A combination of MDMA (methylenedioxymethamphetamine also known as molly, or ecstasy, or E) and psychotherapy is poised to revolutionize treatment of post-traumatic stress disorder (PTSD). PTSD is a condition that can arise following an extremely adverse event. Cues present at the time of the event including sights, sounds, or smells, can serve as triggers that remind the person of the trauma, leading to unconscious fear and anxiety despite the absence of danger. Persistent PTSD episodes can cause substantial decrease in quality of life and affect more than 1 in 12 people worldwide [1]. While treatments exist for PTSD using a combination of therapy and antidepressant drugs, many patients are unable to recover, necessitating the need for more effective treatments [2]. Studies utilizing MDMA in treatment of PTSD, an unforeseen use when it was originally synthesized, show promising results.
PTSD treatment and the potential of MDMA
PTSD is primarily treated using a combination of selective serotonin reuptake inhibitors (SSRIs) and therapy [3]. About 40% of patients taking SSRI for anxiety or depression do not show improvement, and symptoms may worsen in the first 3 weeks of treatment before improvements are seen in the remaining 60% [4-7]. SSRIs need to be taken daily and, even then, a substantial portion of patients do not see an improvement. A new treatment, which works rapidly and requires fewer doses to alleviate symptoms, would revolutionize the treatment of PTSD – studies of MDMA suggest it could be such a treatment.
MDMA was first synthesized in 1912 by the chemist Anton Köllisch at Merck, a German pharmaceutical company, as an intermediate step in the production of methylhydrastinine, which was being developed to stop bleeding [8]. In 1927, Max Oberlin, a chemist at Merck, discovered amphetamine-like effects when it was used on animal tissue [8]. In 1965, MDMA was synthesized again by Alexander Shulgin, a chemist at Dow pharmaceutical company, and in 1978, he was the first to publish the psychotropic effect of MDMA in humans [9]. He noted that MDMA “appears to evoke an easily controlled altered state of consciousness with emotional and sensual overtones” [9].
History of MDMA research
In 1977, Shuglin introduced MDMA to Leo Zeff, a friend and retired psychotherapist, who was so inspired by positive emotional effects of MDMA that he came out of retirement and traveled the US and Europe teaching psychotherapists to combine MDMA with psychotherapy [9]. Anecdotally, this was reported to have beneficial effects, but there was much hesitancy about its use due to political controversy; in the UK brewing companies began anti-ecstasy campaigns after increased MDMA recreational use correlated with a decrease in alcohol sales [10]. As time passed, political opposition waned and official research quantifying the effects of MDMA in therapy began anew. These studies are poised to have big impacts on how we treat PTSD as well as our understanding of the neural underpinnings of PTSD.
The first official clinical trials of treatments combining MDMA and therapy for PTSD were conducted in 1988 by the Swiss Medical Society for Psycholytic Therapy, which demonstrated that 90% of patients showed improvements lasting 19 months [11, 12]. However, this study did not have a placebo group, making it hard to discern whether or not the positive effect observed was due to the use of MDMA in the treatment regimen. Research in this area came to a halt due to concerns about the methodology and safety.
More recently, the Multidisciplinary Association for Psychedelic Studies (MAPS) began funding more clinical trials to evaluate the safety and efficacy of treatments using MDMA and psychotherapy, including the first placebo-controlled study of PTSD patients in 2010 [11, 13]. The results of this study were quite remarkable: 83% of MDMA treated patients showed improvements lasting one year compared to 25% of the placebo group. Subsequent phase two clinical trials concurred with phase one results and showed that improvements can last up to 3.8 years – a marked improvement over current treatment with SSRIs [2]. In the most recent phase three clinical trial, as of writing, treatment with MDMA had a larger effect size on alleviating PTSD symptoms compared to other treatment options [5]. FDA approval of treatment using MDMA for PTSD will benefit the lives of patients.
