MDMA in Therapy: Exploring its Origins, Controversies, and Future

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In 1976, pioneering chemist Alexander Shulgin rediscovered 3,4-methylenedioxymethamphetamine (MDMA), a drug that belongs to the class of “entactogens” that are known for producing a sense of empathy, openness, social bonding, and emotional well-being in users. The word "entactogen" derives from the Greek words "en" (within) and "tactus" (touch), suggesting a sense of inner touch or contact.

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While entactogens share some similarities with classic psychedelics, they are distinct in their effects on emotional processing and social behavior. 

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Shulgin felt that MDMA had therapeutic promise and later introduced it to psychologist Dr. Leo Zeff, who used it in his psychotherapy practice and described it as a powerful tool for promoting empathy and emotional healing. Zeff reportedly went on to train 4,000 therapists on how to incorporate the use of MDMA into their therapy practice. 

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During this time, some therapists found that MDMA helped patients to open up emotionally and to connect more deeply with others. Many patients reported that the experience of taking MDMA in a therapeutic context was profound and transformative. 

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However, it's important to note that research into the therapeutic uses of MDMA was limited during this time, and there were also reports of recreational use and abuse of the substance. Shulgin himself was not particularly interested in the recreational use of drugs. He believed that they should be used with great care and respect for the profound changes they can bring about, and that they could be invaluable tools for scientific research.

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The use of MDMA in therapy became controversial and eventually led to the substance being classified as a Schedule I drug in the United States in 1985. In recent years, there has been renewed interest in studying the therapeutic uses of MDMA, particularly in the treatment of post-traumatic stress disorder (PTSD), and early research has shown promising results.

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MDMA-assisted Psychotherapy for PTSD

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The Multidisciplinary Association for Psychedelic Studies (MAPS), a non-profit research and educational organization, has been conducting clinical trials investigating MDMA-assisted psychotherapy for the treatment of PTSD in the United States, Europe, and other parts of the world.

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Early results have shown promise in reducing symptoms of PTSD, and the therapy has been granted "Breakthrough Therapy" designation by the US Food and Drug Administration (FDA), indicating that it may provide significant advantages over existing treatments for the condition. 

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For example, a 2019 analysis of six randomized, double-blind, controlled clinical trials, in which PTSD patients received active doses of MDMA or placebo during two or three 8-hour manualized psychotherapy sessions spaced a month apart, found that 54.2% of those that received MDMA no longer met PTSD diagnostic criteria at the end of treatment, compared to 22.6% that received placebo. 

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Recently, MAPS announced that its second Phase 3 trial of MDMA-assisted therapy for PTSD confirmed prior positive results. If further research confirms the safety and efficacy of the therapy, it could become a legal medicine for the treatment of PTSD in the United States and elsewhere, following on from Australia’s legalization of MDMA-assisted psychotherapy in 2023. 

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It is important to emphasize the key role of psychotherapy in MDMA-assisted psychotherapy. MDMA-assisted psychotherapy involves a trained therapist who helps the patient work through their emotions and experiences while under the influence of MDMA. MDMA itself is not a cure for mental illness but rather a tool that, when used in conjunction with psychotherapy, can facilitate the therapeutic process. 

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Researchers believe that MDMA-assisted psychotherapy could be a particularly valuable treatment option for war veterans and first responders suffering from PTSD who have a higher risk of suicide compared to the general US population. 

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Psychedelics for End-of-life Anxiety

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Some studies have suggested that psychedelics, particularly psilocybin and LSD, may be helpful in reducing anxiety in people with life-threatening illnesses, including end-of-life anxiety. 

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In 2014, Gasser et al. conducted a double-blind, randomized, active placebo-controlled study to investigate the effects of LSD in patients with anxiety associated with life-threatening diseases. In this trial, two 200 microgram doses of LSD combined with psychotherapy produced significant reductions in anxiety in nine participants. Reductions in anxiety were sustained for at least 12 months.

