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Chronic pain and psychedelics: a review and proposed mechanism of action

Abstract

The development of chronic pain is a complex mechanism that is still not fully understood. Multiple somatic and visceral afferent pain signals, when experienced over time, cause a strengthening of certain neural circuitry through peripheral and central sensitization, resulting in the physical and emotional perceptual chronic pain experience. The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT2A) receptor agonism, to ‘reset’ areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT2A activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.
Castellanos, J. P., Woolley, C., Bruno, K. A., Zeidan, F., Halberstadt, A., & Furnish, T. (2020). Chronic pain and psychedelics: a review and proposed mechanism of action. Regional Anesthesia & Pain Medicine., http://dx.doi.org/10.1136/rapm-2020-101273
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Psychedelics and Psychedelic-Assisted Psychotherapy

Abstract

Objective: The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders.
Methods: Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on “psilocybin,” “lysergic acid diethylamide,” “LSD,” “ayahuasca,” “3,4-methylenedioxymethamphetamine,” and “MDMA,” in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms “clinical trial,” “therapy,” or “imaging” in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care.
Results: The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as “breakthrough therapies” for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders.
Conclusions: Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.

Keywords: Ayahuasca; Drug-Psychotherapy Combination; Lysergic Acid Diethylamide; MDMA; Psilocybin; Psychedelics.
Reiff, C. M., Richman, E. E., Nemeroff, C. B., Carpenter, L. L., Widge, A. S., Rodriguez, C. I., … & Work Group on Biomarkers and Novel Treatments, a Division of the American Psychiatric Association Council of Research. (2020). Psychedelics and psychedelic-assisted psychotherapy. American Journal of Psychiatry177(5), 391-410., https://doi.org/10.1176/appi.ajp.2019.19010035
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Psychedelic Psychiatry’s Brave New World

Abstract

After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results. Outcomes of neuroscience and clinical research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin, show promise for addressing a range of serious disorders, including depression and addiction.

Nutt, D., Erritzoe, D., & Carhart-Harris, R. (2020). Psychedelic Psychiatry’s Brave New World. Cell181(1), 24-28.
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Experience of Music Used With Psychedelic Therapy: A Rapid Review and Implications.

Abstract

Bonny Method of Guided Imagery and Music emerged following discontinuation of psychedelic therapy research in the early 1970s, but psychedelic therapy research has since revived. Music remains a vital component. This study examined participants’ experiences of music in psychedelic therapy research. A rapid review of qualitative and quantitative journal articles in four major databases was conducted in February to April, 2019, using the terms hallucinogens, psychedelic, “lysergic acid diethylamide,” psilocybin, ayahuasca, music, and/or “music therapy.” Of 406 articles retrieved, 10 were included (n = 180; 18-69 years old). Participants had varied backgrounds. Music was widely considered integral for meaningful emotional and imagery experiences and self-exploration during psychedelic therapy. Music transformed through its elicitation of anthropomorphic, transportive, synesthetic, and material sensations. Music could convey love, carry listeners to other realms, be something to “hold,” inspire, and elicit a deep sense of embodied transformation. Therapeutic influence was especially evident in music’s dichotomous elicitations: Music could simultaneously anchor and propel. Participant openness to music and provision of participant-centered music were associated with optimal immediate and longer-term outcomes. Many studies reported scarce details about the music used and incidental findings of music experienced. Further understanding of participants’ idiosyncratic and shared responses to music during drug therapy phases will inform optimal development of flexible music protocols which enhance psychedelic therapy. Music therapists could be involved in the psychedelic therapy research renaissance through assisting with research to optimize music-based protocols used. If psychedelics become approved medicines, music therapists may be involved in offering psychedelic therapy as part of therapeutic teams.

O’Callaghan, C., Hubik, D. J., Dwyer, J., Williams, M., & Ross, M. (2020). Experience of Music Used With Psychedelic Therapy: A Rapid Review and Implications. Journal of Music Therapy., https://doi.org/10.1093/jmt/thaa006
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Reviewing the Potential of Psychedelics for the Treatment of PTSD.

