Lifting the Veil: A Review of the History, Clinical-Usage and
Safety of LSD, Ibogaine and MDMA in a Psychotherapeutic Context

By Christopher D. Lovett
The University of Arizona
Program in Cognition and Neural Systems

Part IV - MDMA

(The voice of Alexander Shulgin): Janice, her son, and I, all three of us, took 120 milligrams of MDMA in the early afternoon, and the son went off by himself. At about the half hour point, the usual "awareness" time, Janice gave no indication of effects, nor were there any changes at the 40 minute nor 50 minute point. A few off-hand comments were offered.

"My throat is dry."

"I'll get you a glass of water." Which I did. It did no good.

"I'm having trouble breathing."

"So, breathe as best you can." I noticed by the reflection in the window where we were, at the back of the house, that she had no difficulty breathing when I wasn't watching her.

We walked up the hill, to an area I had leased out to the condominium builders on the neighboring land for storage of lumber. There were several 'no smoking' signs around as fire warnings.

"Do you think I smoke too much?"

"Do you think you smoke too much?"

"I don't think so."

"Then the answer is: probably not."

It was now an hour into the experiment, and still no acknowledgment of any activity from the MDMA. Then, came the unexpected question, the "off the wall" question.

"Is it all right to be alive?"

"You bet your sweet ass it's all right to be alive! It's grace to be alive!"

That was it. She plunged into the MDMA state, and started running down the hill, calling out that it was all right to be alive. All the greens became living greens and all the sticks and stones became vital sticks and stones. I caught up with her and her face was radiant. She told me some of her personal history which she knew well, and which I knew well, but with which she had never come to peace.

She had come into the world by an unexpected Caesarean section and her mother had died during the delivery. And for fifty years she had lived in the guilt of having had her life given her at the cost of her mother's life. She had been in therapy with her family physician for about three years, largely addressing this problem, and apparently what she needed was the acknowledgment that it was all right to be alive.

I didn't hear from her for a couple of months. When she did call, she volunteered that she still felt very much at peace, and had discontinued her therapy.
[from Shulgin & Shulgin, 1992: pp. 71-72]

3,4-Methylenedioxymethamphetamine (MDMA) is yet another compound with a long and circuitous history as a psychotherapeutic adjunct. MDMA is the N-methylated congener of 3,4-methylenedioxyamphetamine (MDA), a popular street-drug and psychotherapeutic agent of the late 1960s. MDA, also known as the "Hug Drug" or "Mellow Drug of America" within the 1960s counter-culture, has been described as enhancing feelings of well-being, empathy, insight and self-awareness while decreasing levels of anxiety and emotional inhibition (Perrine, 1996). For these effects, MDA has been used during psychotherapy to help facilitate the expression and integration of meaningful, disturbing emotional content that a patient might be chronically experiencing and dwelling upon (e.g., Naranjo, 1973; Stolaroff, 1997; Yensen, et al., 1976). Andrew Weil has also reported an increase in muscular coordination with MDA: "I have also tried things like rock climbing and swimming after taking MDA and again find that my body works in a more coordinated, smoother fashion and that I can do things with it that I usually cannot," (Weil, 1976: pg. 335). Also, in contrast to LSD which seems to 'demand' inner exploration, MDA has been reported to be more gentle in 'inviting' introspection (Yensen, et al., 1976).

MDMA, which didn't become very well-known until the early 1970s, was actually first synthesized some time during 1912. The pharmaceutical firm E. Merck applied for a patent on the compound on December 24th, 1912 and was issued that patent on May 16th, 1914 (though the patent has since expired making the compound public domain) in Darmstadt, Germany (Shulgin, 1986). There is a common myth sometimes heard that MDMA was first patented as an appetite suppressant, but this rumor is completely false. MDMA was synthesized during an investigation of precursors to be used in making other compounds (Cohen, 1998).

