself bind, albeit weakly,
to the 5-HT2A receptor. A further complicating factor is that MDMA-induced release
of serotonin stimulates the 5-HT2C
receptors. Activation of the 5-HT2C receptors serves to mask
expression of MDMA-induced hyperactivity, sometimes evidently more effectively
than others. The various subpopulations of 5-HT2C receptor located on GABAergic
neurons in the ventral tegmental area and the substantia nigra tend to exert a
tonic inhibitory influence over the mesolimbic dopamine system. Thus 5-HT2C receptors
tonically inhibit dopamine release in the nucleus accumbens, mostly it seems in
virtue of their constitutive activity i.e. entering the activated receptor state
in the absence of an agonist. Other things being equal, activation of 5-HT2C receptors
is anxiogenic, demotivating and generally unpleasant. Certainly the stimulant
effects of MDMA are greatly enhanced following treatment with a 5-HT2C antagonist.
Sustained antagonism of the 5-HT2C receptors might well we harnessed to intensify
the hedonic properties of long-lasting E-like consciousness. Less speculatively,
5-HT2C antagonists such as agomelatine
are under investigation as potential clinical antidepressants.
usual, there are complications: all 5-HT2C receptors are not the same. Numerous
5-HT2C receptor isoforms are produced as a result of RNA
editing, and their individual roles in modulating the MDMA effect aren't properly
understood. In general, the receptor story illustrates at the molecular level
that being blissful isn't the same as being blissed out. To sustain empathetic
love, simply banishing all capacity for social anxiety isn't going to work. Specific
and selective 5-HT2C receptor antagonism may well prove a worthwhile goal; but
it's too early to say what the MDMA experience may gain or lose in consequence,
whether socially or subjectively. Empathy entails caring about others, not lacking
a care in the world. Thus the MDMA-induced disinhibition from social anxiety,
and the lowering of psychological defensive barriers, is radically distinct from
the sort of anxiolysis
induced by SSRIs or the benzodiazepines
- or indeed by alcohol or
opiates. With none of these drugs or drug
categories is a reduction in the user's social anxiety matched by an E-like upwelling
of empathy or sensitivity to the feelings of others - in fact quite the reverse.
There are subtleties of the MDMA experience that haven't yet been explored.
If acute serotonin-mediated enhanced
dopamine-release is indeed essential to the magic of MDMA, then a wide range of
safe long-acting dopaminergics are already on offer to augment any hypothetical
subtype-selective "serotonergic" therapies. Compared to our descendants, we're
probably all anhedonic. So some form of dopaminergic augmentation is a therapeutic
step in the right direction. "Dual-deficit"
models of everyday E-less malaise are plausible; and they naturally invite dual-action
remedies. Clearly, inhibition of
glutamate-evoked firing in the nucleus accumbens is an ingredient of the E-magic:
it is known that firing-inhibition depends on both dopamine and serotonin release;
and this process is mediated by both dopamine and serotonin receptors. But beyond
these superficial generalities, working out how to replicate sustainably at the
molecular level the precise neurochemical signature of peak experiences will be
hard. Until the dawning of the era of wholesale genomic rewrites and true designer
babies, using a cocktail of subtype selective serotonin agonists and gentle dopaminergic
psychostimulants still looks like the easiest way to mimic and enhance the entactogenic-empathogenic
effect induced by MDMA-like compounds. However, there are many pitfalls in choosing
the right dopaminergic for the job.
contrast with intracranial electrical stimulation, a direct chemical assault on
the hedonic treadmill rarely works. This failure is witnessed by the unsatisfying
and usually counterproductive
effects of using catecholamine-depleting psychostimulants. Darwinian-era mood
and motivation is regulated via a multitude of indirect mechanisms of feedback-inhibition.
So it's worth reviewing how and why the substrates of human well-being are held
in check; and what can be done about it. First, an unavoidably fast-and-furious
tour of the dopamine system
is in order. The CNS has three main dopaminergic pathways. They regulate movement,
hormonal secretion, and emotion. Each projects from dopaminergic cell groups in
the midbrain. 1) The nigrostriatal pathways extend from the substantia
nigra pars compacta to the striatum. This pathway is critical to the control of
involuntary motor movement; its dysfunction is implicated in the tremor, rigidity
and akinesia of the "dopamine deficiency disorder" Parkinson's
disease, and several other neuropsychiatric disorders such as Tourette's
Syndrome. 2) The tuberoinfundibular system extends from the hypothalamus
to the pituitary gland. It's involved in prolactin- and growth hormone-secretion,
and the regulation of lactation and fertility. 3) The mesocorticolimbic
pathway extends from the ventral tegmental area to the nucleus accumbens and the
medial prefrontal cortex. The mesocorticolimbic system is central to emotion,
motivation, willed action and, more subtly, the modulation
of thought-processes. In crude terms again, dopamine is critical to sensorimotor
integration; appetitive behaviour of all kinds; the capacity to switch from one
course of behaviour to another; and the orchestration and activation of the motor
output system. Dopamine has also traditionally been described as the brain's "pleasure
chemical", cueing potentially (Darwinian) fitness-enhancing stimuli so they can
acquire control over an organism's behaviour. Certainly, consistent with the
dopamine theory of reward, electrically or pharmacologically stimulating microcircuits
in the rostromedial shell
of the nucleus accumbens produces intense pleasure in the absence of any goal-seeking
behaviour. But this formulation can be misleading. The mesolimbic dopamine system
mediates "wanting" more
than "liking"; and its drug-induced
or electrical stimulation
may increase incentive-salience rather than the raw intensity of pleasure itself.
Dopaminergic neurotransmission is critical to incentive-motivation and all forms
of purposeful behaviour. Dopamine levels tend to rise if one is anticipating a
rewarding event; and levels then tend to fall if the anticipated reward fails
to materialise. Couched in the language of psychology rather than neuroscience,
enhanced dopamine release in the pleasure centres imparts a sense of urgency,
significance and a feeling of things-to-be-done. The molecular substrates
of pure pleasure are still
At the cellular
level, the dopamine system doesn't quite rival the molecular, pharmacological
and functional diversity of the serotonin system; but the two "classic" types
of dopamine receptor (D1-like and D2-like receptors) have several subtypes and
alternate splice-forms. Further, the number of different messenger RNA and dopamine
binding sites substantially exceeds the five dopamine receptor genes of the human
genome, a diversity that reflects the genetic polymorphism and alternative splicing
events in normal dopamine gene-expression. However, each type of dopamine receptor
belongs to the superfamily of G-protein-coupled receptors that activates or inhibits
different forms of adenylyl cyclase inside the cell. Intriguingly, the presence
or absence of variant alleles of dopamine receptor subtypes and their signal-transduction
mechanisms is correlated with variants of human behaviour and personality. For
example, individuals with genotypes containing the seven-repeat allele of the
dopamine D4 16-amino acid repeat
polymorphism tend to exhibit the personality trait of "novelty-seeking".
This trait is characterised by a tendency to impulsiveness, risk-taking, exploration,
excitability, and an optimistic mood, though alas not a loving, E-like temperament.
For better or worse, within a few decades prospective parents will be able to
select such alleles and their rationally redesigned enhancements when choosing the parameters of their
future offspring. Such naturally loved-up kids may prove more easily adorable
than today's Darwinian default-models.
the other catecholamine neurotransmitters, dopamine itself is synthesised from
the non-essential amino acid L-tyrosine. L-tyrosine is transported across the
blood-brain barrier into the dopaminergic nerve cell. L-tyrosine is converted
to L-dopa by the enzyme tyrosine hydroxylase. L-dopa is then rapidly converted
to dopamine by L-amino acid decarboxylase. Next dopamine is sequestered in synaptic
vesicles by a dopamine transporter. At the synapse, the dopamine nerve terminal
displays high-affinity uptake sites. They rapidly terminate the action of the
neurotransmitter on the receptors if it isn't metabolised by the MAO or COMT enzymes.
Depending on concentration gradient, the dopamine carrier can transport dopamine
back into the nerve cell, recycling it as normal, or alternatively,
after a user has taken a classic amphetamine, the carrier
can transport dopamine from the cell terminals into the synaptic cleft. In common
with amphetamine, MDMA inhibits the neuronal reuptake of dopamine, albeit more
weakly than MDA. Further,
increased post-E administration activity of the serotonin 5-HT1B and 5-HT2A receptors causes
the dopaminergic neurons themselves to fire more rapidly. This higher impulse-frequency
causes increased dopamine-release via exocytosis of the dopamine-containing vesicles
in the normal manner.
leaves so many "normal" Darwinian people - who are neither clinically
depressed nor loved-up on MDMA - comparatively anhedonic and hypodopaminergic?
The dopamine neurotransmitter is under powerful homeostatic control. So is the
density and signal-transduction efficiency of the receptors to which it binds.
Feedback-inhibition of dopamine synthesis, dopamine release and spontaneous action-potential
generation in dopamine-producing cells is modulated by a variety of functionally
distinct dopamine autoreceptors that regulate membrane excitability. The dopamine
neurotransmitter itself functions as an end-product inhibitor of tyrosine hydroxylase,
the rate-limiting step in dopamine production. Dopamine plays this role by competing
with a tetrahydrobiopterin co-factor for a binding site on the enzyme. Dopamine
synthesis is also modulated by the rate of impulse-flow from the nigrostriatal
pathway. In addition, presynaptic dopamine receptors modulate the rate of tyrosine
hydroxylation; and most mesolimbic dopamine neurons possess cholecystokinin-autoreceptors
and neurotensin-autoreceptors that regulate dopamine function as well. Indeed
activity of the mesocorticolimbic dopamine system is regulated by multiple neuronal
pathways containing different neurotransmitters, notably serotonin, opioids,
GABA and glutamate.
Precisely what dopamine actually does in the all-important dopamine-sensitive
shell of the nucleus accumbens is unclear. The main effect of its release seems
to be the inhibition of the GABAergic medium spiny projection neurons (MSNs).
