OPEN Foundation

Anxiety disorders / PTSD

Posttraumatic Stress Disorder After a Psychedelic Experience, a Case Report

Abstract

In the last 2 decades, there is a renaissance in the scientific investigation of the therapeutic potential of psychedelic compounds. It is studied for the treatment of many psychiatric disorders, including posttraumatic stress disorder. The treatment is always done in the setting of psychedelic-assisted psychotherapy. A little is known about the potential effects, outside of the setting of psychedelic-assisted psychotherapy, on people diagnosed with a mental disorder or have a significant trauma history. In this case report, we present a young man who developed posttraumatic stress disorder after a psychedelic experience, induced by both Lysergic Acid Diethylamide (LSD) and N, N Dimethyltryptamine (DMT). In the psychedelic experience, a repressed memory of childhood sexual abuse was recovered. To our knowledge, this is the first report on posttraumatic stress disorder onset after a psychedelic experience. We believe that this case report is important since the history of trauma is prevalent among individuals with substance use disorder. Medical staff that treat people with either substance use disorder or trauma should be familiar with irregular presentations, such as the one described in this case.

Rubin-Kahana, D. S., Hassan, A. N., & Le Foll, B. (2021). Posttraumatic Stress Disorder After a Psychedelic Experience, a Case Report. Journal of addiction medicine, 15(3), 248–251. https://doi.org/10.1097/ADM.0000000000000734

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Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies

Abstract

Objective: To conduct a systematic review of modern-era (post-millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented.

Method: A systematic literature search (1 Jan 2000 to 1 May 2020) was conducted in PubMed and PsychINFO for studies of patients undergoing treatment with a serotonergic psychedelic.

Results: Data from 16 papers, representing 10 independent psychedelic-assisted therapy trials (psilocybin = 7, ayahuasca = 2, LSD = 1), were extracted, presented in figures and tables, and narratively synthesized and discussed. Across these studies, a total of 188 patients suffering either cancer- or illness-related anxiety and depression disorders (C/I-RADD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD) or substance use disorder (SUD) were included. The reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. For a majority of patients, the therapeutic effects appeared to be long-lasting (weeks-months) after only 1 to 3 treatment session(s). All studies were conducted in line with guidelines for the safe conduct of psychedelic therapy, and no severe adverse events were reported.

Conclusion: The resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.

Andersen, K., Carhart-Harris, R., Nutt, D. J., & Erritzoe, D. (2021). Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies. Acta psychiatrica Scandinavica, 143(2), 101–118. https://doi.org/10.1111/acps.13249

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The effectiveness of intravenous ketamine in adults with treatment-resistant major depressive disorder and bipolar disorder presenting with prominent anxiety: Results from the Canadian Rapid Treatment Center of Excellence

Abstract

Background: Individuals meeting criteria for treatment-resistant depression (TRD) are differentially affected by high levels of anxiety symptoms.

Aims: There is a need to identify the efficacy of novel rapid-onset treatments in adults with mood disorders and comorbid anxious-distress.

Methods: This study included patients with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD) who were receiving intravenous (IV) ketamine treatment at a community-based clinic.Anxious-distress was proxied using items from the Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS-SR16) and Generalized Anxiety Disorder 7-item (GAD7) scales. The difference in QIDS-SR16 total score, QIDS-SR16 suicidal ideation (SI) item and GAD7 score were analyzed between groups.

Results: A total of 209 adults with MDD (n = 177) and BD (n = 26) were included in this analysis. From this sample, 94 patients (mean = 45 ± 13.9 years) met the criteria for anxious-distress. Individuals meeting the criteria for anxious-distress exhibited a significantly greater reduction in QIDS-SR16 total score following four infusions (p = 0.02) when compared with patients not meeting the anxious-distress criteria. Both anxious-distressed and low-anxiety patients exhibited a significant reduction in SI (p < 0.0001) following four infusions.Finally, there was a significantly greater reduction in anxiety symptoms in the anxious-distress group compared with the non-anxious distress group following three (p = 0.02) and four infusions (p < 0.001).

Conclusion: Patients with TRD and prominent anxiety receiving IV ketamine exhibited a significant reduction in depressive, SI and anxiety symptoms.

McIntyre, R. S., Rodrigues, N. B., Lipsitz, O., Nasri, F., Gill, H., Lui, L. M., Subramaniapillai, M., Kratiuk, K., Teopiz, K., Ho, R., Lee, Y., Mansur, R. B., & Rosenblat, J. D. (2021). The effectiveness of intravenous ketamine in adults with treatment-resistant major depressive disorder and bipolar disorder presenting with prominent anxiety: Results from the Canadian Rapid Treatment Center of Excellence. Journal of psychopharmacology (Oxford, England), 35(2), 128–136. https://doi.org/10.1177/0269881120954048

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What is the future of legal MDMA?

