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MDMA-assisted psychotherapy

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MDMA-assisted psychotherapy is the use of prescribed doses of MDMA as an adjunct to psychotherapy sessions. The study of MDMA as an enhancer for psychotherapy has been constrained since 1985 when the drug was classified in the United States as a Schedule I controlled substance. Research by the Multidisciplinary Association for Psychedelic Studies (MAPS) has provided evidence that MDMA can help address trauma-related disease, in particular post-traumatic stress disorder. In 2017, a Phase II clinical trial led to a designation of breakthrough therapy status by the US Food and Drug Administration (FDA).[1][2]

The research is controversial[3][4] due to the risks of taking MDMA recreationally, made evident by the illegal and unregulated use of MDMA in the form of ecstasy[5] and also due to its unpredictable neurochemical effects.[3][6] There were 92 MDMA related deaths in England and Wales in 2018, up from 56 the year before,[7] and 10,000 hospitalizations for MDMA related illness/injury in 2011 in the US.[5] However no such cases have been observed in clinical settings. Systematic reviews of a few trials with a small number of patients indicated that MDMA appeared to be potentially safe and effective in controlled clinical use.[8][9][10]

The use of psychedelics for therapy has been characterized as 'countercultural' in Western cultures.[11]

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 suffer from 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:[4] 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.[12] 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.[12]

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.[4] 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.[1] A phase 3 study indicated that MDMA-assisted therapy represents a potential breakthrough treatment for severe PTSD that merits expedited clinical evaluation.[13] 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,[14][15] 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.[16]

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.[17]

Rationale for MDMA treatment

PTSD inhibits a subject's ability to respond appropriately to trauma-related stimuli.[4] The current model of PTSD proposes that it results from amplified and uncontrolled responses from the amygdala to trauma-specific cues.[12] Oxytocin, which is inreased 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.[18][19][20] 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.[12]

Procedure

In current studies of MDMA therapy a 125 mg capsule of MDMA is orally administered. The subject is monitored, listens to emotionally provocative music, and engages in conversation with the therapist. After 2 hours, a supplemental 62.5 mg dose of MDMA is administered orally. The therapist works with the patient for 6 hours, or until the psychedelic effects of the drug have worn off. Therapists encourage the patients to reach their own introspective conclusions, punctuated by discussion and collective reconsolidation of the memory.[12] The patient stays in the clinic overnight to be monitored.

The following morning, the patient and therapist hold an integration session where they discuss the experimental session and process emotions. Three 90-minute integration sessions are held in the subsequent month. This process is repeated two or three times.

Breakthrough therapy designation

In 2017, the treatment was granted breakthrough therapy status by the FDA, a designation that indicates that there is preliminary evidence that an intervention offers a substantial improvement over other options for a serious health condition.[2] Whether MDMA-assisted psychotherapy for PTSD represents a real, and not only by designation, treatment breakthrough for PTSD has been questioned.[16]

Social anxiety disorder

Researchers at the Los Angeles BioMedical Research Institute reported a study of MDMA-assisted psychotherapy for autistic adults with social anxiety disorder in 2018.[21] The goal of the study was to explore the feasibility of treating the patients' social anxiety with MDMA-assisted therapy, rather than to reduce atypical responses associated with autism. The study used the same procedure as the MDMA-assisted psychotherapy treatment for PTSD. The study also included mindfulness therapies, and was held in a room that included natural elements (e.g. fresh flowers), fidget objects, and other items that are helpful for many autistic adults.[21] Enrollment in the study was contingent on a score of more than 60 on the Liebowitz social anxiety scale - a score that indicates 'difficulties functioning socially and distress'.[21] This study compared the MDMA group with a placebo group. The MDMA group's reduction in anxiety was considerably greater than that for the placebo group, and was retained at 6-month follow up sessions. Side effects of anxiety, difficulty in concentrating, headache, fatigue and depression were noted, however.[21]

Alcohol Use Disorder

There is currently an ongoing study at Bristol Imperial that is using MDMA assisted psychotherapy for people dealing with Alcohol Use Disorder. The study has two MDMA assisted psychotherapy sessions for the estimated 20 participants. The participants in the study are given 125 mg of MDMA as an initial dose and a 62.5 mg booster two hours later. The participants in the clinical trial are patients with alcohol use disorder post-detoxification. The study's estimated date of completion is June 12, 2020.[22] 2019 interim results of a study of four participants found that two participants completely stopped drinking alcohol and two participants each had just one low alcohol use incidents. None of the four used alcohol harmfully between the study and the follow up period.[23]

Other research

MDMA has been proposed as an adjunct for other psychiatric disorders. For example, MDMA-assisted psychotherapy has been tested in a pilot study of anxiety related to advanced stage cancer.[24] This study was terminated due to lack of funding and insufficient patient enrollment. Recreational users have published personal testimonies recounting positive body image experiences both during and following their use of MDMA,[25] and MDMA-assisted psychotherapy has been proposed as a potential treatment for eating disorders.[26]

MDMA molecular structure

Society and culture

Legality

MDMA was first synthesized by German pharmaceutical company Merck KGaA in the early 1900s as an intermediate in the synthesis of another compound. Its empathogenic 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.[27]

In 1985, MDMA was given Schedule I status in the United States due to its high potential for abuse, and most research was stopped.[4][28] 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.[4] Recently in January 2020, the FDA approved a MAPS request for an Extended Access Program for MDMA-assisted psychotherapy for people with PTSD.[29]

Controversy

MDMA is unpredictable and produces different responses in different people. The drug causes neurotransmitter activation across the main neural pathways (including serotonin and dopamine, noradrenaline) that can result in large mood swings and changes. The memories that emerge under the influence of MDMA can evoke unwanted emotions.[3] Side effects of MDMA use by recreational users include appetite fluctuations, food cravings, and disordered eating.[3]

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.[3] 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".[3]

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.[3] However, MDMA is described as a “self-limiting” drug as the intensity of the positive effects decreases with increased use, while negative effects increase. Dependency rates are low compared to other illicit drugs, at 1% of users.

See also

References

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