These neurons come in two types. One subtype expresses dopamine D2 receptors and
enkephalin. This sort of GABAergic medium spiny cell projects from the nucleus
accumbens to the ventral pallidum. It is activated by "reward stimulation" of
the ventral tegmental area. The other subtype of GABAergic medium spiny projection
neuron co-expresses substance
and dopamine D1 receptors. This subtype projects directly back to the ventral
tegmental area. It regulates motivation and pleasure, or our deficit thereof.
So how can this cruel and
complex web of inhibitory feedback
mechanisms best be modified? If our aim were pure-and-simple cloud nine euphoria,
then better drugs to decrease glutamate and GABA currents in the critical medium
spiny neurons of the nucleus accumbens might be adequate - at least until new
genes and gene networks can be more readily inserted in the genome, and the regulation of old
ones improved. But well-controlled, high-functioning euphoria is more elusive
than mind-blowing rapture. Crude "natural" interventions to enrich dopamine function
aren't effective. For instance, some psychonauts, clubbers and alternative therapists
alike have explored taking free-form amino acid supplements of L-tyrosine
and L-phenylalanine in a bid to boost native dopamine levels or reanimate a drug-frazzled
brain. But tyrosine hydroxylase is normally saturated. So unlike tryptophan-loading
and/or 5-HTP-loading to increase neural levels of serotonin production, this "dopaminergic"
precursor strategy typically doesn't work. On the other hand, taking L-dopa does
increase synaptic dopamine levels. This is especially so when L-dopa is combined
(as in Sinemet for Parkinsonians) with a peripheral decarboxylase inhibitor such
as carbidopa to prevent its metabolism outside the brain, At least for a minority
of "normal" subjects, taking L-dopa can be an effective motivator, libido-enhancer
and mood-brightener. In
a more controlled setting, rodents engineered so they can't synthesize dopamine
initially develop quite normally, only to die miserably a few weeks after birth
following a failure to eat, drink or do very much in this world at all. Yet when
such dopamine knock-out mice are abundantly maintained on L-dopa, they can flourish.
Indeed L-dopa-maintained dopamine knock-out mice become hyperactive and sexually
vigorous. This manipulation has not yet been attempted in dopamine knock-out humans.
Augmentation should in any case be tried only cautiously and in controlled-release
preparations (e.g. Sinemet SR) since high levels of L-dopa may increase oxidative
stress. Whatever the mechanism, simply increasing raw dopamine levels per se is not enough.
For instance, an agent such as alpha-methylparatyrosine
that inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine
synthesis, might be expected to produce a state of melancholic
depression; but in non-depressives it doesn't reliably do so. This complicates
any simplistic catecholamine-depletion
theory of retarded depression.
Nevertheless, dopamine-releasing agents demonstrably tend to induce euphoria. By contrast,
dopamine receptor antagonists like haloperidol
are dulling and dysphoric. All the classical dopamine D2-blocking neuroleptics blunt will-power
and flatten emotion. Administering dopamine D2-blockers tends to induce apathy and anhedonia,
and ruins the MDMA magic. Nasty but instructive, such magic-prevention experiments
are an important pointer to what's needed to sustain the MDMA spectrum of consciousness.
It's known that stimulation of the dopamine D2-like receptor causes an increase
in phosphatidylinositol hydrolysis by activating enzyme phospholipase C. Enhanced
phosphatidylinositol hydrolysis is implicated in euphoric mania.
Conversely, the lithium used
to treat "uncontrolled" euphoria inhibits the phosphatidylinositol second messenger
system and darkens mood in nondepressed "euthymic" people. Understanding the principles
behind the pharmacological induction of controllable non-stop euphoria
will be a first step on the route to designing lifelong variations of the subtler
forms of magic.
In the meantime,
dopamine antagonists like amisulpride
(Solian) can be used at low doses preferentially to antagonise the synthesis-,
release- and impulse-modulating presynaptic dopamine D2/D3 autoreceptors. Thus a regimen
of low-dose amisulpride may potentially enhance dopamine release and boost mood
and motivation, whereas many dopamine reuptake inhibitors [e.g. vanoxerine,
"adaptively" diminish the neuronal release of dopamine over time, even though
their action on reuptake inhibition increases the neurotransmitter's synaptic
availability. Unfortunately, pre-treatment with high doses of dopamine reuptake
inhibitors blunts MDMA-induced release of dopamine, though not to the same degree
as SSRIs blunt MDMA-induced release of serotonin. Other crude strategies to augment
dopamine function involve taking dopaminergic agents such as the dopamine agonists
pergolide (Permax) and
the potent, pro-sexual, long-acting D2 agonist cabergoline
(Dostinex); selective D2/D3 agonists such as pramipexole
(Mirapex) or ropinirole
(Requip); catechol-o-methyltransferase (COMT)
inhibitors such as tolcapone
(Tasmar); selective MAO-B inhibitors such as selegiline
(Eldepryl) or rasagiline;
adenosine 2A receptor antagonists;
and centrally active nicotinic receptor agonists. Oral, centrally-active dopaminergic
"pro-drugs" with higher bioavailability and fewer adverse side-effects are also
under investigation. But there are obvious problems. For instance, dopamine-release
promoting agents, if fast-acting and taken in the absence of anything subtype
selectively "serotonergic", may not induce serenely motivated well-being as distinct
from compulsive pleasure-seeking, thought disturbances or manic excitement. Any
tendency to cause uncontrolled dose-escalation is likely to cause toxicity, florid
psychoses and abuse. Regrettably, these worries about the "abuse-potential" of
psychostimulants frequently generalise
in mainstream wisdom to an unwarranted fear of all "dopaminergic"
taboo against "excessive" well-being can have serious medical consequences. Even victims of melancholic
or retarded depression are widely denied access to clinically effective
catecholaminergic antidepressants. This is one reason why so many remain depressed
or "partial responders"; another is opiophobia.
MDMA itself rapidly banishes all kinds of depression, albeit not for long. In
spite of its relatively powerful indirect dopaminergic activity, MDMA is sometimes
likened in the media to the much more commonly prescribed selective serotonin
reuptake inhibitors; fluoxetine
(Prozac) was the first and most famous SSRI. In reality there are profound differences
between MDMA, the SSRIs and other "serotonergic" antidepressants. Like an SSRI,
MDMA occupies the serotonin transporter and prevents serotonin from binding, increasing
its availability in the synapse. However, MDMA is small enough to be taken up
by the serotonin reuptake transporter into the serotonergic cell. The serotonin
transporter pulls the MDMA molecule up into the axon, where its release from the
transporter allows the transporter to bind to intracellular cytoplasmic serotonin,
which it releases into the synapse before taking back more MDMA into the terminal.
Quite aside from their different molecular mechanisms of action, however, there
are striking differences in subjective effect between MDMA and "serotonergic"
centrally active psychiatric medicines. Clinically-licensed SSRIs [fluoxetine/Prozac;
may make a small minority of people feel durably "better than well". More typically,
SSRIs are mood-blunters and even, for some people, psychic anaesthetisers. SSRIs
commonly make those who take them more resilient and less anxious. But they don't
promote depth of feeling, intellectual dynamism or clarity of thought. SSRIs can
also diminish the intensity of love. MDMA, by contrast, is a veritable love-potion,
what Claudio Naranjo aptly christened a "feeling intensifier". On MDMA, emotions
are heightened as well as enriched. Compared to loved-up ecstatics on MDMA, the
rest of us have the emotional intensity of zombies; and zombies have no real insight
into what they're lacking, even if some of us can talk as though we do. Ironically,
at a time when the loss of personal liberty entailed by prohibitionist drug laws
is justified by the societal costs of illicit drug-taking, "psychiatric" drugs
are clinically prescribed by physicians regardless of the likely effect of a medication
on the personal relationships of the patient. SSRIs, by enhancing the user's emotional
self-sufficiency, can either save marital relationships or wreck them. By reducing
"neediness", SSRIs also diminish what today passes for love. SSRIs are prone to
impair romantic ardour as well as libido.
One technical (and ideological) challenge of the pharmacogenomic revolution in
prospect at the interface between genetics and drug-design
will be to investigate how the emotional honesty and extraordinary depth of feeling
induced by MDMA can be sustained over a period of months, years and decades rather
than for two-hour bursts.
are further complications to overcome if any bid to replicate and sustain full-spectrum
E-like consciousness is to succeed. MDMA triggers the release of the neurotransmitter
acetylcholine via a histaminergic
H1 mechanism. MDMA is also a weak agonist of the acetylcholine muscarinic M1 receptors.
MDMA's modest cholinergic activity may contribute to the exquisite lucidity of consciousness
characteristic of pure MDMA taken in a therapeutic setting. For the
cholinergic system is vital to memory, higher thought-processes and verbal fluency.
Cholinergics such as piracetam
(Nootropil) are used as nootropics or
and acetylcholinesterase inhibitors like galantamine
(Exelon), tacrine (Cognex)
and donepezil (Aricept)
are used as palliative treatments of Alzheimer's disease. Acetylcholine-release
and muscarinic receptor activation probably play no direct role in the rewarding
hedonic effects of MDMA. Yet their subtle contribution to the texture of the magic
can't be discounted. "Dumb-drug"
antimuscarinic agents commonly induce mild euphoria
via their indirect enhancement of dopamine function. Their mood-brightening effect
stands in contrast to many cholinergic (e.g. muscarinic M4
receptor) agonists and cholinesterase inhibitors which have a tendency to subdue
mood. A wide range of cholinergics is now under development for the palliative
treatment of Alzheimer's disease,
a progressive neurodegenerative disorder characterised by profound cholinergic
deficits. Some depressives, however, may actually benefit from the antimuscarinic
anticholinergic effects that more intellectually fastidious clinicians would call
an adverse side-effect of the older tricyclics.
