Food For Thought: Student Edition #2

As the neuroscience of addiction lab is also highly involved in teaching at the University of Amsterdam, we would like to share some of the great output from our recent bachelor course on addiction. In our ‘Food for thought: Student Edition’ series we will share some excellent essays on a variety of addiction related topics. This time you will have the opportunity to read Maura Fraikin’s essay on the potential of MDMA as a treatment for post traumatic stress disorder.

About the author: I am currently in my third year of the psychobiology bachelor at the University of Amsterdam. I am very intrigued by the intertwining of biology and psychology and how biological processes influence neurological phenomena. Cognition, psychopharmacology and the neurobiological mechanisms underlying psychiatric disorders are some of my main interests.


Is MDMA a safe and effective way to improve treatment for PTSD?

Post-traumatic stress disorder (PTSD) is a devastating mental disorder that is triggered by a traumatic event (American Psychiatric Association, 2013). Approximately 7.4% of the Dutch population develops PTSD at some point in their lives, with women being more likely than men to develop PTSD (De Vries & Olff, 2009). The symptoms of PTSD can be divided into four categories: repeated memories, avoidance, negative alterations in mood and thinking, and changes in arousal and reactivity (American Psychiatric Association, 2013). PTSD quite often co-occurs with other mental illnesses and PTSD has a large impact on quality of life (Brady et al., 2000). PTSD is even associated with an increased risk of attempting suicide (Tull, 2019), emphasising the relevance to expand research on treating the symptoms patients suffer from.

Currently available treatments include Cognitive Behaviour Therapy, Cognitive Processing Therapy, Eye Movement Desensitisation and Reprocessing and/or pharmacotherapy (American Psychiatric Association, 2013; Thal & Lommen, 2019). However, the rate of treatment resistance is high, often causing impairments for life (Rodriguez, Holowka & Marx, 2012). Another problem in PTSD treatment is that psychotherapy methods are trauma-focused, which can be quite overwhelming leading to many patients to drop out of treatment (Zepinic, 2015; Burge, 2018). Moreover, all currently used pharmacotherapies in PTSD are symptomatic treatments that do not get to the heart of the problems (Katzman, 2014; Burge, 2018; Bahji et al., 2020). Therefore, an effective treatment is needed that is capable of reducing the considerable rates of treatment failure related to current PTSD treatments.

MDMA, or 3,4-methylenedioxymethamphetamine, emerges as a promising therapeutic candidate for this. MDMA was invented in 1912 as a potential medicine and used in psychotherapy in the 1960s. At the same time, it ended up in the party scene, after which it ended up on list one of the Dutch Opium Act (Kuypers, 2019). This means that possession, trade, production, import and export of MDMA is illegal (art. 2 & art. 10 Opiumwet, 2019), making it hard to study MDMA in clinical settings. However, the beneficial effects of MDMA are unique and might be useful in PTSD treatment. It temporarily decreases fear while increasing relational trust and could therefore be effective to enhance the effects of psychotherapy (Mithoefer et al., 2011).

This leads to the question: does MDMA treatment in combination with psychotherapy successfully alleviate PTSD symptoms? I will argue why, in my opinion, MDMA has therapeutic potential for treatment of PTSD due to its unique characteristics, unlike other pharmacotherapies, to make psychotherapy effective and explain why people should be less reluctant to use this abused drug for medical purposes.

The effect of MDMA-assisted psychotherapy in treatment-resistant PTSD patients

The first completed clinical trial to indicate that MDMA might serve as a therapeutic adjunct in PTSD was performed by Mithoefer et al. (2011). In their study, 20 treatment resistant PTSD patients were tested in a randomized double-blind placebo controlled design. In the first stage of the study, patients were divided into an inactive placebo or MDMA group, in which participants received a dose of 125 mg MDMA, followed by an optional supplemental dose of 62.5 mg MDMA 2.5 hours later during two psychotherapy sessions. In the second stage, participants in the placebo group were given the option to participate in an open-label crossover part of the study in which they received 125 mg MDMA as well. MDMA significantly reduced the scores on the Clinician-Administered PTSD Scale (CAPS), which is a standard symptom scale used to quantify PTSD symptoms and assess the severity. The clinical response rate, defined as more than 30% reduction in CAPS score from baseline, was 83% in the MDMA group compared to 25% in the placebo group. Interestingly, the clinical response rate of the initial placebo group who transitioned to MDMA-assisted psychotherapy increased to 100% in stage two. Furthermore, no serious adverse effects related to MDMA were found.  However, the double blinded design in their study did not work. The majority of the participants and researchers correctly guessed the condition of the subjects. This is probably because MDMA is a psychoactive substance and it produces some noticeable physical and psychological effects, which might have influenced the results.

