UTOPIAN PHARMACOLOGY

Mental Health in the Third Millennium

MDMA and Beyond









MDMA/Ecstasy





A brief history of MDMA

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 non-human 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.

MDMA's 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.

The 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 (1925 - 2014) 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..."

Later, in 1991, Dr Shulgin and his wife Ann published PiHKAL [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.

By 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.

Inevitably 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.

The DEA 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.

Ecstasy 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".

Soon 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 nutmeg (Myristica 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.

Early 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.





The MDMA Experience

Onset 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 accumbens. Release of oxytocin, the "cuddle hormone", surges too via stimulation of the serotonin 5-HT(1A) receptors.

First-time 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.

MDMA 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-CH 2 -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-methylamphetime (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.

Culture, 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, psilocybin, or 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.

As 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.

When 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 spiritual practitioners 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)"

MDMA 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 to 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 acts to boost 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.

On 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 anxiolytic benzodiazepines, 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 are rare.

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. MBDB's chemical cousin beta-keto-MBDB (bk-MBDB, "Butylone") is a more enjoyable and stimulating empathogen than MBDB. As of 2014, its human use is still extremely limited.

Against 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 tight-lipped.

Functional 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.

MDMA 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.

Sometimes "Ecstasy" doesn't contain MDMA at all, but MDA; MDEA (3,4-methylenedioxyethylamphetamine: "Eve"); 2C-B (4-Bromo-2,5 Dimethoxyphenethylamine: ''Nexus", "Venus", "Bromo"); 2C-I; PMA (paramethoxyamphetamine); amphetamine ("speed"); ephedrine; pseudoephedrine; caffeine; the dissociative anaesthetic ketamine ("Special K"); DXM (dextromethorphan); GHB (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.



MDMA: neurotoxicity

No 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, less stimulating (-)-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 MDMA 2] toxic metabolites of dopamine 3] impaired cellular energetics

MDMA 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; and in 2009 neurotoxic thioether adducts of MDMA were detected in humans. 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 therapeutic benefit. 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.

Not 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.

In 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

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 whom?

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.

MDMA's 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 Shulgin.

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.

Suppression 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 down."

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.

Alas, 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 and alcohol.

Tolerance to 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. Monoamine neurotransmitters, 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.

There 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 (H 2 O 2 ). 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.

One 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 ketanserin (Sulfrexal) can inhibit the syndrome; but they aren't widely available on the street or average dance-floor.

Milder cases 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.

Unfortunately, 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. Until psychopharmacology 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.

A 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.

The 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.

With 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 2014, 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.

However, the biggest long-term obstacles to preventing neurotoxicity and drug-related mental 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 sensorimotor gating 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.

Even 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.

The 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.

In the 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?

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 gear.

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(?), 5-HT2A(?), dopamine 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.

Alternatively, 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.

Alternatively, 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 tianeptine (Stablon); 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.

So what are the prospects for richer, intenser, sustainable insight-and-empathy drugs from MDMA's phenethylamine sisters and cousins?

Post-Shulgin, 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. In general, different monoamine-releasing amphetamine analogues become less subjectively rewarding as their serotonin-releasing potency is increased relative to dopamine-releasing potency.

Whatever 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. The DEA issued an emergency ban on methylone on October 21, 2011. The drug 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. Its empathogenic qualities diminish. Tolerance soon sets in: a sad and familiar story. Likewise, the empathetic euphoriant mephedrone (4-Methylmethcathinone; 2-Methylamino-1-p-tolylpropan-1-one) can be acutely rewarding; but it is a short-acting stimulant whose pharmacokinetics and toxicology are unknown. Alas our knowledge (2014) of its properties comes wholly from user reports rather than peer-reviewed scientific journals.

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 syndrome.

PMMA's reduced 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 Bentham...

"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."





Of 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.

Fortunately 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.

Needless 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.

First, 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, hyperthermia or idiosyncratic reactions to MDMA need to be eliminated and not just minimised. The really nasty stuff - hepatotoxicity, cardiac arrhythmias, hyponatremia-induced 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?

To 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.

Pessimists 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.

In 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?

Pre-treatment 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 a combination of enhanced oxytocin release and the interplay between the serotonergic and dopaminergic systems that underlies MDMA's discriminative stimulus effects/sublime magic.

The 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. Taking MDMA activates the poorly understood sigma(1) receptors, contributing to its locomotor stimulant action. The role of MDMA in activation the cannabinoid CB1 receptors to modulate its rewarding action is poorly understood. MDMA exerts (weak) binding to the alpha-2 adrenergic and histamine H1 receptors; this bi