MDMA-assisted psychotherapy

MDMA-assisted psychotherapy is the use of prescribed doses of MDMA as an adjunct to psychotherapy sessions. Research suggests that MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), including Complex PTSD, might improve treatment effectiveness.[1][2][3] In 2017, a Phase II clinical trial led to "breakthrough therapy" designation by the US Food and Drug Administration (FDA).[4][5]

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The research is controversial[6][7] in part because recreational MDMA use has been associated with harmful effects among some users.[8][6][9]

Post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is most commonly treated by cognitive behavioral therapy (particularly prolonged exposure and cognitive processing therapy), eye movement desensitization and reprocessing, and psychodynamic psychotherapy. However, over half of these patients continue to have PTSD after completing therapy, with results from military PTSD being especially poor.

PTSD is best treated when a patient is in the 'optimal arousal zone'. This is the zone in which emotions are engaged, yet not overwhelming. In this zone, four symptom clusters of PTSD are sedated:[7] These are:

  1. re-experiencing
  2. avoidance
  3. negative alterations in cognition/mood
  4. alterations in arousal and reactivity

Subjects with PTSD exhibit extreme emotional numbing or anxiety and struggle to remain in the optimal arousal zone during conservative therapies. Threatening interpretations of memories are reinforced when patients are in low emotional states.[10] If traumatic memories are revisited in therapy when a patient is not within the optimal arousal state, therapy for PTSD can actually increase the patient's trauma.[10]

When used in therapy MDMA has been reported to increase empathy, closeness between patient and therapist, relaxation, motivation to engage with therapy and introspective thought, and to reduce depression and anxiety. MDMA makes it easier for a patient to stay in the optimal arousal zone by decreasing feelings of anxiety and defensiveness when revisiting traumatic memories.[7] It also increases feelings of closeness and empathy, improving the patient's trust in the therapist, and encourages introspective thought to reassess memories and actions. These factors may increase the success rate of psychotherapy. With the approval of the FDA in 2017, MDMA has been cleared for the use in assisting with psychotherapy.[4] A phase 3 study indicated that MDMA-assisted therapy represents a potential breakthrough treatment for severe PTSD that merits expedited clinical evaluation.[11] However, given the lack of blinding, several researchers have postulated that the results of the phase 3 trial might be heavily influenced by expectancy effects,[12][13] and there are no trials comparing MDMA-assisted psychotherapy to already existing first-line psychological treatments for PTSD, which based on indirect evidence seems to attain similar or elevated symptom reduction compared with that due to MDMA-assisted psychotherapy.[14]

Adverse effects, which can last from a few hours to several days, include diminished appetite, anxiety, headache, jaw tightness, tinnitus, nausea, asthenia, fatigue, acute sinusitis, nasopharyngitis, upper respiratory tract infection, disturbance in attention, tremor, tics, dysuria, erythema, and depression.[15]

Rationale for MDMA treatment

PTSD inhibits a subject's ability to respond appropriately to trauma-related stimuli.[7] The current model of PTSD proposes that it results from amplified and uncontrolled responses from the amygdala to trauma-specific cues.[10] Oxytocin, which is increased by MDMA, has been found to increase trust and emotional awareness and reduce amygdala responses as well as reduce coupling of the amygdala to brainstem regions associated with autonomic and behavioral characteristics of fear.[16][17][18] It has been proposed that these effects foster memory reconsolidation by allowing the patient to access the traumatic memory while feeling detached from the sense of imminent threat.[10]

Breakthrough therapy designation

In 2017, the treatment was granted breakthrough therapy designation by the FDA, a designation that indicates that there is preliminary evidence that an intervention might offer a substantial improvement over other options for a serious health condition.[5]

Society and culture

The use of psychedelics for therapy has been characterized as 'countercultural' in Western cultures.[19]