MDMA seems to have remained in relative obscurity until the 1950s, when it was investigated by the U.S. Army as Edgewood Arsenal experimental agent 1475 (EA-1475), most likely as a potential 'truth-serum' (Cohen, 1998). There is also a reference to its synthesis being investigated in Poland in 1960 (Shulgin, 1986), and Alexander Shulgin himself did synthesize it in 1965 while working at Dow Pharmaceuticals, but he had never tried consuming it (Shulgin & Shulgin, 1992).

It wasn't until 1967 or 1968 when Alexander Shulgin met Merrie Kleinman, a young chemistry graduate student at the University of California - San Francisco, that his interest in MDMA was renewed. She told him that she had synthesized some of the N-methylated MDA, and with two close friends had tried it (Perrine, 1996). She and her friends each having ingested 100 mg of MDMA, Merrie said of the experience only that it was quite emotional but overall left them with a good feeling. Shulgin then synthesized it again himself and ingested some, finding it "unlike anything I had taken before," (Shulgin & Shulgin, 1992).

Alexander Shulgin's synthesis of MDMA at the end of the 1960s marks the introduction of this compound into the circles of psychotherapists and researchers he knew interested in exploring the hidden recesses of the mind. This time marked the introduction of MDMA onto the street as well, though it did not gain its massive popularity of today until perhaps 1980. By the mid-1970s however, MDMA-assisted psychotherapy had become very popular, as it had not yet been scheduled (unlike MDA, which was included in the Controlled Substances Act of 1970) and had produced amazing results in therapy sessions (Cohen, 1998). The primary benefits with which MDMA is attributed include: having little psychological risk (compared to LSD), effects lasting only 3 to 5 hours (again, compared to LSD's 6-10 hours), enhanced bonding and communication between the therapist and the patient or between the two partners of a couple, facilitation of the expression of emotions and opinions, and little or no perceptual or cognitive distortions or loss of ego control (again, in contrast to LSD) (Greer, 1985; see also Greer and Tolbert, 1986, 1998; Liester, et al., 1992; Nichols, 1986; Stolaroff, 1997; Downing, 1986).

The effects and chemistry of MDMA (and MDA) are in fact so different than typical hallucinogens that they are deserving of their own name as a qualitative class of compounds. The case for this is quite thoroughly and convincingly made by David Nichols (1986), who gives several arguments for the new class name of 'entactogens'. "First of all, MDA itself [and MDMA] is really a unique compound among the so-called hallucinogens. It is not generally used for its hallucinogenic effect, but rather for its affect-enhancing qualities," (Nichols, 1986: pg. 306). Secondly, all other hallucinogenic amphetamines (e.g., the substituted amphetamine DOM) are active only in their levo-, or R-(-), optical isomer while MDMA is active in its dextro-, or S-(+), optical isomer, and MDA is active in both forms though with differing effects in each. Thus, MDMA and MDA cannot be acting at exactly the same site of action in the brain as other hallucinogenic amphetamines, because a "structurally well defined receptor does not suddenly decide to accept the dextro- isomer for one compound, when for all other members of a drug series [(i.e., the substituted amphetamines)] it prefers the levo-isomer," (Nichols, 1986: pg. 307). It is energetically impossible due to bonding constraints at the molecular level.

Finally, it is well-known that in all other hallucinogenic substituted amphetamines, if you change the alpha-methyl group to an alpha-ethyl group, you lose all hallucinogenic activity (most likely because the molecule no longer fits the receptor). To test this out in MDMA, Nichols and his research team substituted an alpha-ethyl group for the alpha-methyl group on MDMA and the resulting compound was N-methyl-1-(1,3-benzodioxol- 5-yl)-2-butanamine, or MBDB. If this compound followed the trend of all other hallucinogenic substituted amphetamines, then it would be expected to lose all hallucinogenic activity. When tested in both humans and rats, however, this was not the case. MBDB did have effects in humans and rats similar to MDMA, though less potent, and also the active form was the dextro- isomer as with MDA and MDMA (Nichols, 1986).