Abstract

There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD). Treatment guidelines have unequivocally designated psychotherapy as a first line treatment for PTSD. Yet, even after psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. Meanwhile, the search and development of drugs with new mechanisms of action has stalled. Therefore, there is an urgent need to explore not just novel compounds, but novel approaches for the treatment of PTSD. A promising new approach involves the use of psychedelic drugs. Within the past few years, two psychedelics have received breakthrough designations for psychiatric indications from the US Food and Drug Administration, and several psychedelics are currently being investigated for the treatment of PTSD. This review discusses four types of compounds: 3,4-methylenedioxymethamphetamine (MDMA), ketamine, classical psychedelics (e.g. psilocybin and LSD) and cannabinoids. We describe the therapeutic rationale, the setting in which they are being administered, and their current state of evidence in the treatment of PTSD. Each compound provides unique qualities for the treatment of PTSD, from their use to rapidly target symptoms, to their use as adjuncts to facilitate psychotherapeutic treatments. Several questions are formulated that outline an agenda for future research.
Krediet, E., Bostoen, T., Breeksema, J., van Schagen, A., Passie, T., & Vermetten, E. (2020). Reviewing the Potential of Psychedelics for the Treatment of PTSD. International Journal of Neuropsychopharmacology., https://doi.org/10.1093/ijnp/pyaa018
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Natural Psychoplastogens As Antidepressant Agents

Abstract

Increasing prevalence and burden of major depressive disorder presents an unavoidable problem for psychiatry. Existing antidepressants exert their effect only after several weeks of continuous treatment. In addition, their serious side effects and ineffectiveness in one-third of patients call for urgent action. Recent advances have given rise to the concept of psychoplastogens. These compounds are capable of fast structural and functional rearrangement of neural networks by targeting mechanisms previously implicated in the development of depression. Furthermore, evidence shows that they exert a potent acute and long-term positive effects, reaching beyond the treatment of psychiatric diseases. Several of them are naturally occurring compounds, such as psilocybin, N,N-dimethyltryptamine, and 7,8-dihydroxyflavone. Their pharmacology and effects in animal and human studies were discussed in this article.

Benko, J., & Vranková, S. (2020). Natural Psychoplastogens As Antidepressant Agents. Molecules25(5), 1172., https://doi.org/10.3390/molecules25051172
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Can MDMA help to treat addiction? Q&A with Ben Sessa