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However, the study had several limitations, including small sample size and imperfect blinding, that could have impacted the accuracy and generalizability of the results. Imperfect blinding in clinical trials refers to situations where the blinding process, which is intended to prevent the study participants and/or the researchers from knowing which intervention the participants received, is not entirely effective. 

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This was followed up by a 2016 study at Johns Hopkins Center for Consciousness and Psychedelic Research in which 50 participants with a potentially life-threatening cancer diagnosis and a diagnosis that included anxiety and/or mood symptoms were administered high doses of psilocybin (22 or 30mg/70 kg). In this study, psilocybin-assisted therapy was observed to produce a sustained and significant decrease in symptoms of depression, anxiety, and mood disturbance, as well as an increase in quality of life, life meaning, death acceptance, and optimism.

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Also in 2016, researchers at New York University conducted a double-blind, placebo-controlled, crossover trial in which 29 patients with cancer-related anxiety and depression were randomly assigned to receive a single dose of psilocybin (0.3 mg/kg) or a placebo (niacin), both in conjunction with supportive psychotherapy. In this study, psilocybin produced rapid and sustained improvements in anxiety and depression and led to substantial decreases in cancer-related demoralization and hopelessness, improved spiritual well-being, and increased quality of life.

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A long-term follow-up (average of 4.5 years) of this study found that 57% of participants continued to show a clinically significant anxiolytic response and 71% percent reported clinically significant reductions in global psychological distress. Importantly, the authors warned that the effectiveness of this therapy cannot be conclusively determined due to limitations associated with the design of the original 2016 study.

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A 2021 systematic review of 14 studies on classical psychedelics such as LSD and psilocybin, and 19 studies on atypical psychedelics such as MDMA and ketamine, concluded that these may be promising treatment options in patients with a terminal illness. However, the authors warned that some of these studies have serious methodological flaws, and emphasized the need for larger high-quality studies. 

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Most recently, a relatively large randomized, double-blind, placebo-controlled Phase II study found that 200 micrograms of LSD administered in combination with psychotherapy to patients with anxiety associated with and without a life-threatening illness produced strong reductions in anxiety, depression, and general psychiatric symptomatology compared with placebo. Reductions in anxiety were statistically significant 16 weeks after the last LSD treatment, while reductions in depression and general psychiatric symptomatology were also sustained for up to 16 weeks.

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While the study had several notable strengths, such as a large sample size and rigorous methodology, there were also some limitations that need to be considered in interpreting the results.

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Psychedelics for Depression 

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Preliminary research suggests that psilocybin may have the potential to provide long-lasting relief for individuals with depression who have not found success with traditional treatments. 

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While the use of psilocybin in a therapeutic setting is still in its early stages, the results of recent studies have been promising and have spurred continued research in this area, and prompted the FDA to grant Breakthrough Therapy Designation to psilocybin for major depressive disorder and treatment-resistant depression.

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In 2021, researchers at Imperial College of London conducted the first-ever double-blind, randomized, controlled trial comparing the antidepressant effects of a classical psychedelic with a selective serotonin reuptake inhibitor (SSRI). SSRIs are a type of medication commonly prescribed to treat depression, anxiety, and other mental health conditions.

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Psilocybin administered in a controlled environment with supportive therapy demonstrated similar and potentially superior antidepressant effects than the widely prescribed SSRI medication, escitalopram (sold under the brand names Lexapro and Cipralex). However, the study’s authors stressed the importance of conducting larger and longer clinical trials before drawing any strong conclusions regarding psilocybin’s efficacy as an antidepressant. 

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Since then, a 12-month follow-up study conducted by Johns Hopkins researchers found that psilocybin-assisted therapy significantly reduced depression in 18 of 24 participants diagnosed with treatment-resistant major depressive disorder. More than 50% of participants were observed to be in remission 12 months after their psilocybin treatment. Remission refers to a period where a person with depression experiences minimal or no symptoms of depression for a certain period of time.

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However, this study also had some limitations. A significant percentage of participants reported using antidepressants during the follow-up period, making it difficult to determine the effects of psilocybin alone. Additionally, the study design did not allow for a comparison group at long-term follow-up, and placebo effects and psychotherapy may have accounted for some of the therapeutic benefits observed.