While a great many depressed people report intellectual sluggishness and poverty
of thought, other melancholic and introspective depressives endure "hypercholinergic
frenzy", possibly owing to dysregulation of the cholinergic-adrenergic
axis. Sadly, innumerable depressives among life's walking wounded today find the
examined life scarcely worth living: they cope with life only by "just getting
on with it". By contrast, MDMA allows introspection to become insightful and enjoyable
even to the naturally angst-ridden. On MDMA, both philosophising and emotional
self-honesty can be illuminating and fun. It's a shame that such self-insight can't
more readily be prolonged.
enigma is the role of DHEA.
MDMA causes a rise in the adrenal corticosteroid dehydroepiandrosterone (DHEA).
DHEA is the precursor to testosterone,
and other steroids. The rise and peak physiological values of DHEA between around
1 to 2½ hours post-MDMA administration is correlated with user-reported
euphoria, though DHEA's precise contribution to the mood-elevation is unclear.
In general, levels of DHEA decline with age after early adulthood. Long-term supplementation
with DHEA seems to have beneficial effect on libido, immune function and some
forms of cognition. However, in spite of a wealth of research, no firm conclusions
have yet been reached on the advisability of taking DHEA supplements, or an optimal
dosage if taken. Nor is it known what role enhanced DHEA might play in sustaining
enriched quality of life over the longer term. Taken on its own, DHEA may brighten
mood; but it's scarcely an E-like effect.
unwanted effect of MDMA, especially when taken at higher doses, is its
tendency inhibit to tryptophan
hydroxylase by triggering a rapid oxidation of the enzyme's sulphydryl sites.
Tryptophan hydroxylase is the rate-limiting enzyme in serotonin synthesis. Even
though the acute functional loss of tryptophan hydroxylase in the cell terminal
is reversible, the axon's vulnerability to oxidative stress is increased. In order
sustainably to enhance our capacity for empathetic bliss, and certainly to prevent
any functional serotonergic deficit, tryptophan hydroxylase function must be enhanced,
not inhibited. However, to date no stimulator (or inhibitor) of the biosynthesis
of serotonin has been commercially marketed. Interestingly, the use of interventions
to increase the biosynthesis of serotonin prior to MDMA use tends to trigger an
increased synaptic release of dopamine, thereby enhancing the user's euphoria.
Unfortunately, increased serotonin synthesis also aggravates post-E neurotoxicity.
The two mechanisms are separable in principle. In the meantime, restraint is prudent.
Ultimately, we may be able
to generate sublime MDMA-like states - at will, to order, and indefinitely - only
when the intracellular signal-transduction mechanisms, and regulation of genetic
switching beyond the post-synaptic cascade, are better understood. The orchestrated
"overexpression" of some genes and the receptor proteins they code, the redesigned
"under-expression" of others, and perhaps the selective silencing
of gene expression via RNA-mediated interference of anything really nasty, can
amplify desirable facets of our consciousness and suppress its darker and more
poisonous variants. Thus at one terrible extreme, suicide
victims, for instance, tend to show heightened levels of serotonin 5-HT2A
receptors. Before death, they show a greater activity in the genetic machinery
churning out the 5-HT2A receptor itself. So as well as developing gene-therapy
to prevent suicidality
- and forestall the whole spectrum of deeply unpleasant para-suicidal and self-destructive
states - it should be possible, conversely, to engineer an unimaginably richer
love of life, of ourselves and each other by genetically enhancing our own minds.
Freedom to optimise (or at least improve) one's genome should prove at least as
personally liberating as the freedom to optimise one's drug-regimen. Doubtless
a regulatory minefield lies ahead.
One momentous development is perhaps only a decade or so away. In the imminent
era of genomic medicine, we may each enjoy access to a read-out of our own individual
genotype i.e. the set of particular forms of genes - alleles - peculiar to each
individual who isn't a monozygotic twin [triplet etc]. Harnessed to pharmacogenetics,
the study of how an individual's distinctive genetic inheritance affects the body's
response to drugs, such intimate genetic self-knowledge should allow the design
and prescription of a drug-regimen tailored to each unique person, whether for
medical, social, research or "recreational" purposes. At first, only the crudest
stratification of patient populations by genotype may be the medical norm. This
is because commercial drug companies prefer large markets. Yet eventually we should
all have optional access to the gene-expression profile of each neurotransmitter-specific
neuronal subtype in the mind-brain. Such access offers scope for fine-grained
manipulations of the chemistry of our souls inconceivable in the Dark Ages of
personalised medicine offers another bonus. It should eliminate the possibility
of idiosyncratic drug reactions caused by genetic abnormalities - for example
rare polymorphisms of the cytochrome
P450-2D6 system critical
to drug metabolism. Owing to genetic polymorphisms in drug-metabolising enzymes,
receptors and transporters, a range of drugs beneficial to c.99% of the population
can't get regulatory approval. In some cases, valuable licensed medicines are
pulled after post-marketing surveillance. This therapeutic opportunity is wasted
because, say, 1%, 0.1%, or even 0.01% of people who take such agents suffer severe
adverse reactions. The advent of genetically personalised medicine should mean
that these atypical cases can be excluded; and given other medication instead.
Useful older drugs can be dusted off the shelves and re-licensed. New
agents can be developed and given faster regulatory approval.
drug users in particular should benefit from the prospect of genetic
self-knowledge. Cytochrome P450 forms a superfamily of hepatic enzymes with hundreds
of different isoforms that catalyse the oxidative metabolism of a huge diversity
of substrates, including MDMA. The duration of action and/or intensity of the
effect of numerous drugs are determined by their rate of metabolism by cytochrome
P450. Whereas some "housekeeping" enzymes are expressed constitutively i.e. they
are perennially active, other enzymes are expressed essentially only when triggered
by the presence of the exogenous chemical. Inducible enzyme isoforms increase
both in amount and activity in response to drugs.
precise role of CYP2D6 in MDMA pharmacology
is still unclear. MDMA is not merely a substrate for CYP2D6; it also binds to
the enzyme, forming an inhibitory complex. The CYP2D6 enzyme is soon saturated
even in efficient metabolisers. Other human cytochromes P450 such as CYP-1A2,
CYP-3A4 and CYP-2bB are critically involved in the oxidative metabolism of MDMA.
It is possible these other metabolic pathways play an important role in everything
from idiosyncratic responses to MDMA to the notorious "loss of magic". If enzyme
induction accounts wholly or in part for the loss, then the roots of disenchantment
can be investigated and prevented, whether for MDMA or perhaps its still imperfect
successors. If, however, central processes of neuroadaptation are at work, either
instead or as well, then longitudinal neuroimaging studies comparing the brain-scans
of, say, drug-virgins ninety minutes or so after dropping their first magical
E (or perhaps its safer successor(s)) with brain-scans taken during their hundredth-odd
trip should allow the neurochemical basis of any loss of magic to be pinpointed
and reversed. Indeed the magic itself can presumably be amplified, probably more delightfully
than an unenchanted Darwinian mind can grasp.
More broadly, genomic medicine will deliver the freedom to choose who or what
we want be, both as individuals and collectively as a species. In the long run,
a spectrum of mental superhealth that is orders of magnitude richer than anything accessible
today can be genetically pre-programmed. "Phenotypic plasticity" (the nearest
analogue to free will a molecular geneticist will recognise) can be both vastly extended
to enhance personal autonomy and, no less importantly, constrained where it's
cruel and unwanted. Thus better designed gene-and-drug combinations can perpetuate
truly sublime modes of consciousness whereas, conversely, a predisposition to
such ancient Darwinian horrors as sociopathy or suicidality can be genetically
cured. A rewritten genome can potentially liberate us from all trace of psychopathy
and depression - the enemy from without and, all too often, the enemy within.
When taken today, MDMA rapidly banishes the horrors of both. Alas they soon return;
the acute effects of MDMA are mostly all too reversible. Prediction is always a hazardous
business, but to our descendants, breeding kids with anything like our own corrupt
code may seem like wanton child abuse.
the human genome offers the promise of lifelong emotional health via somatic or
germline therapy. Such well-being may be modulated at will via entactogens-empathogens
akin to MDMA; by entheogens, psychedelics,
nootropics; or agents from categories
currently too exotic to imagine. Or alternatively, our descendants may opt to
abandon psychotropic drugs as pollutants of their genetically-enriched minds.
The biotechnology revolution
throws up darker scenarios too. The spectre of biowarfare, bioterrorism, and perhaps
totalitarian state control over our reproductive decisions tends to loom larger
in the contemporary imagination than utopian visions of boundless love and joy.
Clearly genetic engineering and designer-drugs, like the printing press, can be
put to unethical use. Nightmarish
dystopias make spine-chilling science-fiction and, maybe more plausibly, better
futurology than wide-eyed technophilia. The near future may indeed be bleak.
Those of us who aren't morbidly interested in pain and suffering probably underestimate
how dreadful primordial Darwinian life can be at its worst. Some mental and physical
torment is so bad its victims would snuff out the whole world to end it. Disturbingly,
the sense in which its victims could be deluded in evaluating its dreadfulness
Yet human nature
as encoded in our DNA isn't immutable. Mankind's barbaric track-record to date
is an unreliable guide to our post-human future. If Homo sapiens' nastier alleles
and their more sinister combinations can be silenced or edited out of the genome,
and new improved code-sequences inserted instead, then the pessimists will be
confounded. A major discontinuity in the development of intelligent life lies ahead. Providentially,
we've learned that the DNA-driven world isn't written in God-given
proprietary code it would be hubris to tamper with, but in bug-ridden open source
amenable to improvement.
Given our current design-limitations, any planning for a post-human population
endowed with invincible mental health sounds ambitious in scope if not messianic
in spirit. Even granted that paradise-engineering
is technically feasible, the abolitionist
project still amounts, by today's lights, to a breathtakingly bold strategic move
for our species. It may never happen. Most philosophers assume that suffering
will endure as long as life itself. Only the horrific, purposeless cruelty of
a living world evolved by natural selection makes an abolitionist agenda of "unnatural"
selection so morally urgent. That said, any mental health plan aimed at underwriting
lifelong emotional well-being for the world's population no more entails developing
a millenarian blueprint for a post-human Utopia, or prophesying the imminent End
Of History à la Francis Fukuyama, than the still radically incomplete
conquest of "physical" pain dictates specifying the particular kinds of pain-free
lives we should all lead. The lifestyle options following success in either case
are effectively limitless. Thus any fleshed-out examples of possible post-Darwinian forms of
life are purely illustrative. If mental superhealth does become the societal norm, then
gradients of genetically predestined bodily and emotional well-being can constitute
the presupposed backdrop to the diversity of everyday life, not its focus.