To evaluate the durability of the outcomes, the same research group assessed CAPS scores again in a follow-up study 3.5 years later. The statistically and clinically significant reduction in PTSD symptoms was maintained. This is indicative of a persistent effect of MDMA-assisted psychotherapy. None of the subjects reported they felt harmed from participating. Importantly, none of the participants used MDMA recreationally afterwards (Mithoefer et al., 2013).

Oehen et al. (2013), however, did not find a significant reduction of MDMA-assisted psychotherapy in clinical PTSD symptoms, although they did find a positive effect on self-reported PTSD symptoms. They examined the efficacy and safety of MDMA-assisted psychotherapy in 12 treatment-resistant PTSD patients in a randomized double-blind trial. Participants were randomly assigned into either full dose MDMA or placebo groups in stage one. As previously mentioned, MDMA has a psychoactive effect, making it hard to maintain the double blind status in clinical studies. To overcome this methodological challenge, an active placebo control of 25 mg followed by 12.5 mg MDMA 2.5 hours later was used, instead of the inactive placebo used by Mithoefer et al. (2011). The full-dose group received 125 mg MDMA, with a supplemental dose of 62.5 mg 2.5 hours later. This also differs from the study of Mithoefer et al. (2011) in which the supplemental dose of MDMA was optional.

In stage two, subjects in the active placebo condition were given the opportunity to continue in an open-label part of the study, receiving the full active dose of MDMA in conjunction with psychotherapy, similar to the method of Mithoefer et al. (2011). A 23.5% decrease in CAPS scores was found in the full-dose group, although this was not statistically significant. Furthermore, scores on the Posttraumatic Diagnostic Scale (PDS), which serves as a self-reporting measure to assess the presence of PTSD symptoms, significantly improved. Similar to results found in the earlier study (Mithoefer et al., 2011), patients in the active placebo group did not respond to treatment at first, but after receiving the full-dose MDMA in stage 2 they all responded to treatment, with half of the subjects no longer fulfilling PTSD criteria. At the one year follow-up, there was a further reduction in CAPS scores of 35% in the full-dose and 52% in the crossover group, thus indicating clinical response. Regarding the safety, no drug-related serious adverse events occurred, indicating that MDMA can be administered safely in a clinical setting in PTSD patients. Moreover, participants did not report any recreational use of MDMA at 12-month follow-up.

Discussion

These findings indicate that MDMA-assisted psychotherapy can successfully alleviate PTSD symptoms. There is empirical evidence that MDMA has therapeutic potential to be a successful, long-lasting and overall safe intervention for treatment-resistant PTSD patients. However, there are some limitations to the studies that need to be considered. All studies had small sample sizes and the majority of participants were female and Caucasian. It is possible that both gender and ethnic differences exist in response to psychotherapy in combination with MDMA. Furthermore, both durations of treatments and the extent of treatment before entering the study differed across studies, which makes the results difficult to compare. Moreover, the double-blinding was not effective in one study (Mithoefer et al., 2011), which could have influenced the results due to a bias of participants. These limitations emphasise that the conclusions must be drawn with caution.

Critics argue that the risk of abuse increases when MDMA gets legalised for medical use, since patients might use the drug afterwards to get the same feeling (Parrot, 2014) and as a non-patient it might be easier to gain access to MDMA. However, MDMA will be used in conjunction with psychotherapy in PTSD patients, meaning it will only be available under therapeutic supervision in certified clinics (Burge, 2018). Thus, PTSD patients will not be able to resell MDMA, as is done with Ritalin for example. Moreover, the fact that all studies showed that MDMA was not used for recreational purposes after treatment suggests that MDMA given in the context of psychotherapy has low abuse liability. Although we do need to be very wary about misuse, under appropriate supervision the risk seems small.

Another argument against the use of MDMA in PTSD treatment is that in studies of recreational ecstasy use severe adverse effects did occur. However, we should be careful to compare the morbidity and mortality statistics that are related to recreational ecstasy use with medical MDMA use in a controlled setting (Sessa, 2017). Both dose and content play an important role. Recreational dosages of MDMA in ecstasy vary and have increased over the past years. The mean dosage of MDMA in ecstasy in the Netherlands is 160 mg with outliers above 200 mg of MDMA (Drugs info team, 2018). Considering that recreational users quite often use more than one pill, the dosages of recreational MDMA are often higher than those in medical setting. Also, ecstasy does not always consist of pure MDMA—it may contain other substances. Furthermore, patients will have to be thoroughly screened in advance to minimize risks (Burge, 2018).