Until now, MDMA has mostly been studied in the context of treating PTSD and helping with autism. Psychiatrist Ben Sessa is now conducting the world’s first clinical study using MDMA-assisted psychotherapy to treat alcohol addiction, at the University of Bristol. According to him MDMA can be effective to treat addiction issues, because it “brings a particular emphasis on empathy and connection with the positive, loving part of the self, and that’s why it’s good for trauma.”
You often say that 2/3 of people with addictions have been traumatised or abused. Do you think there is addiction without trauma?
It depends on how you define trauma. There’s what I call ‘big T trauma’ and ‘little t trauma’. Not all people with addictions have suffered severe physical or sexual abuse. But if you ask people what was their experience of childhood, a vast majority of them will say it was cold: they didn’t feel loved or wanted, their parents weren’t really there for them. Those experiences fit in with what you’d call emotional abuse. Most people don’t recognise it as such, but they’re left feeling somewhat empty by it. It’s the most common factor in people with addictions.
Given this knowledge about where addiction comes from, why are most conventional treatments largely unsuccessful?
It’s a very difficult illness to treat, because of the availability of drugs and alcohol, the problem of social deprivation and poverty, homelessness and poor housing, racism, exclusion, poor education, lack of childcare, etc. If I had a magic wand and could instantly cure an addiction patient, but then sent them back to their dire home situation with transgenerational lack of hope, poverty and exclusion, they’re just going to pick up their addiction again. So it’s a very multidisciplinary problem with multiple factors that cause and maintain it, and we need to address all those factors.
Why then do psychedelics seem to do better in the treatment of addictions than conventional treatments?
Because underlying addiction, and many if not most chronic mental disorders, is rigidity. Stuck rigid mental narratives about self and the world, which arise early in life as a results of early experiences, in other words, the very core building blocks of our personality, which stay with us for life. The majority of mental health treatments, and certainly all the medicines we use, like SSRI’s, don’t do anything to those narratives, they just paper over the cracks and treat the overlying symptoms. In my experience, psychedelics are the best new form of pharmacology that we’ve come across that has the potential to actually tackle those narratives and allows people to build them up in a new, more positive way.
You’re currently conducting a study with MDMA to treat alcohol addiction. This is the first time MDMA is used for that indication. Why did you choose MDMA over psilocybin?
I was always interested in doing an MDMA study. Five years ago, I was in communication with MAPS about an MDMA/PTSD study. But then I got an offer from a rich benefactor which allowed me to do whatever I wanted. As I was working in addictions at the time, I decided to branch away from PTSD. I was acutely aware of alcoholism as being the number one addiction problem with a massive clinical and personal burden, and a very difficult one to treat. I also liked the fact that no-one else had ever suggested MDMA for addiction. Since trauma appears to be a big part of addictions, and MDMA has been shown to work in trauma treatment, it seemed to make sense that MDMA could work for addictions.
Do you think MDMA therapy and psilocybin therapy share the same paradigm?
They clearly have massive overlaps and similarities, for instance the fact of using a non-ordinary state of consciousness as an augmentation of psychotherapy. People would argue that MDMA isn’t a psychedelic, or at least not a classic one. However, I do think it fits into the same paradigm and I consider it a psychedelic psychotherapy tool. There are clearly also some big differences. With MDMA, you don’t get the ego dissolution that occurs on high doses of classic psychedelics. What you do get is a particular emphasis on empathy and connection with the positive, loving part of the self, and that’s why it’s good for trauma. The barrier to addressing trauma for many patients is this brick wall they hit, that prevents them from believing that they are worthy, after often spending decades believing they’re not. MDMA has this greater capacity than psilocybin to put you in a predominantly loving and warm state.
Where’s your MDMA/alcohol study at right now?
We have 14 participants, we finished dosing at the beginning of December, and we’re following everyone up to 9 months from the date of initial detox, so that will be until June. We’re assessing and analysing the data, and we’re writing the papers, which will be published in the first half of this year. This is a safety and tolerability study, with no placebo control group, which is what you have to do when using a new drug in a new condition for the first time. Obviously, we’re also looking at the subjects’ drinking behaviour and maintenance of abstinence and we’ll report on that, and the results look extremely promising. With conventional therapy, about 80% of patients go back to drinking in the next few months, and so far we have about 17% of people who went back to drinking again.
In his talk at ICPR 2020, Ben Sessa will elaborate on his MDMA/alcohol study and sketch future perspectives of psychedelic therapy research.

Posttraumatic Growth After MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder

Abstract

3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder (PTSD) has been shown to significantly reduce clinical symptomatology, but posttraumatic growth (PTG), which consists of positive changes in self-perception, interpersonal relationships, or philosophy of life, has not been studied with this treatment. Participant data (n = 60) were pooled from three Phase 2 clinical studies employing triple-blind crossover designs. Participants were required to meet DSM-IV-R criteria for PTSD with a score higher than 50 on the Clinician-Administered PTSD Scale (CAPS-IV) as well as previous inadequate response to pharmacological and/or psychotherapeutic treatment. Data were aggregated into two groups: an active MDMA dose group (75-125 mg of MDMA; n = 45) or placebo/active control (0-40 mg of MDMA; n = 15). Measures included the Posttraumatic Growth Inventory (PTGI) and the CAPS-IV, which were administered at baseline, primary endpoint, treatment exit, and 12-month follow-up. At primary endpoint, the MDMA group demonstrated more PTG, Hedges’ g = 1.14, 95% CI [0.49, 1.78], p < .001; and a larger reduction in PTSD symptom severity, Hedges’ g = 0.88, 95% CI [-0.28, 1.50], p < .001, relative to the control group. Relative to baseline, at the 12-month follow-up, within-subject PTG was higher, p < .001; PTSD symptom severity scores were lower, p < .001; and two-thirds of participants (67.2%) no longer met criteria for PTSD. MDMA-assisted psychotherapy for PTSD resulted in PTG and clinical symptom reductions of large-magnitude effect sizes. Results suggest that PTG may provide a new mechanism of action warranting further study.