Legality

MDMA was first synthesized by German pharmaceutical company Merck KGaA in 1912 as an intermediate in the synthesis of another compound. Its psychoactive effects were not noted until the early 1960s. In the 1960s and 1970s, the drug was used in psychotherapy, although it was not an approved drug and no clinical trials had been performed. The drug was studied in Switzerland for use in individual, couple, and group therapies until 1993, when the Swiss Ministry of Health withdrew permission to use MDMA and LSD by psychiatrists due to concerns about lack of research methodology.[20]

In 1986, MDMA was classed as a Schedule 1 drug by the United Nations according to its Convention on Psychotropic Substances of 1971 due to its high potential for abuse, and most research was stopped.[7] Researchers interested in MDMA for use in psychotherapy founded and funded the Multidisciplinary Association for Psychedelic Studies (MAPS) in response. The US Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA) granted approval for researching MDMA's efficacy as an adjunct to psychotherapy in 2004, and the first trial was carried out in 2011.[21]

Controversy

MDMA's effects vary across people and settings and include adverse outcomes.[6][9] The drug causes neurotransmitter activation across the main neural pathways (including serotonin and dopamine, noradrenaline) that can result in large mood swings. The memories that emerge under the influence of MDMA can evoke unwanted emotions.[6] Side effects of MDMA use by recreational users include appetite fluctuations, food cravings, and disordered eating.[6]

Once the effects of MDMA wear off, there is a "period of neurochemical depletion" that invokes anhedonia, lethargy, anger, depression, irritability, brooding, greater everyday stress, altered pain thresholds, changes in sleep, and bad dreams, especially in female participants.[6] The symptoms are thought to be due to depletion of serotonin, as a result of the large release of serotonin triggered by MDMA, and have been called "neurotoxic in terms of causing serotonergic dysfunction".[6]

There are also concerns surrounding "drug-dependent learning" — the theory that patients will return to the drug to access the state they were in when on the drug in therapy.[6]

There were 92 MDMA related deaths in England and Wales in 2018, up from 56 the year before,[22] and 10,000 hospitalizations for MDMA related illness/injury in 2011 in the US.[8] However no such cases have (as of 2021) been reported for clinical settings.

Media reports and statements of academic authors have often transmitted the view of MDMA as a possible medicine or treatment rather than as an adjunct to psychotherapy.[7] This has been considered as dangerous, because it could lead people to believe that MDMA is an effective treatment alone, without concomitant psychotherapy.[7]

