Background
Major depressive disorder (MDD) is a world-leading cause of disability. The available treatments are not effective in all patients, and there is a significant need for more effective ...treatment options. Here we present the protocol for an investigator-initiated and publicly funded trial of MDMA-assisted therapy (MDMA-AT) for MDD. This single-site, open-label study investigates the proof of principle and safety of MDMA-AT in participants with MDD and provides an initial impression of treatment effectiveness.
Methods
A total of 12 participants >18 years with DSM-5 diagnosis of MDD will receive a flexible dose of MDMA in a therapeutic setting on two dosing days over a 4 week period preceded by three preparatory sessions. Each MDMA dosing session will be followed by three integration sessions. The primary outcome is change in MDD symptom severity, as measured by the mean change in MADRS scores from Baseline to 8 weeks after the second MDMA session. The secondary outcome is change in functional impairment, as evaluated by the mean change in Sheehan Disability Scale scores from Baseline to 8 weeks after the second MDMA session. Safety measures include vital signs, the incidence of Adverse Events and suicidality as measured by the Colombia-Suicide Severity Rating Scale.
Discussion
This proof of principle trial will inform the development of fully powered clinical trials, optimize the protocol for the administration of MDMA-AT in participants with MDD and explore uncertainties including barriers to recruitment, retention and acceptability of MDMA-AT as a treatment for MDD.
Clinical trial identification
EudraCT number 2021-000805-26.
3,4-Methylenedioxymethamphetamine (MDMA) is being investigated in controlled clinical trials for use as an adjunct medication treatment for post-traumatic stress disorder. MDMA is metabolized by ...N-demethylation, primarily by CYP2D6, to its main inactive metabolite, 4-hydroxy-3-methoxymethamphetamine. It is also metabolized to a lesser extent by CYP1A2, CYP2B6, and CYP3A4 to its active metabolite, 3,4-methylenedioxyamphetamine. Considering the extensive hepatic metabolism and excretion, MDMA use in psychiatry raises concerns over drug-induced liver injury (DILI), a rare but dangerous event. Majority of the drugs withdrawn from the market for liver injury caused death or transplantation at frequencies under 0.01%. Unfortunately, markers for liver injury were not measured in most published clinical trials. At the same time, no visible DILI-related symptoms and adverse events were observed. Idiosyncratic DILI cases are rarely registered during clinical trials due to their rare nature. In this study, we surveyed a larger, over 1,500, and a more diverse set of reports from the FDA Adverse Event Reporting System and found 23 cases of hepatic injury and hepatic failure, in which MDMA was reported to be taken in addition to one or more substances. Interestingly, 22 out of 23 cases had one or more listed drugs with a known DILI concern based on the FDA’s DILIrank dataset. Furthermore, only one report had MDMA listed as the primary suspect. Considering the nearly 20 million doses of MDMA used annually, this single report is insufficient for establishing a significant association with DILI.
On estime que le syndrome de stress post-traumatique (PTSD) reste chronique et sévère pour 25 à 50 % des patients malgré une prise en charge psychothérapeutique. La MDMA (« ecstasy ») possèderait des ...propriétés psychopharmacologiques qui renforcent l’alliance thérapeutique et permettent au patient de travailler sur le contenu traumatique sans être submergé par la peur et l’anxiété. Les résultats d’essais cliniques de phase II confirment que la MDMA améliore efficacement la prise en charge psychothérapeutique des patients atteints de PTSD sans effets secondaires sérieux. Des essais de phases III sont en cours. La Multidisciplinary Association for Psychedelic Studies (MAPS) a mis en ligne une proposition de méthode et forme des thérapeutes pour mener des psychothérapies assistées par la MDMA. La Food and Drug Administration (FDA) et l’European Medicines Agency (EMA) pourraient autoriser cet outil thérapeutique dans les prochaines années.