Gradients of lifelong happiness can enrich
our autobiographical narratives, not supplant them. Ecstasy needn't be orgasmic;
though it can be.
today, scenarios of a post-Darwinian era of lifelong bliss demand a greater effort
of imagination than the possibility of lives spent "merely" without "physical"
suffering. The futuristic scenarios feel "unreal". The prospect of lifelong happiness strikes
us as far more utopian in conception than the prospect of lifelong bodily health.
Yet in both cases, gradients of well-being can play a role informationally analogous
to their nastier Darwinian counterparts while shorn of their unpleasant (and sometimes
harrowing) subjective textures. Assuming here without argument a functionalist
model of computational mind, what's indispensable to intelligence in the broadest
sense of the term are the triple processes of information, computation and feedback. The "raw
feels" of unpleasantness are neither necessary nor sufficient for intellectual
progress. Thus our silicon robots don't suffer anguish, even when we recode their
"affect programs"; and it seems they're getting smarter
a lot faster than we are.
The existence of lives animated by gradients of well-being should be distinguished
from lives spent in a state of uniform well-being. Chronic heavenly bliss,
like chronic pain and despair, is a condition that's technically possible
to implement in the vertebrate CNS. For good or ill, such uniformity would be
a recipe for stasis. The intra-cranially self-stimulating rat or monkey - or human
wirehead - isn't going
anywhere. By contrast, if a predisposition to gradients of ecstatic well-being
is ever genetically encoded as our default mood-spectrum, then critical discernment
can be functionally retained, and self-motivation enhanced, without sacrificing
the humane ethic of a cruelty-free
world. This conjecture isn't idle. Some bioethicists
would argue a world without suffering is the precondition for any civilised society.
Plausible or not, the lack of any inevitable tradeoff between happiness
and critical insight undercuts one ideological obstacle to global mood-enrichment.
Predicting the dial-settings
on the emotional thermostats of our descendants is unavoidably speculative. But
if (very controversially) post-Darwinian humans will innately feel superwell,
albeit in varying degree, precisely what modes might their genetically enhanced
and perhaps pharmacologically modulated well-being most plausibly take? Will such well-being
be the egoistic happiness of amoral, emotionally self-reliant ubermenschen?
Or could being loved-up on Ecstasy, or perhaps long-acting brands of entactogen-empathogen
cleaner and safer than MDMA, offer a better model of social life in centuries
This sort of crystal-ball
gazing clearly demands scepticism as well as a lively imagination. As Dr Shulgin
reminds us elsewhere, any
prediction is hopelessly entangled with the wishes of the predictor. Such bias
might seem to defeat the enterprise from the start. Fortunately (or otherwise),
however, some scientific prophecies can become self-fulfilling if ever their makers acquire
the power to implement them. In this instance, technically at least, Homo
sapiens will soon have the collective scientific expertise to redesign our
own nature. So if we ever aspire to enjoy, say, lifelong ecstasy for our minds
and bodies, then we can have it. If we're so minded, then apes can become angels.
The ultimate stumbling-block, if there is one, will be traditional Darwinian-era
ideologies, not scientific ignorance of how to redesign the molecular machinery
of emotion. For sure, the vision of a whole civilisation, and not just an all-weekend
rave, founded on the neural substrates of an E-like "Peace, Love, Understanding
and Respect" sounds sociologically naïve and (socio-)biologically impossible.
Stated so bluntly, the loved-up edition of scientific utopianism is perhaps the
most implausible (and unreadable) premise for a sci-fi novel one can imagine.
The non-specific prediction of genetically preprogrammed well-being for
our descendants is contentious enough as it stands. Any more detailed explorations
of the possibility that such enriched well-being might be, say, E-like rather
than egoistic are therefore hugely more speculative; and quite probably
mistaken. But for the following reasons, a civilization based on relationships
of, say, mutual loving empathy and intensified E-like consciousness is not impossible,
just far-fetched. At a minimum, it's worth sketching out an extended family of
E-like scenarios as a corrective to a routine but unargued assumption that underlies
rival predictions. This assumption is that societies based on the behavioural
genetics of primate-style dominance-and-submission hierarchies will endure indefinitely.
Thankfully, both the reproductive biology and mode of selection pressure at work
in the new era of genomic medicine will be different from the evolutionary past. Our genetic programming
will no longer be "blind", even if its early (re-)programmers will be only partially
sighted. Varieties of (post-)human genotype won't just be quasi-randomly generated
via sex, genetic crossing-over and mutation. Instead, genotypes will be purposely (re)designed
- even if the early designers barely know the ramifications of what they'll be
For we're presently
on the brink of the era of "unnatural" selection. Throughout the living world,
a regime of blind natural selection acting on effectively random mutations has governed the
evolution of information-bearing self-replicators since the origin of life itself.
The Darwinian Era has lasted for over four billion years. Most recently, in the
aftermath of the post-Cambrian explosion of multicellular animal life and the
evolution of central nervous systems, selection pressure has created suffering
beyond belief. Mercifully, a regime change is imminent. Within a few centuries
at most, intelligent life will be able to rewrite the vertebrate genome and redesign
the planetary ecosystem. Sooner
still, if we want our genetically enriched (grand-)children to be happy,
then in the impending reproductive era of preplanned designer babies we will also
have to choose - either actively or by default - whether the kinds of heritable
well-being our offspring enjoy will tend to be solipsistic or social, orgasmic
or intellectual, hypomanic or serene, loving or self-centred, or perhaps ultimately
take forms that can't be grasped by the contemporary Darwinian mind. Whatever
criteria are used, an increasing range of genotypes will soon be chosen in deliberate
anticipation of their phenotypical effects. Needless to say, no such calculated
sets of genetic decisions can be taken by prospective breeding couples at present.
"Genetic choice" in the early 21st century usually means nothing more ambitious than choosing the gender
of one's child, often in less than ideal circumstances. Yet as the human genome
is deciphered, and eventually the "transcriptome"
and proteome beyond,
a staggering extension of freedom of choice will be thrust upon us. As wiring
up the neural reward centres with microelectrodes shows, the practicalities of
inducing - and then sustaining - the neural substrates of bliss are technically
quite easy. Viewed as an engineering problem, no one needs to suffer; suffering is an unnecessary evil. This is true even
with today's embarrassingly clumsy interventions. Modulating
bliss in controllable ways is trickier - whether by drugs, microelectrodes
or gene-therapy. Short-term technical snags aside, our state-space of life-enriching
options is poised rapidly to expand. Of course even with utopian biotechnology
and mature nanotechnology, constraints
won't be absent. The menu of practical choices on offer to our enriched descendants
isn't entirely limitless. For instance, decades spent in unceasing, paroxysmal
super-orgasms, or perhaps
immersion in fantasy wish-fulfilment in virtual
reality software, may well be viable lifestyle options one day for individuals.
They are technically feasible to implement. Yet it's hard to imagine parents wanting
such modes of existence for their kids, or to devise evolutionary game-theoretic
models where the prevalence of genotypes that permit such lifestyles could be
globally stable. In any post-Darwinian
reproductive era ahead, "unnatural" selection pressure will still be at work,
at least until the abolition of senescence
brings the throwaway era of traditional DNA mortals to a close. Thus any currently
foreseeable civilisation will be social in character, not quasi-solipsistic. If
so, then one urgent challenge will be to make our social interactions less emotionally
costly. Today, for a few hours, MDMA offers perhaps the richest chemical tool
for social intimacy in existence. If nothing else, the MDMA experience demolishes
the conventional wisdom that "artificially"-induced happiness must be amoral and
selfish - hedonistic, one-dimensional and shallow. More generally, the
sense of heightened authenticity, love and self-insight induced by entactogen-empathogens
will no longer seem an escapist holiday from Real Life when entactogenic-empathogenic
states can be sustained indefinitely - whether by gene-therapies or soul-medicines
or varieties of both. In theory, at least, mental superhealth can become the new
benchmark of consensus-reality against which any departures are defined, not
drug-induced psychotic episodes.
safe to say MDMA itself isn't going to change the world. Yet as a taster of what's
feasible in post-prohibitionist
culture and a possible genetically-enriched future beyond, the MDMA experience
shows social life at its best. MDMA promotes a more altruistic mode of consciousness
than has maybe ever existed on the planet, certainly among testosterone-driven
young males. On MDMA, one can love thy neighbour as thyself; and the lion can
lie down with the lamb. Feelings of
hostility, bigotry and intolerance evaporate. Competitiveness is replaced by love,
tolerance and respect. Such social harmony seems "unnatural" if not miraculous
when viewed from the poisonous miasma of mainstream society. For outside the embraces
of loved-up ecstatics, we tend to pay a terrible price for the benefits of group
living. The costs of social existence are attested by the grisly chronicles of
human history, Gibbon's "register of the crimes, follies, and misfortunes of mankind".
It's not as though we have much choice about living together. Even in the absence
of MDMA, human beings are still compulsively sociable. This compulsion to socialise
is generally seen as healthy rather than dangerously addictive, despite the traumas
it brings. In abnormal conditions of social isolation, the personality starts
to deteriorate: solitary isolation, whether real or figurative, is rightly viewed
as a cruel and unusual punishment. Our genes, via the reward pathways and the
neural projections they code, make us chronically hooked on the company of others.
