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Is MDMA Safe and Effective for PTSD?

Do we know whether the benefits of ecstasy outweigh its risks?

Key points

  • MDMA, or ecstasy, has been shown to positively augment psychotherapy for the treatment of post-traumatic stress disorder.
  • The lack of confirmation of MDMA’s safety suggests that clinicians should be cautious.

MDMA, known as ecstasy and 3,4-methylenedioxymethamphetamine, has been shown to positively augment psychotherapy in a series of recent small clinical trials for the treatment of post-traumatic stress disorder (PTSD).

Is MDMA effective?

A recent study examined the results of MDMA trials, which were double-blinded and randomized. They compared MDMA-assisted psychotherapy to psychotherapy and placebo. The MDMA was administered only once in one of three doses (75, 100, 125 mg). As compared to placebo, patients taking 75 or 125 mg, when combined with psychotherapy, had significant decreases in Clinician-Administered PTSD Scale scores. A modest decrease in depression symptoms was only seen at 75 mg. These results demonstrate an important, and disturbing, feature of MDMA: Its effects are notoriously non-linear. Recent studies that have compared the benefits of MDMA alone, with the benefits of psychotherapy, or a combination of the two treatments have reported that MDMA only enhances psychotherapy. MDMA-assisted psychotherapy is clearly a promising intervention that needs further investigation. However:

Is MDMA safe?

A study about to be published in Nature Medicine and summarized in The New York Times reported “no serious adverse side effects among the participants who had MDMA.” In my opinion, this statement is completely indefensible until the brains of the subjects can be examined histologically— which is, of course, impossible to do until autopsy.

I have extensively studied the neurotoxicity of MDMA while training at Johns Hopkins University. MDMA is a highly effective chemical “scalpel” that efficiently destroys serotonin and, to a lesser degree, dopamine neurons in the brain. My research focused on the neurotoxic mechanisms of MDMA’s actions in the brain as well as the behavioral consequences of a single dose. I demonstrated that although there were no observable consequences of MDMA on rodent behavior, there was extensive destruction of serotonin neurons in the brain. However, humans are not rodents. Unfortunately, primates are far more vulnerable than rodents to the toxic effects of MDMA. Humans are primates.

The typical “recreational” dose of MDMA produces blood levels in the range of 0.1–0.25 mg/L. Most of the cases of acute serious toxicity or fatality have involved blood levels ranging from 0.5-10.0 mg/L. Yes, it takes much more MDMA to produce immediate death. However, some of the fatalities actually had blood levels as low as 0.11–0.55 mg/L. Yes, some humans show serious toxicity, and even death, at blood levels that overlap with the so-called “normal” range. Everyone responds differently to the same dose of MDMA depending on their age and health. In addition, women are usually more vulnerable than men.

The toxic dose of MDMA in the monkeys (5 mg/kg) closely approaches the dose typically used by humans (1.7 to 2.7 mg/kg). Plasma concentrations of MDMA that produce lasting serotonergic deficits in squirrel monkeys overlap those reported by other laboratories in some recreational 'ecstasy' consumers, and are two to three times higher than those found in humans administered a single 100-150 mg dose of MDMA. A single 5-mg/kg oral dose in monkeys has been proposed to be equivalent to a 1.4-mg/kg dose in a 70-kg human, based on interspecies dose scaling. These data suggest that there is a risk of serotonergic damage in humans even after a single dose 100 mg dose. Recall that the recent clinical trials are giving patients 75 to 125 mg doses. The plasma levels produced by 100 mg of MDMA in monkeys produced lasting serotonergic deficits that are similar to those reported in recreational ecstasy users.

Investigations using monkeys are predictive because studies have shown that the metabolism and disposition of MDMA in monkeys closely parallel those in humans. Studies in monkeys have confirmed that the primate brain shows degenerative changes in serotonin neurons at doses that overlap with those being tested on humans with PTSD. The lack of confirmation of MDMA’s safety by histopathological examination suggests that clinicians should proceed with caution. Similar to my rats, humans do not show observable adverse behavioral effects of a single dose of MDMA. However, similar to my rats, human serotonin neurons are likely damaged by a single dose of MDMA.

References

Wenk GL (2019) Your Brain on Food, 3rd Ed. (Oxford University Press)

Ricaurte GA,.. Wenk GL et al (1993) MDMA, serotonin and memory. Journal of Pharmacology and Experimental Therapeutics, 266: 1097-1105.

Illingworth BJG et al (2020) A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis. Journal of Psychopharmacology, Article Number: 0269881120965915.

Hoskins MD et al (2020) Pharmacological therapy for post-traumatic stress disorder: A systematic review and meta-analysis of mono-therapy, augmentation and head-to-head approaches. European Journal of Psychotraumatology, 12(1), 1802920. doi:10.1080/20008198.2020.1802920.

Mueller M et al., (2013) Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) metabolism and disposition in rats and mice: relationship to neuroprotection and neurotoxicity profile. Journal of Pharmacology and Experimental Therapeutics, vol 344, p 479 DOI: https://doi.org/10.1124/jpet.112.201699

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