Posttraumatic stress disorder (PTSD) is estimated to remain chronic and severe for 25–50% of patients despite psychotherapeutic treatment. Part of the reasons is that patients with PTSD can have difficulties in establishing a good therapeutical alliance with the therapist. Moreover, they often fail to re-think the content of the trauma without being overwhelmed by negative emotions and tend to rely on avoidance strategies and/or to abandon the therapy. MDMA (“ecstasy”) is a drug classified as an entactogen (en “within”, tactus “touch”, and gen “produce”), an amphetamine with psychedelic properties that possesses psychopharmacological properties to overcome these issues. Indeed, MDMA triggers the release of oxytocin, which favors the establishment of interpersonal relationship based on kindness and trust. Moreover, MDMA diminishes the activity of the amygdale, allowing patients to work on challenging memories with less fear and anxiety. Finally, MDMA may also provide access to meaningful spiritual experiences, release of tensions and a sense of healing on a non-verbal level that are not completely understood. But are viewed as important by patients. Today, there is no evidence that the use of MDMA in a clinical setting has bad neurologic, psychological or cognitive consequences. Results of phase II trials in the United States and Europe confirm that MDMA favors psychotherapy's outcome without severe adverse effects. Phase III trials are underway. The Multidisciplinary Association for Psychedelic Studies (MAPS) has published online a method proposal and trains therapists in MDMA-assisted psychotherapy.
Food and Drug Administration (FDA) and European Medicines Agency (EMA) could approve this therapeutic tool in the coming years.
At first glance, it appears there is little difference between the molecular structures of methylenedioxymethamphetamine (MDMA), which has an
-methyl attached to its amino group, and ...methylenedioxyamphetamine (MDA), a primary amine that is recognized to have hallucinogenic activity. It is known from studies with other hallucinogenic amphetamines that
-methylation of hallucinogenic amphetamines attenuates or abolishes hallucinogenic activity. Nevertheless, MDMA is biologically active and has a potency only slightly less than its MDA parent. Importantly, it is the Ievo-isomer of hallucinogenic phenethylamines that is more biologically active, whereas it is the dextro isomer of MDMA that is more active. This reversal of stereochemistry for the activity of two very closely related molecules is a very powerful clue that their mechanisms of action differ. Finally, extension of the alpha-methyl of hallucinogenic amphetamines to an alpha-ethyl moiety completely abolishes their hallucinogenic activity. Ultimately, we extended the alpha-methyl group of MDMA to an alpha-ethyl to afford a molecule we named (N-Methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) that retained significant MDMA-like psychoactivity. Hence, there are three structural features that distinguish MDMA from the hallucinogenic amphetamines: (1) the
-methyl on the basic nitrogen, (2) the reversal of stereochemistry and, (3) tolerance of an alpha-ethyl moiety as contrasted with the alpha-methyl of hallucinogenic phenethylamines. Clearly, MDMA is distinct from classical hallucinogenic phenethylamines in its structure, and its psychopharmacology is also unique. Thus, in 1986 I proposed the name "Entactogen" for the pharmacological class of drugs that includes 3,4-methylenedioxymethamphetamine (MDMA) and other substances with a similar psychopharmacological effect. The name is derived from roots that indicate that entactogens produce a "touching within." Rather than having significant psychostimulant, or hallucinogenic effects, MDMA powerfully promotes affiliative social behavior, has acute anxiolytic effects, and can lead to profound states of introspection and personal reflection. Its mechanism of action is now established as involving transport of MDMA by the neuronal serotonin reuptake carrier followed by carrier-mediated release of stored neuronal serotonin.
Considered the β-keto analogue of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), 3,4-Methylenedioxymethcathinone (methylone) is a synthetic cathinone. Over the years, methylone has been used as a ...substitute for conventional psychostimulants, such as MDMA. To date, little is known about the human pharmacology of methylone; the only available information has been provided by surveys or published intoxication reports. In the present observational–naturalistic study, we evaluate the acute subjective and physiological effects of methylone after oral self-administration in comparison to MDMA in healthy poly-drug users. Fourteen participants (10 males, 4 females) selected their single oral doses of methylone from 100 to 300 mg (n = 8, mean dose 187.5 mg) or MDMA from 75 to 100 mg (n = 6, mean dose 87.5 mg) based on their experience. Study variables were assessed at 0, 1, 2, and 4 h (h) and included vital signs (non-invasive blood pressure, heart rate, cutaneous temperature) and subjective effects using visual analogue scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI) short form, and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) questionnaire. Additionally, oral fluid concentrations of methylone and MDMA were determined. Acute pharmacological effects produced by methylone followed the prototypical psychostimulant and empathogenic profile associated with MDMA, although they were less intense. Methylone concentrations in oral fluid can be considered a useful biomarker to detect acute exposure in oral fluid. Oral fluid concentrations of MDMA and methylone peaked at 2 h and concentrations of MDMA were in the range of those previously described in controlled studies. Our results demonstrate that the potential abuse liability of methylone is similar to that of MDMA in recreational subjects.