Because of these three key pieces of evidence, Nichols and his team felt a new term was needed for this chemical class of compounds. Rejecting empathogen as too limiting and also suggesting deleterious effects (i.e., "pathogen"), they came up with the term entactogen. In Nichols' words: "It seemed that the effect of these drugs was to enable the therapist - or patient to reach inside and deal with painful emotional issues that are not ordinarily accessible. Just as the word 'tact' has the connotation of communicating information in a sensitive and careful way, so as to avoid offense, it seemed that the Latin root of this word, tactus, would be appropriate as part of the term. Addition of the Greek roots en (within or inside) and gen (to produce) created the term 'entactogen', having the connotation of producing a touching within," (Nichols, 1986: pg. 308).

By the mid-1980s, while still prospering as a psychotherapeutic agent, MDMA had caught-on in the dance-club scene, especially in Texas. "What had been a low-level production from chemists in the Boston area was superseded when one of their Southwest distributors started his own operation in Texas, and renamed the drug 'Ecstasy,'" (Perrine, 1996: pg. 304). It became so available in Texas bars and nightclubs at one point, that supposedly some establishments even allowed purchases by credit-card and sometimes even handed it out as a free promotional item (Cohen, 1998). 1984, however, was the beginning of the end when Lloyd Bentsen, a Texas Senator, made the first request to the DEA to schedule MDMA.

This action sparked off two years of heated debate about whether or not to place MDMA in Schedule I, with both sides emphatic in their beliefs. A crucial piece of evidence used by the DEA, though resting on the misinformation of MDMA being synonymous with MDA, was a paper published in Science in 1985 by George Ricaurte and his team (i.e., Ricaurte, et al., 1985). The data of this paper indicated that a 10 mg/kg dosage of MDA (equivalent to a 500-1000 mg dose in humans) caused a reduction in serotonin levels in the rat forebrain. Although, ironically, one of the conclusions made by the authors was that "the doses of MDA typically ingested by humans may not be sufficiently high to induce serotonin neurotoxicity, unless humans are more sensitive than rats to the toxic effects of MDA," (Ricaurte, et al., 1985: pg. 988). After evven more court hearings, MDMA was eventually placed in Schedule I, temporarily in July of 1985, and permanently on November 13, 1986 (Cohen, 1998). On December 22nd, 1987, it was temporarily placed in Schedule III (accepted medical use but moderate potential for abuse and physical and/or psychological dependency) due to subsequent court hearings and a decision that there were indeed acceptable medical uses for MDMA, but unfortunately this decision was reversed and on March 23rd, 1988 it was placed back in Schedule I (Liester, et al., 1992).

Not much changed in any positive way with the scheduling of MDMA, in my opinion. Effectively, these were the real consequences: the price on the street soared to $20-$25 per tablet or capsule; the quality, puurity and exact amount of MDMA in each capsule or tablet became even more uncertain; previously legal psychotherapy was forced underground; the criminal element of the 'black market' brought a new factor of potential violence, inherent in such illegal dealings involving large sums of money, to all levels of MDMA manufacture, distribution and, now, smuggling of both product and precursors; and lastly, the consumption of MDMA seems to have went up, not down, since 1985 with the massive popularization oof the drug (now known as 'E', 'X' and 'XTC') in the underground dance-club, or 'rave', scene which emerged in the United States and England in the mid-1980s.

Despite the usual governmental propaganda, perhaps we should examine the real risks involved in MDMA use. It seems, at least psychologically, extremely safe especially when compared to most legally-prescribed drugs: "... in 1986, J. Newmeyer conducted a review showing that adverse reactions to MDMA averaged fewer than 20 per year from all emergency rooms nationwide, despite literally millions of individuals using the drug," (Perrine, 1996: pg. 304). A very real risk, however, which is associated with MDMA use in the rave-scene, is the danger of heat-exhaustion when dancing for hours on end without drinking any water or juice, especially when the venue is indoors and over-crowded. Heat-exhaustion and hyperthermia have caused many casualties and even fatalities associated with, though not caused by, MDMA use.