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British biotech company Compass Pathways recently published the results of a Phase 2b clinical trial that investigated the antidepressant effects of COMP360, Compass Pathways’ proprietary formulation of psilocybin. This study is the largest psilocybin therapy trial conducted to date. By week 3, a single 25-milligram dose of COMP360 administered as an adjunct to psychological support produced more than a 50% reduction in depressive symptoms in 37% of participants. 29% of participants that received 25 milligrams of psilocybin were observed to be in remission at week 3. 

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Notably, Compass Pathways reported a high occurrence of adverse serious events in the trial. Albeit somewhat expected considering the patient population and the powerful nature of psilocybin’s effects, further research is needed to determine the extent to which serious adverse events were associated with the psilocybin treatment. 

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In a 2023 clinical trial conducted by researchers at the University of Zurich, Switzerland, a single moderate dose of psilocybin administered alongside supportive psychotherapy was found to significantly reduce depressive symptoms in individuals diagnosed with major depressive disorder. 54% of participants in the psilocybin-assisted psychotherapy group met remission criteria at the end of treatment. 

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Ketamine for Depression 

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Ketamine, a dissociative anesthetic known for its ability to produce feelings of detachment from one's body and environment, alterations in perception of time and space, and changes in thought processes, has gained attention in recent years for its potential as a rapid-acting antidepressant.

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Unlike classic psychedelics like psilocybin and LSD or entactogens like MDMA, ketamine has a long history of medical use and is an FDA-approved medication for anesthesia and pain management. Though ketamine is not currently approved for the treatment of depression, it can be prescribed off-label by a licensed physician for the treatment of depression or other mental health conditions.

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Researchers have conducted a number of studies investigating the antidepressant effects of ketamine. These studies have shown promising results, with some participants experiencing significant improvement in depressive symptoms within hours of receiving ketamine treatment.

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While the mechanisms underlying the antidepressant effects of ketamine are still not fully understood, research in this area has the potential to impact the treatment of depression, particularly for individuals who have not responded to traditional antidepressant medications.

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To date, 24 systematic reviews have reported rapid and robust antidepressant effects of ketamine infusions lasting roughly 1-2 weeks. As a result of the clinical findings demonstrating ketamine’s efficacy for depression, a nasal spray that contains a compound derived from ketamine called esketamine (brand name “Spravato”) was approved by the FDA for use in adults with treatment-resistant depression and suicidal ideation.

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Ketamine has also demonstrated potential efficacy for anxiety, suicidal ideation, PTSD, OCD, and substance use disorders. 

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When administered under the supervision of a medical professional, ketamine has a relatively favorable safety profile. However, it is important to note that ketamine also carries certain risks such as moderate to high abuse potential that are not associated with classic psychedelics. Furthermore, chronic long-term ketamine use has been shown to cause physical changes in the brain and changes in how the brain functions, swelling of the kidneys, and inflammation of the bladder, making careful consideration of its use necessary.

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Navigating the Psychedelic Landscape: Balancing Potential and Precautions

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In conclusion, the emerging research on psychedelics for mental health care is promising. That said, it is important to recognize that these substances are not a panacea and it is advised that they be used in a controlled setting under the guidance of a trained professional or experienced, trusted guide, and after a thorough medical and psychological evaluation to determine if they are safe and appropriate for the individual. 

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Also, there are several specific medical conditions, circumstances, or medications that make psychedelic treatment potentially harmful or dangerous, including but not limited to: personal or family history of psychosis or schizophrenia, severe or unstable medical conditions, use of certain medications such as monoamine oxidase inhibitors (MAOIs), history of substance abuse or addiction, and pregnancy. 

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While there is still much to learn about the therapeutic potential of psychedelics, they offer hope for individuals struggling with treatment-resistant mental health conditions. As the field of psychedelic therapy continues to develop, it is important to approach it with an open mind, but also with a critical eye toward ensuring safe and effective treatments for those in need.

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It is clear that psychedelics have potential in mental health care, but further research is needed to fully understand their therapeutic benefits and potential risks.