Our very identities are bound up with our social roles. We are physiologically
dependent on the opioidergic,
and serotonergic mechanisms that friends, family and colleagues may trigger within
At its best, this chronic
dependence on human company gives short-term highs and even warm afterglows. But
dependency, craving, and withdrawal-reactions are common when significant others
are taken away from us or adulterated. Purity varies; supply is erratic; and adverse
reactions are common. Cue-elicited craving readily triggers relapse. Our sociability
can spin out of control into a financially ruinous habit. We spend lots of time
and effort thinking about how to get more of whoever stimulates our mesolimbic
reward circuitry most vigorously, possibly romanticised under more poetic descriptions.
Without friends, lovers or family, most people tend to become lonely, sometimes
agonisingly so. In extreme cases, loneliness and lovesickness can induce suicidal
despair. Bereavement and abandonment can be as traumatic as heroin-withdrawal;
and they share similar neural substrates.
given a Darwinian genome the compulsion to socialise is all too often a dangerous,
self-destructive addiction. Living without Ecstasy, we are predisposed by our
genes to conflict with each other: mothers and children, men and women, brothers
and sisters, friends and relatives - all have different and often conflicting
genetic interests. Only monozygotic ("identical") twins may hope to be spared
this insidious rivalry. Camouflaged genetic conflict underlies our disposition to squabble
and fight amongst ourselves, even though we compulsively need each other's company
too. Thus testosterone-driven males find themselves enacting decades-long competitive
rituals to attract and retain genetically superior mates. Competitive status-seeking
in its subtle - and not-so-subtle - guises is a cross-cultural universal, deeply
rooted in our biology. Conflict to the point of warfare is genetically predisposed
in our make-up. It's endemic to human society. Right from conception and the implantation
of the conceptus in the womb, genetically-driven conflict
plays itself out, often leading to trauma (e.g. preeclampsia etc.) for mother
and unborn child alike. Later on, even the noblest of human sentiments are fragile.
Love all too easily turns into hatred, admiration into contempt. By way of illustration,
consider, say, proverbial "lover's quarrels". There are innumerable "proximate"
explanations of why star-crossed lovers often argue so painfully and vehemently.
But the "ultimate" evolutionary explanation seems to be, at least in part, that
tempestuous rowing and its consequences serve as a brutal but effective way for
prospective breeding couples to test each other out. Evolutionary psychology suggests
that, from a gene's eye view, it's better to discover if a prospective partner
will let you down sooner, when (s)he's goaded under conditions of stress, rather
than later after you've sunk a substantial investment of time and resources in
the partnership. Arguing can be traumatic; but the capacity to do so is [genetically]
can bring psychological rewards too. Anyone having fun right now would find this drumbeat
of misery, heartache and emotional squalor all a bit overblown. Yet if anything
the nastiness alluded to here is understated; the worst pains in life are inexpressible. Under
the genetic status quo, most of us are condemned at different stages of
a lifetime to re-enact the messy - and sometimes desperately sad - personal dramas
of our ancestral past. TV soap-operas and teledramas serve to sanitise just how
emotionally unpleasant Darwinian life can be. For as human generation succeeds human generation,
we replay the age-old sagas of sexual betrayal, jealousy, loneliness, and rejection.
We are forced to endure the savage competition of lookism - an inadequate, frivolous
term for a cruel and omnipresent phenomenon in human society. Less colourfully,
a multitude of pettier but still wounding frustrations, humiliations and misunderstandings
can mar daily social life and sour personal relationships.
genetic rot goes deeper. Evolutionary psychiatry suggests that the cross-culturally
ubiquitous phenomenon of depression,
and the wider spectrum of depressive and dysthymic
disorders, is not a genetically dysfunctional anomaly. Counter-intuitively, a
conditionally activated tendency to depression may represent a fitness-enhancing
adaptation to group living.
The (involuntary) capacity for depression is one of a number of ancient, genetically
adaptive mechanisms and strategies for dealing with "social
defeat" in a tribal environment. Group living conferred advantages on otherwise
vulnerable individual primates on the African savannah. Embracing tribal life
forms a valuable defence for a puny "naked ape" against big predators. But thanks
to the pressure of sexual selection, human tribal society imposes a cruel pecking-order
of subordination relationships among members of the tribe. For sure, depression has many
proximate causes; there are many subtypes of depression; and not all depressive
moods and behaviours are genetically adaptive. Yet viewed in evolutionary perspective,
a syndrome of sustained melancholy, behavioural suppression, and a preoccupation
with personal failure and inadequacy is the internalised correlate of the yielding
or "losing" behavioural sub-routine. On this "rank theory" hypothesis, the involuntary activation
of submissive and depressive states is an unpleasant but effective defence-mechanism
for weaker individuals where any tendency to initiate or escalate conflict with
a powerful dominant rival might easily be disastrous. Thus states of depression
or low mood ensure the weak "keep their heads down" and don't overreach themselves.
By contrast, the (hypo-)manic
spectrum of mood and behaviour is a manifestation of the "winning subroutine".
Clearly, not all submissive people are unhappy, and not all dominant and/or aggressive
people are (hypo-)manic. So there are complications to the hypothesis and a legion
of exceptions. A capacity to switch mode can sometimes be adaptive too; hence
the probable evolutionary origins of bipolarity. Yet down at the bottom of the
social heap, there are proportionately far more crushed and wounded spirits than
there are at the top. Socially dominant Alpha males tend to be temperamentally
expansive and optimistic. Conversely, even life's "winners", if deposed
and defeated, may become depressed themselves, and slink away to die, metaphorically
or otherwise. Depression in human societies is far more prevalent than (hypo-)mania,
albeit far less visible. This greater prevalence probably reflects conditions
in the evolutionary environment of adaptation where the spectrum of depression,
mania and bipolarity first arose. But whatever the ultimate evolutionary roots
of mood variation and affective disorders as interpreted by rank theorists, contemporary
humans in all known societies are obsessively status-conscious. Status-competition
corrupts personal relationships in societies stratified by caste, class and money
alike. Even apparent counter-examples don't challenge the generalisation. Thus
societies based around the potlatch, the Pacific Coast Native American custom
of conspicuous gift-giving rather than wealth-accumulation, reflect
a disguised expression of competitive power relationships. Indeed the tradition
of rival displays of gift-giving finds echoes today in the competition between
billionaire American plutocrats to endow the biggest charitable trust foundations.
The poison of competitive
status-seeking might seem incurable. ["If everybody is somebody, then nobody
is anybody"; "It's not enough to succeed. Others must fail"] Yet short-term
symptomatic relief for this syndrome already exists; and its long-acting analogues
may one day offer complete remission. Taken communally, MDMA induces an almost
miraculous transformation in the structure and relationships of any social group.
At MDMA-animated raves, no one who's loved-up is trying to "diss" anyone else. MDMA
abolishes the desire to put anyone down. On MDMA, primate dominance hierarchies
dissolve in an egalitarian love-in. A lifetime's inferiority-feelings,
snobberies, and status-anxieties dissipate in a flood of augmented serotonin and
dopamine release. Intriguingly, the euphoria experienced by MDMA users doesn't
take the form of uncontrolled manic excitement, even where the drug induces "behavioural
activation". MDMA's indirect, serotonin-mediated
enhanced dopamine-release produces psychostimulant, emotional and perceptual effects
that feel very different from crude dopamine-releasing amphetamine. Even the most
animated ravers taking pure MDMA tend to experience a profound sense of inner
calm, a "peace that passeth all understanding". Identifying the neurochemical signature of states combining inward serenity
and outer dynamism presents a wonderful therapeutic opportunity. The contrast
between raves packed with loved-up clubbers on hugdrugs and parties fuelled by
alcohol or cocaine is striking.
Back in the harsh, E-less world, inferior social status is associated with low serotonin
function and low mood. Thus dominant males tend to have far higher serotonin function,
as measured by CSF 5-HIAA levels, than subordinate males. The neurological basis
of social rank order can be investigated by various manipulations. Experimentally
boosting or depleting the serotonin levels of social animals enhances or sabotages
an individual's place in the pecking-order. Revealingly, there are also gender
differences in serotonin activity. The mean rate of serotonin
synthesis in men is over 50% higher than the mean rate of serotonin synthesis
in women. Women are more sensitive than men to both the MDMA magic and MDMA's
adverse side-effects. Women are also more likely to suffer from the post-E serotonin
dip; more prone to depression; and more likely to benefit from Prozac. Yet such
comparisons are invidious. Men and women alike of any social status at all can
flourish far better in E-like states - while they last. Unfortunately, communal
E-like consciousness simply isn't sustainable via chronic MDMA use. In wider E-less
society, "winners" probably don't do [serotonin-depleting] drugs, though idealistic
E-users might suggest that zero-sum status-games are best not played at all. For
better or worse, a heavy, serotonin-depleting E-regimen can disrupt the user's
social status in the competitive urban jungle - and probably elsewhere. Admittedly,
there are too many confounding variables to test this hypothesis in methodologically
rigorous studies on humans. Even so, a proposed "E-users are losers" research
proposal is more likely to gain official funding than a well-controlled trial
of, say, the health benefits of MDMA-assisted psychotherapy.
course the aspiration for a civilisation founded on relationships of shared love
and respect sounds impossibly idealistic. A society based on "winners" and "losers"
intuitively strikes us as natural. With today's genes and the kinds of culture
they promote, adversarial social relationships are probably inevitable. Like depression,
the evolutionary roots of everyday sociopathy run deep. For speculatively, applying
here Richard Dawkins' "extended
phenotype" theory, not merely has it been genetically adaptive for weaker social
primates to have an inbuilt conditionally-activated capacity for depression, it
can also be genetically adaptive for Alpha males (and aspiring Alpha males) to
subdue potential rivals by making them depressed too. Perennially chastened,
socially anxious and chronically depressive potential competitors are less likely
to be sexually active and promiscuous. Crushed, anhedonic and submissive, they
are less of a challenge to the inclusive fitness of one's genes. Happy, dominant,
extroverted males, by contrast, are potential sexual rivals who directly or indirectly threaten one's
reproductive success. Thus we witness their downfall with equanimity. Even within
the bounds of holy wedlock, too much happiness for one's nearest and dearest doesn't
always suit one's genetic interests. A cowed and depressive wife, whose only solace
in life is looking after the kids, can be less threatening to one's genetic prospects
than an exuberant, sociable and possibly sexually adventurous bundle of joy. If
we are looking for an evolutionary perspective on why we often behave so vilely
to each other - sometimes seemingly gratuitously so - then this kind of sexual
selection pressure offers one possible explanatory framework. If it is adaptive
to have others exhibit a spectrum of behaviour characteristic of low mood or high
social anxiety, then other things being equal, alleles and allelic combinations
may flourish if they conditionally promote the capacity to induce such anxiety
and depression whether in strangers or tribe members who aren't allies or close
kin - and if occasion demands, even in those who are both. Depending on a lot
of other factors too, the (behavioural effects of the) happiness of others, male
or female alike, can indirectly detract from our own Darwinian fitness. Consequently
their perceived happiness doesn't tend to give us as much joy as moralists might
wish. Sad to say, reports of good fortune befalling our fellows do not always
inspire a warm glow of vicarious satisfaction. On the contrary, news of another
person's lottery-win, for instance, or its traditional counterpart on the African savannah,
is liable to trigger involuntary feelings of jealousy and resentment, or at best
an envious ambivalence. Of course, it's worth stressing that natural/sexual selection
doesn't care about the subjective textures of misery or happiness per se.