Psychiatrists and psychotherapists in the US (1970s to 1985) and Switzerland (1988–1993) used MDMA legally as a prescription drug, to enhance the effectiveness of psychotherapy. Early reports suggest ...that it is useful in treating trauma-related disorders. Recently, the first completed pilot study of MDMA-assisted psychotherapy for PTSD yielded encouraging results. Designed to test the safety and efficacy of MDMA-assisted psychotherapy in patients with treatment-resistant PTSD; our randomized, double-blind, active-placebo controlled trial enrolled 12 patients for treatment with either low-dose (25 mg, plus 12.5 mg supplemental dose) or full-dose MDMA (125 mg, plus 62.5 mg supplemental dose). MDMA was administered during three experimental sessions, interspersed with weekly non-drug-based psychotherapy sessions. Outcome measures used were the Clinician-Administered PTSD Scale (CAPS) and the Posttraumatic Diagnostic Scale (PDS). Patients were assessed at baseline, three weeks after the second and third MDMA session (end of treatment), and at the 2-month and 1-year follow-ups.
We found that MDMA-assisted psychotherapy can be safely administered in a clinical setting. No drug-related serious adverse events occurred. We did not see statistically significant reductions in CAPS scores (p = 0.066), although there was clinically and statistically significant self-reported (PDS) improvement (p = 0.014). CAPS scores improved further at the 1-year follow-up. In addition, three MDMA sessions were more effective than two (p = 0.016).
Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, ...placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.
Feeling ecstatic in Shakespeare Edwards, Jennifer J
The Lancet (British edition),
05/2023, Volume:
401, Issue:
10389
Journal Article
Peer reviewed
Open access
In other literature of the period, Shakespeare's work offers a snapshot of the early modern interest in ecstasy as a secular, common experience, one that had begun to extend beyond its associations ...with religious rapture to encompass feelings of desire, sex, grief, loss, anger, jealousy, and alienation, and which could be used as an umbrella term for intense feeling across the emotional spectrum, from the desirable to the torturous. In Macbeth, for example, the contagious grief that afflicts Scotland after the murder of the King is described as a “modern ecstasy”—an intensity of suffering that is so familiar and widespread that it has become an everyday (a now obsolete meaning of “modern”) emotion: “Alas, poor country,Almost afraid to know itself. In his essay “That to Philosophise Is to Learn How to Die”, the French philosopher Michel de Montaigne similarly retells a story of a priest “whose soul was ravished into such an ecstasy, that for a long time the body remained void of all respiration or sense”, leaving him with “neither pulse nor breath”. Discussion of epilepsy was unquestionably more clinical than its ecstatic sister-state, but by the second half of the 17th century ecstasy would come to earn a place in Swiss Physician Felix Platter's A Golden Practice of Physick (1662) as a “Consternation of the Mind”, and under an index of “distempers of the brain” in a chapter on “Inward Diseases, and Distempers of the Body” in Alderman Randle Holme's encyclopaedic text of early modern society and daily life, The Academy of Armory (1688).
Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the ...PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
Display omitted
•Serotonergic psychedelics increase neuritogenesis, spinogenesis, and synaptogenesis•Psychedelics promote plasticity via an evolutionarily conserved mechanism•TrkB, mTOR, and 5-HT2A signaling underlie psychedelic-induced plasticity•Noribogaine, but not ibogaine, is capable of promoting structural neural plasticity
Ly et al. demonstrate that psychedelic compounds such as LSD, DMT, and DOI increase dendritic arbor complexity, promote dendritic spine growth, and stimulate synapse formation. These cellular effects are similar to those produced by the fast-acting antidepressant ketamine and highlight the potential of psychedelics for treating depression and related disorders.
PDF