Research into the effectiveness of MDMA in alleviation of PTSD symptoms is scarce. The described studies that investigated the effectiveness were more or less the only ones. Thus, more research is needed to confirm the findings and to study long term outcomes. Also, gender and ethnic differences should be taken into consideration in future studies. Furthermore, research into the effective dosage and sessions of MDMA-assisted psychotherapy is useful. If the positive results of MDMA-assisted psychotherapy are replicated in phase three trials, MDMA might be approved by the FDA. Next to the fact that MDMA is on list 1 of the Dutch Opium Act, it will then also be included in the medicines law. If MDMA-assisted psychotherapy can indeed effectively be used in patients with treatment-resistant PTSD, the percentage of patients who commit suicide could decrease, as a result of increased quality of life. Altogether, MDMA is a potential medicine for PTSD and people should be less reluctant to use it for medical purposes, but more research is needed to get to conclusive results.

References

American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders, (5th ed.). Washington, DC: Author

Bahji, A., Forsyth, A., Groll, D., & Hawken, E. R. (2019). Efficacy of 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 109735. DOI:10.1016/j.pnpbp.2019.109735

Burge, B. (2018). MDMA, Psychotherapy, and the Future of PTSD Treatment. Retrieved from: https://www.ted.com/talks/brad_burge_mdma_psychotherapy_and_the_future_of_ptsd_treatment

Brady, K. T., Killeen, T. K., Brewerton, T., & Lucerini, S. (2000). Comorbidity of psychiatric disorders and posttraumatic stress disorder. The Journal of clinical psychiatry

de Vries, G. J., & Olff, M. (2009). The lifetime prevalence of traumatic events and posttraumatic stress disorder in the Netherlands. Journal of Traumatic Stress: Official Publication of The International Society for Traumatic Stress Studies22(4), 259-267. DOI: 10.1002/jts.20429.

Drugs info team. (2018). Xtc feiten. Retrieved from: https://www.drugsinfoteam.nl/drugsinfo/xtc/xtc-feiten

Katzman, M. A., Bleau, P., Blier, P., Chokka, P., Kjernisted, K., & Van Ameringen, M. (2014). Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC psychiatry, 14(S1), S1. DOI:10.1186/1471-244X-14-S1-S1

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Kuypers, K. (2019, 17 oktober). Waarom zeggen alle psychiaters ‘ja’ tegen mdma? AD. Retrieved from: https://www.ad.nl/wetenschap/waarom-zeggen-alle-psychiaters-ja-tegen-mdma~a8b97feb/

Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2011). 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. Journal of Psychopharmacology, 25(4), 439-452. DOI: 10.1177/0269881110378371

Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., Martin, S. F., Yazar-Klosinski, B., … Doblin, R. (2013). Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. Journal of psychopharmacology (Oxford, England)27(1), 28–39. DOI:10.1177/0269881112456611

Oehen, P., Traber, R., Widmer, V., & Schnyder, U. (2013). A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Journal of Psychopharmacology27(1), 40–52. DOI:10.1177/0269881112464827

Opiumwet (2019). Retrieved from: https://wetten.overheid.nl/BWBR0001941/2019-07-19#BijlageI

Parrott, A. (2014). The Potential Dangers of Using MDMA in Psychotherapy. Journal of Psychoactive Drugs46 (1): 37–43. DOI:10.1080/02791072.2014.873690

Rodriguez, P., Holowka, D. W., & Marx, B. P. (2012). Assessment of posttraumatic stress disorder-related functional impairment: A review. J Rehabil Res Dev49(5), 649-65 DOI: 10.1682/JRRD.2011.09.0162

Sessa, B. (2017). MDMA and PTSD treatment:“PTSD: from novel pathophysiology to innovative therapeutics”. Neuroscience letters649, 176-180. DOI: 10.1016/j.neulet.2016.07.004

Thal, S. B., & Lommen, M. J. (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

Tull, M. (2019, 23 november). The Connection Between PTSD and Suicide. Retrieved from: https://www.verywellmind.com/ptsd-and-suicide-2797540

Zepinic, V. (2015). Treatment Resistant Symptoms of Complex PTSD Caused by Torture During War. Canadian Social Science, 11(9), 26-32. DOI:10.3968/7551



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