Selection pressure works on the spectrum of behaviour such mood traits engender.
What was selected for [as distinct from adventitiously selected] in the
ancestral environment of adaptation wasn't the capacity to make others feel miserable
as distinct from behave miserably. To selfish DNA, our suffering itself is incidental.
The distinction, however, is of limited comfort to its victims.
Fortunately we're not systematically spiteful, even though we're not naturally
loved-up. If human malice were really genetically hardwired, then any nostrums for
social reform, life-enriching lovedrugs or improving the vertebrate genome would
be futile. Thankfully, a malignant streak of human nastiness is matched by a
common if ineffectual desire to improve ourselves and help others. This good-will
just needs genetic and pharmacological amplification.
granting human beings no more than a minimal and diffuse benevolence, what can
be done to make us temperamentally nicer to each other as well as happier and
smarter? Would we individually
and collectively be better off if perpetually loved-up on more advanced and sustainable
analogues of E? Or are loved-up ecstatics just too vulnerable to genetic invasion
by "defectors" and wolves in sheep's clothing for such genes or allelic combinations
to flourish? Vulnerability to predatory and Machiavellian genetic rivals is presumably
the reason why sweetheart suckers living in blissfully E-like states are thin
on the ground in the drug-free Darwinian world. What reasons are there, if any,
for predicting that the nature of adaptive traits in the era of genetic engineering
will change in ways that make beautiful minds more widespread?
If genetic engineering or rational drug design are to deliver us from the Darwinian
rat-race into everyday states of ecstatic grace, or anything at all like it, then
there are short-term and wider evolutionary constraints to be overcome. Truly
far-sighted genetic re-programming is a formidable challenge. Some genetic manipulations
may involve computing the interactions between dozens or ultimately hundreds of
alleles. Often their contributions to mental and behavioural traits won't be additive
but dependent on a plethora of environmental contingencies. This Problem of Conditional
Activation threatens a combinatorial explosion of possibilities to calculate.
It presents a daunting task of prediction and control. Other interventions, however,
might seem (comparatively) more straightforward. For instance, the action of testosterone,
and its hormonally active dihydrotestosterone metabolite, is in large part responsible
for war, social violence and competitive dominance behaviour, territoriality, sexual aggression, reduced male life-expectancy,
and going bald. The genetic and/or pharmacological manipulation of testosterone
may play a vital role in undercutting the darker horror scenarios for the future
so popular in the science-fictional literature.
Yet first there are many problems to be resolved here too. Testosterone can't,
realistically, just be edited out of the genome, as distinct from edited and re-regulated.
The eradication of testosterone would indeed spell a world without war. But androgenic
hormones can't be deleted altogether, even if the option of rearing functionally
emasculated or chemically castrated offspring were an idea palatable to prospective
parents, an unlikely prospect right now. Testosterone is the stereotypical "male
hormone". Yet testosterone is present in women too, albeit in smaller amounts:
it's important to female sexual
response, just as it's responsible for spontaneous nocturnal erections in males.
Testosterone plays a role in female bone-strength, muscle-mass and a general sense
of well-being. Moreover,
expository convenience aside, androgenic hormones are no more intrinsically evil
than the MDMA molecule is intrinsically good. Thus testosterone promotes what
might be described as "strong-mindedness". Today the trait of strong-mindedness
fosters what's often little more than callousness in pursuit of unworthy ends.
But not always. Even in a mature post-Darwinian civilisation, most of us may well
prefer to cultivate "strong personalities". The popularity of performance-enhancing
anabolic steroids with
athletes and bodybuilders stems only in part from the way such drugs enhance strength,
power, speed, endurance and muscle-mass. For anabolic steroids are popular because
they can also act as mood-elevating, mind-toughening personality-pills. Taking
anabolic steroids induces a sense of well-being sometimes amounting to euphoria,
an increased tolerance of stress, and a sense of competitive "edge". The price
of using such drugs can be hypermasculine aggressiveness ["roid rage"], increased
dominance behaviour and even a propensity to sexual violence. Normal endogenous
male production of their native anabolic counterparts is risky enough already.
If our species is to survive its newfound capacity to build weapons of mass-destruction,
and tackle the genetic origins of male violence and all-round nastiness, then
we must somehow curb the biological roots of masculine aggression. This particular
intervention strikes us as a disconcerting prospect. Darwinian sexual and gender
identities are central to social existence today, and usually integral to who
we think we are. However, the long-term role of the Y chromosome in the evolution
of intelligent life is uncertain; and the ethical value of testosterone-driven
masculinity is unproven at best. The phenomenon of sexual reproduction itself
has only persisted and evolved as a defence against parasitism; an additional
mechanism that promotes genetic variability is a powerful weapon in the evolutionary
arms race against pathogens. In the new reproductive era ahead, however, genetic
diversity can be intelligently pre-planned. So at the very least, enlightened
biomedicine should be able to edit out a predisposition to the more sociopathic
forms of masculinity from the genome. More far-reaching strategies can be contemplated
too. On the other hand, recalling H.G. Wells' The Time Machine (1898),
we don't want to turn into enfeebled and weak-minded Eloi, even if we live in
a world without Moorlocks. It's good to wake up each morning feeling ready to
take on the world and win, even if we eventually discover that the rest of the
world is on our side; and some day it may be conspiring to help us.
the world generally isn't on our side. Low testosterone function is associated
with social defeat, passivity and subordination. Low testosterone levels are also
implicated in depressed mood. The syndrome of depression has both proximate and
evolutionary roots. Depression is popularly viewed as a sign of weakness; and
folk-wisdom is right. Such a perception leads to its systematic underreporting,
especially among males, thereby painting a falsely rosy picture of (male) mental
health. Depressive illness is reported to be twice as common among women as men.
Conversely, it's sexy for men to be cool, confident and 'sussed' - the sort of
personality often faked if you aren't, though for evolutionary reasons depressives
find it harder to bluff. Therapists and sensitive physicians may take determined
steps to reassure their clients that depression
isn't a sign of weakness. Alas this assurance typically isn't true. Depressives
characteristically tire quickly, act ineffectually and give up too easily. Potential
new antidepressants are correspondingly tested for their capacity to reverse the
learned helplessness and behavioural despair induced by chronically "stressing"
[torturing] non-humans in "animal models". Whereas exuberant hypomania is a signal
of strength and resolve, albeit a risky signal, depressives can't pursue their
projects with fanaticism, nor can they work indomitably to pursue what they believe
to be morally right. For their capacity to anticipate reward is blunted. Life
for depressed people too easily seems meaningless,
absurd and pointless - the nihilistic polar opposite to a hyperdopaminergic sense
of urgency and significance. For the mesocorticolimbic dopamine system mediates
not just the salience and intensity of anticipated
reward; it also determines strength
of will. By contrast, the spirit of depressives is easily broken; and there's
no natural remedy for weakness of will.
grim diagnosis isn't a counsel of despair. On the contrary: well-designed genetic
and pharmacological interventions should in principle allow weaker spirits to
be invigorated and frailer personalities empowered. With better drugs and better
genes, one's idealised persona can be made flesh. We'll soon have the option of
making ourselves stronger, better-motivated
and more steely-minded in character than even the bravest palaeo-Darwinian primitive
or Nietzschean ubermensch. It's an open question whether such strength
of character will be egoistic or empathetic, cocaine-like or E-like, or something
different altogether. Yet with the right gene-and-drug combos, we can be superheroes,
even if the need for heroism may shortly pass. In the meantime, innovative pharmacotherapy
and/or genetic medicine will be vital if the weak-mindedness and weak willpower
blighting so many lives today is to be overcome.
takes many forms. One effect of administering MDMA is the way it eliminates jealousy.
Even anti-abolitionists, normally so
eager to hymn the character-building virtues of suffering stoically borne, rarely
find many positive words to say about the ennobling attributes of the green-eyed
monster. Jealousy is a persistently nasty, vicious, and pervasive feature of Darwinian
human social relationships. It's also about as voluntary as sneezing; and far
harder to cure. Like MDMA, SSRIs
tend to diminish jealousy. SSRIs also act more sustainably than short-acting clubdrugs.
But SSRIs also tend to diminish the intensity of being in love. On MDMA, by contrast,
people of either sex can and frequently do spontaneously embrace and caress each
other - complete strangers as well as intimate friends. On MDMA, everyone naturally
tends to love each other, almost as if we were clones
rather than genetic rivals.
behavioural effects present a bizarre and perhaps disturbing spectacle to the
E-less Darwinian outsider. Yet the lessons to be drawn from the use of today's
crude hugdrugs and lovedrugs extend far wider than the recipe for a good weekend
out clubbing. One way to put the world to rights invokes the tired nostrums of
socio-economic and political reform. Such social engineering hasn't proven effective
at curbing the frightfulness of life to date. Pursued in a biological vacuum,
so to speak, any kind of environmental approach to building a world without cruelty,
fear and pain is bound to fail.