A New York Times article from May 2021 highlighted the potential of MDMA for the treatment of PSTD (re-published with permission via CC BY 4.0)
Big impact of MDMA research on understanding trauma recovery
Despite its profound impact on treating PTSD, scientists do not fully understand how MDMA exerts its therapeutic effects. MDMA causes neurons to release the neurotransmitters serotonin, dopamine, and norepinephrine, which can have many different effects depending on where in the brain they are released and what receptors they activate. Given the broad effect of MDMA, scientists would like to know where and which receptors in the brain are needed for its pro-therapeutic effects because this knowledge could allow for a better understanding of PTSD pathogenesis as well as the development of more target specific drugs. Using functional magnetic resonance imaging (fMRI), which allows visualization of blood flow in a human brain, scientists are able to approximate neural activity since active brain areas require more oxygenated blood [14]. Subjects who took MDMA before undergoing fMRI showed reduced neuronal activity in a brain area critical for defensive responses to threats, called the amygdala [15, 16]. These subjects also show changes in the connectivity between areas of the brain that allow for conscious control over emotion, such as the prefrontal cortex and hippocampus [15, 16]. These effects likely allow the patient to discuss the trauma without excessive fear responses. Several hypotheses have been put forward based on MDMA’s neurochemical mechanism of action that have been supported by work done in humans and mice.
A short video illustrating MDMA’s general mechanism of action can be found here: https://www.youtube.com/watch?v=bWoOZovQNpU&t=4s
One hypothesis is that MDMA enhances fear extinction, a kind of learning that reduces responses to a previously dangerous sensory cue after many exposures without negative outcomes. This learning is the basic principle of current exposure-based PTSD therapies. Studies done in mice show that MDMA can enhance fear extinction which suggest MDMA works synergistically with this kind of therapy [2, 17, 18].
A short video illustrating data from a study showing MDMA’s can enhance fear extinction can be found here: https://youtu.be/zFZbi3NlLPw
Alternatively, based on studies in mice [17,18], it has been hypothesized that MDMA can alter memory reconsolidation, a process where parts of a recalled memory are altered. During memory reconsolidation, the way a memory is modified depends on a person’s current state when it is recalled. For someone with PTSD, ruminating over negative aspects of a traumatic memory can lead to strengthened negative associations with that memory, which worsen the PTSD symptoms. In contrast, during therapy, the therapist provides novel perspectives to the patient as they recount their trauma, allowing the memory to be reconsolidated in a way that weakens the negative aspects of the memory. Research suggests that by combining MDMA with therapy, memory of the trauma is reconsolidated such that the negative response is reduced when it is later recalled.
A short video illustrating data from a study showing MDMA’s can enhance memory reconsolidation can be found here: https://youtu.be/vzfCJ9-yaQ4
Another hypothesis is that MDMA reopens critical periods of learning, which are time windows during childhood and adolescence when learning capacity is at its greatest [19]. Many traumas happen during these critical periods, leading to enhanced threat memory formation. PTSD due to childhood trauma is one of the most difficult to treat and the reopening of critical periods would likely allow for new learning related to the trauma [5]. This suggests that combining MDMA with therapy can allow for more flexible learning about past childhood traumas and thereby enhance therapeutic outcomes.
A short video illustrating data from the study showing MDMA’s can reopen critical periods of learning can be found here: https://youtu.be/tFOOMwcN9PQ
MDMA has come a long way from being synthesized as an intermediate to methylhydrastinine to showing promise as the most effective PTSD treatment to date. Treatment of PTSD using MDMA requires fewer doses and can reduce symptoms for years after the session, possibly due to its effect on fear extinction, memory reconsolidation, and reopening critical periods of learning.
Edited by Vijendra Ramlall
Citations:
1. Kessler, Ronald C., et al. “Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication.” Archives of General Psychiatry, vol. 62, no. 6, American Medical Association, June 2005, pp. 593–602, https://doi.org/10.1001/ARCHPSYC.62.6.593.
2. Jerome, Lisa, et al. “Long-Term Follow-up Outcomes of MDMA-Assisted Psychotherapy for Treatment of PTSD: A Longitudinal Pooled Analysis of Six Phase 2 Trials.” Psychopharmacology 2020 237:8, vol. 237, no. 8, Springer, June 2020, pp. 2485–97, https://doi.org/10.1007/S00213-020-05548-2.
3. de Moraes Costa, Gabriela, et al. “Pharmacological Treatments for Adults with Post-Traumatic Stress Disorder: A Network Meta-Analysis of Comparative Efficacy and Acceptability.” Journal of Psychiatric Research, vol. 130, Pergamon, Nov. 2020, pp. 412–20, https://doi.org/10.1016/J.JPSYCHIRES.2020.07.046.
4. Steenkamp, Maria M., et al. “Psychotherapy for Military-Related PTSD: A Review of Randomized Clinical Trials.” JAMA, vol. 314, no. 5, American Medical Association, Aug. 2015, pp. 489–500, https://doi.org/10.1001/JAMA.2015.8370.