See also

References
  1. Bahji A, Forsyth A, Groll D, Hawken ER (January 2020). "Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 96: 109735. doi:10.1016/j.pnpbp.2019.109735. PMID 31437480. S2CID 201069918.
  2. Smith KW, Sicignano DJ, Hernandez AV, White CM (October 2021). "MDMA-Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review With Meta-Analysis". Journal of Clinical Pharmacology. 62 (4): 463–471. doi:10.1002/jcph.1995. PMID 34708874. S2CID 240072663.
  3. Illingworth BJ, Lewis DJ, Lambarth AT, Stocking K, Duffy JM, Jelen LA, Rucker JJ (May 2021). "A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis". Journal of Psychopharmacology. 35 (5): 501–511. doi:10.1177/0269881120965915. PMID 33345689. S2CID 229341150.
  4. Pitts EG, Curry DW, Hampshire KN, Young MB, Howell LL (February 2018). "(±)-MDMA and its enantiomers: potential therapeutic advantages of R(-)-MDMA". Psychopharmacology. 235 (2): 377–392. doi:10.1007/s00213-017-4812-5. PMID 29248945. S2CID 3343930.
  5. Burns J. "FDA Designates MDMA As 'Breakthrough Therapy' For Post-Traumatic Stress". Forbes. Retrieved 2019-07-19.
  6. Parrott AC (2014). "The potential dangers of using MDMA for psychotherapy". Journal of Psychoactive Drugs. 46 (1): 37–43. doi:10.1080/02791072.2014.873690. PMID 24830184. S2CID 23485480.
  7. Morgan L (2020). "MDMA-assisted psychotherapy for people diagnosed with treatment-resistant PTSD: what it is and what it isn't". Annals of General Psychiatry. 19: 33. doi:10.1186/s12991-020-00283-6. PMC 7218633. PMID 32435270.
  8. Solon O (2016-09-16). "'My therapist gave me a pill': can MDMA help cure trauma?". The Guardian. ISSN 0261-3077. Retrieved 2019-05-14.
  9. Karlsen SN, Spigset O, Slørdal L (January 2008). "The dark side of ecstasy: neuropsychiatric symptoms after exposure to 3,4-methylenedioxymethamphetamine". Basic & Clinical Pharmacology & Toxicology. 102 (1): 15–24. doi:10.1111/j.1742-7843.2007.00159.x. PMID 18047478.
  10. Thal SB, Lommen MJ (2018). "Current Perspective on MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder". Journal of Contemporary Psychotherapy. 48 (2): 99–108. doi:10.1007/s10879-017-9379-2. PMC 5917000. PMID 29720767.
  11. Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, Parker-Guilbert K, et al. (June 2021). "MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study". Nature Medicine. 27 (6): 1025–1033. doi:10.1038/s41591-021-01336-3. PMC 8205851. PMID 33972795.
  12. Burke MJ, Blumberger DM (October 2021). "Caution at psychiatry's psychedelic frontier". Nature Medicine. 27 (10): 1687–1688. doi:10.1038/s41591-021-01524-1. PMID 34635858. S2CID 238635462.
  13. Muthukumaraswamy SD, Forsyth A, Lumley T (September 2021). "Blinding and expectancy confounds in psychedelic randomized controlled trials". Expert Review of Clinical Pharmacology. 14 (9): 1133–1152. doi:10.1080/17512433.2021.1933434. ISSN 1751-2433. PMID 34038314. S2CID 235215630.
  14. Halvorsen JØ, Naudet F, Cristea IA (October 2021). "Challenges with benchmarking of MDMA-assisted psychotherapy" (PDF). Nature Medicine. 27 (10): 1689–1690. doi:10.1038/s41591-021-01525-0. PMID 34635857. S2CID 238636360.
  15. Tedesco S, Gajaram G, Chida S, Ahmad A, Pentak M, Kelada M, et al. (May 2021). "The Efficacy of MDMA (3,4-Methylenedioxymethamphetamine) for Post-traumatic Stress Disorder in Humans: A Systematic Review and Meta-Analysis". Cureus. 13 (5): e15070. doi:10.7759/cureus.15070. PMC 8207489. PMID 34150406.
  16. Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, et al. (December 2005). "Oxytocin modulates neural circuitry for social cognition and fear in humans". The Journal of Neuroscience. 25 (49): 11489–11493. doi:10.1523/JNEUROSCI.3984-05.2005. PMC 6725903. PMID 16339042.
  17. Kamilar-Britt P, Bedi G (October 2015). "The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled studies in humans and laboratory animals". Neuroscience and Biobehavioral Reviews. 57: 433–446. doi:10.1016/j.neubiorev.2015.08.016. PMC 4678620. PMID 26408071.
  18. Gangopadhyay P, Chawla M, Dal Monte O, Chang SW (January 2021). "Prefrontal-amygdala circuits in social decision-making". Nature Neuroscience. 24 (1): 5–18. doi:10.1038/s41593-020-00738-9. PMC 7899743. PMID 33169032.
  19. Valentish J (2018-08-30). "The hidden world of underground psychedelic psychotherapy". ABC News. Retrieved 2019-05-14.
  20. Sessa B, Higbed L, Nutt D (2019). "A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy". Frontiers in Psychiatry. 10: 138. doi:10.3389/fpsyt.2019.00138. PMC 6435835. PMID 30949077.
  21. Hutchison, Courtney A.; Bressi, Sara K. (2018-08-31). "MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder: Implications for Social Work Practice and Research". Clinical Social Work Journal. Springer Science and Business Media LLC. 48 (4): 421–430. doi:10.1007/s10615-018-0676-3. ISSN 0091-1674. S2CID 150130179.
  22. "Ecstasy 'too child-friendly' as deaths rise to record levels". BBC News. 2019-08-15. Retrieved 2020-10-22.
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