Gorman, I., Belser, A. B., Jerome, L., Hennigan, C., Shechet, B., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Feduccia, A. A. (2020). Posttraumatic Growth After MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder. Journal of traumatic stress, 33(2), 161–170. https://doi.org/10.1002/jts.22479

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Posttraumatic Growth After MDMA‐Assisted Psychotherapy for Posttraumatic Stress Disorder

Abstract

3,4‐Methylenedioxymethamphetamine (MDMA)–assisted psychotherapy for posttraumatic stress disorder (PTSD) has been shown to significantly reduce clinical symptomatology, but posttraumatic growth (PTG), which consists of positive changes in self‐perception, interpersonal relationships, or philosophy of life, has not been studied with this treatment. Participant data (n = 60) were pooled from three Phase 2 clinical studies employing triple‐blind crossover designs. Participants were required to meet DSM‐IV‐R criteria for PTSD with a score higher than 50 on the Clinician‐Administered PTSD Scale (CAPS‐IV) as well as previous inadequate response to pharmacological and/or psychotherapeutic treatment. Data were aggregated into two groups: an active MDMA dose group (75–125 mg of MDMA; n = 45) or placebo/active control (0–40 mg of MDMA; n = 15). Measures included the Posttraumatic Growth Inventory (PTGI) and the CAPS‐IV, which were administered at baseline, primary endpoint, treatment exit, and 12‐month follow‐up. At primary endpoint, the MDMA group demonstrated more PTG, Hedges’ g = 1.14, 95% CI [0.49, 1.78], p < .001; and a larger reduction in PTSD symptom severity, Hedges’ g = 0.88, 95% CI [−0.28, 1.50], p < .001, relative to the control group. Relative to baseline, at the 12‐month follow‐up, within‐subject PTG was higher, p < .001; PTSD symptom severity scores were lower, p < .001; and two‐thirds of participants (67.2%) no longer met criteria for PTSD. MDMA‐assisted psychotherapy for PTSD resulted in PTG and clinical symptom reductions of large‐magnitude effect sizes. Results suggest that PTG may provide a new mechanism of action warranting further study.
Gorman, I., Belser, A. B., Jerome, L., Hennigan, C., Shechet, B., Hamilton, S., … & Feduccia, A. A. (2020). Posttraumatic Growth After MDMA‐Assisted Psychotherapy for Posttraumatic Stress Disorder. Journal of Traumatic Stress., https://doi.org/10.1002/jts.22479

A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses

Abstract

Though there was initial interest in the use of psychedelic drugs for psychiatric treatment, bad outcomes and subsequent passage of the Substance Act of 1970, which placed psychedelic drugs in the Schedule I category, significantly limited potential progress. More recently, however, there has been renewal in interest and promise of psychedelic research. The purpose of this review is to highlight contemporary human studies on the use of select psychedelic drugs, such as psilocybin, LSD, MDMA and ayahuasca, in the treatment of various psychiatric illnesses, including but not limited to treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. The safety and efficacy as reported from human and animal studies will also be discussed. Accumulated research to date has suggested the potential for psychedelics to emerge as breakthrough therapies for psychiatric conditions refractory to conventional treatments. However, given the unique history and high potential for misuse with popular distribution, special care and considerations must be undertaken to safeguard their use as viable medical treatments rather than drugs of abuse.

Chi, T., & Gold, J. A. (2020). A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. Journal of the Neurological Sciences, 116715., 10.1016/j.jns.2020.116715
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