5. Mitchell, Jennifer M., et al. “MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.” Nature Medicine 2021 27:6, vol. 27, no. 6, Nature Publishing Group, May 2021, pp. 1025–33, https://doi.org/10.1038/s41591-021-01336-3.
6. Cell Press. "Why some antidepressants may initially worsen symptoms." ScienceDaily. ScienceDaily, 17 December 2014. <www.sciencedaily.com/releases/2014/12/141217131430.htm>.
7. Cools, R., Roberts, A. C., & Robbins, T. W. (2008). Serotoninergic regulation of emotional and behavioural control processes. Trends in Cognitive Sciences, 12(1), 31–40. https://doi.org/10.1016/J.TICS.2007.10.011
8. Bernschneider-Reif, Sabine, et al. “The Origin of MDMA (‘Ecstasy’) - Separating the Facts from the Myth.” Pharmazie, vol. 61, no. 11, Nov. 2006, pp. 966–72.
9. Benzenhöfer, Udo, and Torsten Passie. “Rediscovering MDMA (Ecstasy): The Role of the American Chemist Alexander T. Shulgin.” Addiction, vol. 105, no. 8, John Wiley & Sons, Ltd, Aug. 2010, pp. 1355–61, https://doi.org/10.1111/J.1360-0443.2010.02948.X.
10. Carey J. Recreational Drug Wars: Alcohol Versus Ecstasy. ‘Ecstasy Reconsidered’ by Nicholas Saunders (1997)
11. Sessa, Ben, et al. “A Review of 3,4-Methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy.” Frontiers in Psychiatry, vol. 0, no. MAR, Frontiers, 2019, p. 138, https://doi.org/10.3389/FPSYT.2019.00138.
12. Gasser P. Psycholytic “Therapy with MDMA and LSD in Switzerland.” Newslett Multidiscipl Assoc Psychedelic Stud. (1995) 5:3–7
13. Mithoefer, Michael C., et al. “The Safety and Efficacy of ±3,4-Methylenedioxymethamphetamine-Assisted Psychotherapy in Subjects with Chronic, Treatment-Resistant Posttraumatic Stress Disorder: The First Randomized Controlled Pilot Study:” Http://Dx.Doi.Org/10.1177/0269881110378371, vol. 25, no. 4, SAGE PublicationsSage UK: London, England, July 2010, pp. 439–52, https://doi.org/10.1177/0269881110378371.
14. Logothetis, Nikos K. “What We Can Do and What We Cannot Do with FMRI.” Nature 2008 453:7197, vol. 453, no. 7197, Nature Publishing Group, June 2008, pp. 869–78, https://doi.org/10.1038/nature06976.
15. Carhart-Harris, Robin L., et al. “The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level–Dependent Resting State Functional Connectivity.” Biological Psychiatry, vol. 78, no. 8, Elsevier, Oct. 2015, pp. 554–62, https://doi.org/10.1016/J.BIOPSYCH.2013.12.015.
16. Feduccia, Allison A., and Michael C. Mithoefer. “MDMA-Assisted Psychotherapy for PTSD: Are Memory Reconsolidation and Fear Extinction Underlying Mechanisms?” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 84, Elsevier, June 2018, pp. 221–28, https://doi.org/10.1016/J.PNPBP.2018.03.003.
17. Hake, Holly S., et al. “3,4-Methylenedioxymethamphetamine (MDMA) Impairs the Extinction and Reconsolidation of Fear Memory in Rats.” Physiology & Behavior, vol. 199, Elsevier, Feb. 2019, pp. 343–50, https://doi.org/10.1016/J.PHYSBEH.2018.12.007.
18. Young, M. B., et al. “3,4-Methylenedioxymethamphetamine Facilitates Fear Extinction Learning.” Translational Psychiatry 2015 5:9, vol. 5, no. 9, Nature Publishing Group, Sept. 2015, pp. e634–e634, https://doi.org/10.1038/tp.2015.138.
19. Nardou, Romain, et al. “Oxytocin-Dependent Reopening of a Social Reward Learning Critical Period with MDMA.” Nature 2019 569:7754, vol. 569, no. 7754, Nature Publishing Group, Apr. 2019, pp. 116–20, https://doi.org/10.1038/s41586-019-1075-9.