The neurotoxicity of MDMA however, remains somewhat unclear, though if there is any at all it seems to be no more than that caused by such prescription drugs as Fenfluramine, a Schedule IV drug used to treat obesity (e.g., see Frederick, et al., 1998 and McCann & Ricaurte, 1995). The glaringly obvious difference which automatically appears here, however, is that while Fenfluramine (which has been used by over 50 million patients) is taken daily for sometimes many consecutive months, a dose of MDMA used in psychotherapy may be given only once or twice a year, if that. Even McCann and Ricaurte (proponents of MDMA neurotoxicity) have said, "Although it is not clear why the potential for serotonin neurotoxicity in humans receiving Fenfluramine has not received much attention, it may be, in part, related to its use in a more socially acceptable therapeutic setting," (McCann & Ricaurte, 1995).

Regarding the actual neurotoxicity caused by both MDMA and Fenfluramine in animals (not humans), they have both been found in monkeys and rats to deplete serotonin levels as measured by reduced levels of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, in the cerebral spinal fluid (CSF) (e.g., Ricaurte, et al., 1988a; Steele, et al., 1994; Hegadoren, et al., 1995; Fischer, et al., 1995; McCann, et al., 1996),reduced levels of serotonin as measured directly (e.g., Ricaurte, et al., 1988b), and increased locomotor activity (Nagilla, et al., 1998). The reduced serotonin levels seem to be due to changes in serotonergicc neurons, specifically at pre- synaptic serotonin uptake sites (Sprague, et al., 1998). Even though these studies with high dosages and/or repeated administrations of MDMA have shown some serotonin depletion in animals, a 1993 primate study was conducted by George Ricaurte that unfortunately was never published indicating that a single experimental/therapeutic dose MDMA was probably not neurotoxic at all. In an October, 1999 letter to Neuropsychopharmacology, Franz X. Vollenweider, et al., state: "Finally, 2.5 mg/kg MDMA given p.o. once every 2 weeks for 4 months did not alter 5-HT and 5-HIAA brain content in squirrel monkeys (Ricaurte 1993, pers. comm. to the Swiss Federal Ethical Committee)," (Vollenweider, et al., 1999: pg. 599).

There are several problems with neurotoxicological studies being generalized to humans occasionally using a therapeutic dose of MDMA in a clinical setting. First, the dosages used in rats and monkeys have been anywhere from 20-80 mg/kg, sometimes administered subcutaneously, intramuscularly or intraperitoneally (i.e., without a 'first pass' through the stomach and liver) (Hegadoren, et al., 1999). Also, 20-80 mg/kg in a 50-100 kg (110- 220 lb) human equals 1000-80,000mg of MDMA consumed, and in these studies this dosage was sometimes given repeatedly in one day or over a few days to elicit the reported neurotoxicity. These dosages are quite high, to say the least, given the normal therapeutic dose of 50-250 mg. Another problem, perhaps supporting the strongest case against the neurotoxicity data, is that generalizing findings across species is by itself inconclusive. Dan Perrine (1996) points out that "while serotonin neurodamage in monkeys from MDMA appears to be permanent, in rats function seems slowly to return to normal," (pg. 305). So presently, the debate still rages on as to whether MDMA cause neurotoxicity or not. It does seem tragic however, that because of its Schedule I status, the research which needs to be done on MDMA to show its probable harmlessness and already-proven clinical efficacy has been severely hampered while drugs such as Fenfluramine continue to be prescribed on a regular basis.

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Refs
Structure
MDMA safety
MDMA advert
Designer Drugs
PiKHAL on EROWID
Protect and Survive
MDMA: controversies
MDMA/ecstasy: review
Post-E Prozac protection?
Alexander and Ann Shulgin
Alexander Shulgin Interview
Alexander Shulgin and 2C-T-7
Dr Michael Mithoefer's PTSD trial