The other, biologically based strategy for saving the world will involve treating
our, say, congenital androgenic, serotonergic, opioidergic,
dopaminergic, PEA and endocannabinoid
dysfunction via gene-therapy and rationally designed pharmaceuticals. Critically,
it entails choosing kinder
genotypes for our offspring. This option doesn't amount to a very soul-stirring
prospect. Like our notions of psychoactive drugs, the concept of "eugenics" is
horribly tainted. The word itself, originally a coinage of Sir Francis Galton
(1822-1911), is indelibly tarred with the pseudoscientific quackery of the Third
Reich - though it's worth recalling that Nazi "race-hygienists"
didn't use happiness as their touchstone of genetic excellence. Yet the lethal
dangers posed by the genetic status quo coupled with advanced military
technology are far greater than the risks of a genetic reform program predicated
on the goal of world-wide personal happiness. Warnings from history aside, unless
the Darwinian masculine identities of our evolutionary past are superseded, then
jealousy, conflict and warfare will go on for ever (or kill us off); and the prophets
of doom will be right.
Ecstasy itself is something of a false prophet. MDMA-induced love is no more everlasting
than its older and fitness-enhancing counterpart. Two days after taking the magic
lovepill(s), the drug-catalysed outpouring of affection has subsided. "Natural"
love sometimes lasts longer; but Darwinian love is still ephemeral, eventually
killed off by receptor desensitisation and down-regulation no less effectively
than E-induced love is ended by serotonin depletion. For the fickleness of Darwinian
affection has hitherto been genetically adaptive. It's an adaptation that remains
a shabby substitute for genetically-underwritten true love. Only by subverting
some exceedingly cruel feedback-inhibition mechanisms can the depth and range
of our affection for each other be enriched and sustained. As it is, most Darwinian
social life is soulless and loveless. But our genes do allow their vehicles to
fall in and out of love with a small percentage of prospective mates in ways that
tend to serve our reproductive success. In a largely anonymous mass-society, love
and affection are in even shorter supply than among tribal hominids in African
prehistory. Where love does sporadically flicker or flare up among us, its expression
is tightly regulated. E-less love is rarely all-embracing: such Darwinian love
tends to be jealous, possessive and exclusive. The law and social sanction impose
penalties for loving too much or too little, loving the wrong person at the wrong
age or the wrong gender. "He who is rational about love is incapable of it"; but
this isn't true in the eyes of the law or of our peers.
MDMA-driven raves, by contrast, women can feel safe in public, gay people feel
truly at ease, and sexually straight or bisexual clubbers can express love and
affection for each other free from overt or internalised homophobia. Taboos on
touching and the whole gamut of tactile experience are relaxed. The body no longer
feels like a prison for the soul but an extension of it. The classic dopaminergic
psychostimulants like cocaine promote a hard-edged, don't-touch-me egoism. MDMA
promotes intimacy, warmth, and an empathetic sense of other humans beings as fellow
subjects rather than objects.
course, after a weekend of being "loved-up", mood-congruent post-E "reality" soon
sets in. Did one really let slip those gushing effusions to strangers one barely
knew? Did one really hug that hateful brute of a rival for the affections of one's
heart's desire? Viewed from [state-dependent] "reality" again a few days later,
being nice to everyone, truly loving oneself, and feeling (and being) wonderful
all seem faintly embarrassing, perhaps even a chemically-fuelled madness. "It
was the just the E talking". One may recall from English literature the effect
of taking soma, the "ideal
pleasure drug" featured in Aldous Huxley's uncannily prescient Brave
New World (1932). After John
the Savage threatens to disrupt their soma supply, the angry low-caste Deltas
riot. They are promptly pacified by the riot police with soma-gas, and the rioters
end up hugging each other:
"Two minutes later the Voice and the
soma vapour had produced their effect. In tears, the Deltas were kissing and hugging
one another - half a dozen twins at a time in a comprehensive embrace. Even Helmholtz
and the Savage were almost crying. A fresh supply of pill-boxes was brought in
from the Bursary; a new distribution was hastily made and, to the sound of the
Voice's richly affectionate, baritone valedictions, the twins dispersed, blubbering
as though their hearts would break. "Good-bye, my dearest, dearest friends, Ford
keep you! Good-bye, my dearest, dearest friends, Ford keep you. Good-bye my dearest,
dearest..." Too far-fetched? In 1998, a former South African
government scientist told a hearing of the Truth Commission that the minority
Apartheid government had planned to use MDMA on rioters. Desperate to retain their
faltering grip on power, the embattled regime apparently ordered its chemists
to make one tonne of Ecstasy for riot-control. Thus the Calgary Herald
(10 June 1998) reports:
"Dr. John Koekemoer, former head of chemical
and biological weapons research, at the secret Delta G facility, said he disapproved,
"I did not believe Ecstasy was a good incapacitant and I told my superiors that",
he told the commission, which is investigating human rights abuses during the
apartheid era. "Ecstasy enhances interpersonal relationships. I told them I did
not want to kiss my enemy." The scary notion of kissing one's
enemies, perhaps half-recalled cameos from Huxley's satirical fiction - and the
reality of strangers of either sex at raves hugging each other on E and telling
each other how wonderful they are - contribute to the perception that E-like states
of blissful empathy are inauthentic, shallow or false. How can the MDMA experience
have true emotional depth if the cosmic hug-bunny of the dance-floor reverts back
at the office next week to his old Darwinian mindset - and the (anti-)social vices
it spawns? A corrosive cynicism easily sets in. For that's the nature of
social reality, an emotionally frazzled post-Ecstatic may reflect, not the magical
interlude of Peace, Love and Understanding and Respect.
in today's world, this may be so. The depressive
realism of the serotonin-depleted and jaded cynicism of the chronically world-weary
are often justified. Yet our descendants may recognize that we are the
sociopathic emotional primitives in the grip of an affective psychosis. Jealousy,
envy, resentment, ridicule, hate, anger, disgust, spite, contempt, schadenfreude
and a whole gamut of nameless but mean-spirited states we undergo each day are
a toxic legacy of our Darwinian past. More commonly, perhaps, our genetic make-up
ensures we simply feel indifference to the plight of all but a handful of significant
others in our lives. Right now, for instance, one knows dimly at some level that
there is frightful and preventable suffering in the world. Yet most of us feel
no overpowering moral urgency to do anything about it. Idealists might vaguely
entertain the second-order desire to care more deeply and give, say, a larger
proportion of one's money to Third World charities dedicated to those who need
the resources more urgently than we do. Yet the biological roots to sustain "saintly"
self-sacrifice just aren't there in most of us. In contrast, taking MDMA can give
rise to a prodigious sense of compassion in even the otherwise morally inert.
Regrettably, such compassion is usually ineffectual; it's too short-lived to do
much good. If and when we understand the neurochemical basis of empathy, however,
then sustaining the molecular substrates of empathetic love can turn boundless
compassion into an automatic reaction to distress, not a sign of drug-induced
psychiatric disorder. Intervention can go further. If we decode and opt to amplify
the molecular machinery of volition too, then such heightened compassion can be
translated into effective action.
compassion if not empathy for others may ultimately be redundant. In the long
run, if biotechnology can be used to eradicate
suffering from the living world, then a shared celebration of life, not sympathy
for the misfortunes of others, may come to seem as natural as breathing. Yet right
now too many people walk the Earth who have no cause to celebrate anything. Therapeutic
agents designed to deepen empathy and sustainably awaken our compassion are a
priority. The functional prototype of what's needed exists today in the form of
a fast-acting hugdrug; but MDMA itself is not the recipe for perpetual sainthood.
The design of richer functional
analogues of MDMA entails more than finding medicines to make us sweeter-natured.
Improving human nature is perhaps ethically all-important, but MDMA is also an
entactogen - a more elusive concept than that of an empathogen. MDMA offers "insight
without fear" (Dr Shulgin). The nature of entactogenesis is far harder to fathom,
let alone communicate, than the nature of empathy. The word for such states comes
close to being a primitive term, its sense semantically inaccessible to the MDMA-naïve.
The clarity of MDMA-mediated self-insight is perhaps a form of what Dr
Charles Tart calls "state-specific knowledge". E-less cynics may be sceptical.
Just what's the propositional content of this so-called "insight"? Couldn't it
be delusive? ["It's not hard to hear voices. It's knowing whether they tell you
the truth."] But on pure MDMA, the subject can inwardly access the kind of person
s/he wants to be; "the ideal me". Whether this idealised self-identity is created
or discovered may be philosophically debatable. But the deeply-felt sense of authenticity
and emotional self-honesty of the MDMA experience is an unexpected delight. One
just won't ever get to read about its nature in the peer-reviewed Journal of
Western culture, a capacity for reflective self-insight is not highly prized.
Introspective genius and a talent for meditation aren't respected in either academia
or business. Nothing in our education system is geared toward making young people
feel that introspective self-analysis, enhanced self-awareness or personal growth
matters in the slightest. How can they be tested, graded and quantified? What's
their market value? Anyone in Western society with a tendency to quiet contemplation
is likely to be stigmatised as lazy, feckless and unenterprising - unlike the
sound and fury of the lionised Man Of Action, and his larger-than-life ego on
whose life-energies lesser mortals may feed. In similar manner, our (limited)
vision of future civilisations tends to focus on their technological marvels -
and the supposed Darwinian dominance-battles of their science-fictional inhabitants
- rather than on odysseys into the inner depths of their souls. Yet the design
of long-acting entactogens - and their neurological analogues - should allow introspective
depth and a capacity for higher-order self-reflection to be fabulously enriched
as well. Tomorrow's counterparts of today's bunch of furtive adolescent introspectionists
won't have to shuffle around faint little tickles of thought for ever. Drugs to
enrich self-insight and heighten self-reflection may eventually become commonplace.
They may be distributed as freely as aspirin if not smarties; and prove safer
in excess than either.
prospect is some way off. Full-blooded pharmacological and genetic emancipation
is still decades away. Even so, we are poised to acquire a literally life-transforming
technology - a toolkit for enlightenment powerful enough to implement Heaven-On-Earth
and beyond - yet we balk at the sorts of public health policy decision needed
to accelerate the transition. An enriched conception of mental health is blocked
by entrenched elites who've never sampled what they outlaw - whether designer
genes or utopian pharmacology. In the jaundiced eyes of (most of) the older generation,
Ecstasy and rave-culture are an aberration, not a portent. "Peace, Love, Understanding
and Respect" sounds like a hollow slogan. Today, in the wider world, the words
can't be anything else. Ecstasy itself is too short-acting, unsustainable and
neurotoxic at high doses to form part of anyone's global health plan. But a permanent
distillation of the MDMA magic, if feasible, offers an extraordinary if unorthodox
vision of one post-Darwinian paradise to come.
Beyond MDMA : mental
superhealth?Moore's Law in computing is named after semiconductor engineer
and Intel co-founder Gordon Moore. It states that processing power in computers
doubles every eighteen months or so. Moore's Law has roughly held good since 1965
when it was first propounded. It's a rule-of-thumb about how many transistors
we can cram onto successive generations of chip rather than a fundamental truth
about Nature. Yet the trend it captures seems set to continue, at least until
chip designers run up against the physical constraints of the nanoscale later
next decade, or perhaps until quantum computers allow calculations orders of magnitude
more powerful than today's toys.
the dizzying rate of technical progress that Moore's law quantifies hasn't been
matched by an analogous law of progress for generations of human mental health.
On average, we are probably no happier than our malaise-ridden hominid ancestors.
We aren't noticeably fonder of each other. By way of consolation, we can
take refuge in the pre-scientific notion that happiness is unquantifiable. Yet
if such quasi-objective indices of mental health as suicide rates are anything
to go by, then we would probably be psychologically better off as hunter-gatherers. Over 800,000 people
in the world took their own lives last year. The World Health Organisation (WHO)
estimates that this figure will rise to around 1.5 million by the year 2020. Here
in the UK, suicide is the most common cause of death for men under 35 years old.
Globally, several hundred million people are clinically or "sub-clinically" depressed;
and a spectrum of chronic anxiety disorders
afflicts further hundreds of millions more. Even as we progressively conquer physical
disease as conventionally defined, the toll of psychological distress is still
rising. Admittedly, "mental illness" and "mental health" are value-laden, ideologically
contested terms. Even the new scientific discipline of biological psychiatry is
inescapably culture-bound. Yet "Progress" that doesn't leave us emotionally better off
would seem something of a misnomer.
merely has there been no discernible growth in average mental health to
match the tempo of scientific advance, technophobes claim there never will be such a mental health revolution.
As long as we rely on the same legacy wetware to animate our lives, the neo-Luddites
and religious fundamentalists may even be right. Our levels of well-being - and
ill-being - compute fitness functions that served the inclusive fitness of our
DNA in our ancestral environment in Africa. Our genes didn't design us with the emotional
welfare of their throwaway vehicles in mind. So the genetically adaptive hedonic
treadmill - for many of us better named the dolorous treadmill - ensures that
average levels of well-being/ill-being of Darwinian life remain stagnant. Six
months after winning the national lottery or becoming quadriplegic in a catastrophic
accident, the winner/victim statistically reverts to his or her average level
of ill-being/well-being before the win/trauma. Illustrating the treadmill at its
most extreme, "locked-in syndrome" leaves its victims paralysed.
The subject is fully conscious but unable to move any extremities, talk, or make
horizontal eye movements. Yet in the words of James Hall, longest surviving (2002)
American victim of a midbrain pontine stroke: "In some ways, my stroke was a blessing....Since
my stroke, I've published books, articles, poems. I'm busier and happier than
I've ever been." Completely paralysed, Mr Hall communicates by focusing on particular
letters that his computer picks up from his limited eye-motions.
stories are comforting, up to a point. The downside of emotional homeostasis is
that millions of temperamentally depressive and dysthymic people would feel gloomy
in the Garden of Eden. Again, this hypothesis isn't easy to test rigorously. The
more dramatic manifestations of emotional homeostasis at work are hard to investigate ethically
in well-controlled prospective studies. Anecdotes and impressions aren't science.
Yet the cumulative evidence for a genetically constrained "set-point"
in our pleasure-pain axis is compelling. The dismally low dial-setting doesn't bode
well for any utopian project based around mere social reform.
there is no reason, in principle, why an analogue of Moore's law can't be implemented
in successive generations of the reward circuitry of organic life-forms. The affective,
aesthetic, intellectual, interpersonal (and spiritual?) well-being of neurochemical
robots like us can be genetically pre-coded. If rationally redesigned, our enlightened
successors may view today's "natural" rewards as poor surrogates for genetically underwritten
happiness. When the mechanisms underlying bliss and its gradients are understood,
the molecular machinery of the sublime can be modulated - and amplified indefinitely. Within a
few decades at most, we will be scientifically enlightened enough to redesign the neurochemical
pathways of emotion. Meanwhile our pleasure centres are too small for us to flourish; and their functional
architecture is inefficient. They needn't be either: our normal homeostatic "set-point"
of well-being can be genetically switched up to a far higher plane; and archaic Darwinian
notions of mental "illness" and "wellness" consigned to oblivion. Gradients of
indescribable happiness can potentially animate our lives no less powerfully than gradients
of ill-being. Until this fabulous era dawns, then - to borrow the words of Oscar Wilde - we are all in the gutter, but some of us are looking
at the stars.
gradients of celestial bliss can also be lucid,
serene, entactogenic and empathetic - i.e. MDMA-like and better, not manic or
vulgarly hedonistic. The godlike powers of tomorrow's biotechnologists
will allow the neurological substrates of empathy and self-insight to be permanently
up-regulated. Aesthetically, the mundane ugliness of life in the present epoch can be replaced
by gradations of (to us) unimaginable beauty. Potentially again, an E-like magic
can imbue the texture of normal waking consciousness. If we so wish, our emotional
palette can be genetically enriched, mixed and then pharmacologically refined
in ways that transcend the crude primary colours of our Darwinian past.
yet indispensably for the long-term evolutionary stability of a ecstatic society
post-humans, allelic combinations that promote blissful empathy
can also potentially be fitness-enhancing - in the technical Darwinian as well
as in the popular sense of "fitness". The dawning reproductive era of "designer-babies"
promises to be empowering not least because the capacity for parental love and nurture
can be genetically and pharmacologically enhanced, not just levels of personal
happiness, health and superintelligence.
The age-old scourge of child-neglect (and worse) can be relegated to evolutionary history. Very
speculatively, our future offspring may not merely be more loved by their caregivers,
but much more "loveable" too. For if given the [genetic] freedom to choose, then
parents-to-be may understandably want their offspring to be loving as well as
smart and happy.
of unleashing such parental freedom is disturbing to most of us. Why not leave babymaking,
as before, either to the mysterious workings of Providence or the blind shufflings of
selfish DNA? Yet now we're imminently free to choose, there is nothing self-evidently
morally admirable about playing genetic Russian-roulette with the lifeforms we
create. Many of the nastier behaviours and modes of consciousness that so often
proved fitness-enhancing in the ancestral environment will cease to be adaptive
if the alleles that promote them tend to be shunned by prospective parents intent
on creating the children of their dreams. The "nastier" alleles may well get out-competed.
Selection pressure will tend to favour a very different range of heritable adaptive
traits once evolution is no longer "blind" i.e. when genotypes are parentally
chosen or designed in anticipation of their likely effects on a child's
behavioural phenotype. If we want to, humans can systematically redesign ourselves
and choose the traits of our offspring. The details, for sure, are sketchy. Reproductive
science and genetic engineering are in their infancy. But Homo sapiens is poised to bootstrap its
way out of the cruel Darwinian abyss.
talk of treating humans like organic robots, and then mooting a baseline of mental
health many orders of magnitude richer than the Darwinian mind can contemplate,
sounds fantastical today. In the context of our traditional conceptual framework,
the idea of an analogue of Moore's law for successive generations of human mental
health evokes cloud-cuckoo-land, not a global health-plan. Amid the messiness
of our daily lives, the prospect of using biotechnology to abolish suffering,
and a post-Darwinian transition to paradise-engineering, strikes most of us as
fanciful, its liberatory potential just a mirage. At best, such heady words fall
lifelessly off the page or screen. Yet a major discontinuity - a momentous evolutionary
transition in the development of life on earth - is imminent as the biotechnology
revolution unfolds. The advent of genomic medicine is set to challenge the old
Darwinian regime of natural selection and the emotionally crippled minds it
In the long run,
genomic medicine can underwrite mental and physical superhealth for everyone.
For in principle, lifelong well-being can be genetically hardwired from conception.
In the short run, better-designed research tools and therapeutic agents can probe,
and then repair, our damaged minds. As chemical stopgaps go, MDMA is a magical
revelation. It's perhaps the best aid to insight-oriented psychotherapy ever synthesized.
Tragically, when MDMA is used to excess the outcome can be harmful, not healing. So as a weekend
club drug, MDMA is seriously
flawed. Today, of course, empathogens and entactogens are outlawed for any purpose. The altered states
of consciousness they induce are criminalised. People who take such agents are
stigmatised as "drug abusers". Yet some MDMA users feel, rightly or wrongly, they've
been granted a tantalising glimpse of what true mental health may be like in centuries
to come; and an insight into what the rest of us are missing.
This article was exerpted from: MDMA.net
There is an ecstasy that marks the summit of life, and beyond which life cannot rise. And such is the paradox of living, this ecstasy comes when one is most alive, and it comes as a complete forgetfulness that one is alive.
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