There has been a renaissance in the research of psychedelics, and much of it has been led by promising studies over the past two or three decades. Aside from the discussion of whether MDMA is a true ‘psychedelic’, it is clear that recent studies have created momentum to reconsider these substances as medication for severe mental health problems such as depression, anxiety or addiction.
MDMA’s application to trauma therapy has become one of the central priorities of psychedelic researchers. So what is the current state of knowledge and where do we stand in the regulatory process? According to MAPS-founder Rick Doblin, MDMA will be legal soon if the hard work continues. “I keep saying it’s going to be 2035”.
MDMA Treatment
Victims of war or sexual assault are prone to develop anxiety and avoidance behaviors as a result of these tragic experiences. Some of them may be diagnosed with Post-Traumatic Stress Disorder (PTSD), a condition characterized by severe feelings of fear and distress in response to trauma-related details. The increasing prevalence of PTSD is aggravated by the lack of treatment options.
Current trauma-focused psychotherapies, such as exposure and cognitive-behavioral therapy, have important problems of access for certain high-risk populations, as well as high dropout rates. In regard to efficacy, some reviews have found that up to 70% of patients retain their PTSD diagnosis after treatment.
The only two pharmaceuticals with FDA approval also seem to be inefficient for many. One third of all PTSD patients are estimated to be treatment-resistant. This diagnosis is given when several different treatments fail to improve symptoms.

MDMA trials have focused on this specific population because of strategic reasons. It is easier to get permission to test a new drug on patients for whom everything else has failed. Psilocybin trials have taken a similar approach by focusing on treatment-resistant depression or anxiety related to the end of life.
Current clinical research employs a hybrid treatment model that combines the administration of 75 to 125mg of MDMA with therapeutic support provided in preparation and integration sessions. During the drug sessions, therapists monitor the patient and adopt a non-directive approach that allows the person under the effects of MDMA to dive into the experience with minimal interruptions. This model of psychedelic-assisted psychotherapy entails a groundbreaking paradigm in psychiatry that goes beyond mere medications and talk therapy.
A long path
It has taken a while before these modern trials were set up. MDMA is an amphetamine derivative first synthesized by Merck Laboratories in 1912 and later rediscovered by chemist Sasha Shulgin in the 1970s. At the time, psycholytic therapy was being developed with LSD and psychiatrists saw a new potential tool for psychotherapy in MDMA and its empathogenic properties.
Unfortunately, the increasing popularity of “Ecstasy” in recreational contexts and the ensuing anti-drug propaganda soon led to the classification of MDMA as a Schedule 1 substance in 1986, which introduced immense obstacles to scientists investigating its medicinal application.
Ever since, the Multidisciplinary Association for Psychedelic Studies has been working for the approval of MDMA as a therapeutic treatment in mental health and to remove the immense barriers that were thrown up for the potential medication.
Although preliminary investigations by Charles Grob had successfully proved the safety of administration of MDMA to healthy subjects in the 1990s, the first MAPS-sponsored trial for PTSD conducted in Spain by José Carlos Bouso was shut down because of political pressure from the Spanish authorities.
Placebo challenges
So far, six phase-2 clinical trials have been completed, and despite the small samples and the methodological limitations, the results are very promising. The first randomized controlled trials with PTSD patients began to take place in the late 2000s, and resulted in a landmark paper from 2011 by Michael Mithoefer, Mark Wagner, Ann Mithoefer, Lisa Jerome, and Rick Doblin. It concluded that ‘the rate of clinical response was 10/12 (83%) in the active treatment group versus 2/8 (25%) in the placebo group’.
One year later, most of these patients for whom all other treatments had failed still showed a persistent and significant improvement. More importantly, the lack of serious adverse effects pointed at the safety of MDMA in a clinical context and paved the way for more trials.

Skeptics pointed at the methodological weaknesses of this first trial. They criticized the use of lactose as placebo and the difficulties to blind the effects of MDMA to patients and investigators, a common problem in psychedelic therapy trials. An attempt of replication in Switzerland by Peter Oehen which circumvented the blinding problem with an active placebo group (25mg MDMA) showed good results, but were not statistically significant.
Researchers suspected that differences in the work and style of the Swiss therapists might have been behind these suboptimal results, which raised the question of how to standardize the psychotherapeutic part of the treatment. In subsequent trials, MAPS developed an adherence rating system in order to ensure that therapists stick to the standard guidelines of their therapeutic model.
In 2018, Michael Mithoefer published the first dose-response study, which compared the efficacy of three different doses of MDMA: 30mg, 75mg and 125mg. The groups with middle and high doses showed significant remission of PTSD with respectively 86% and 58% of each group’s sample not meeting the diagnostic criteria anymore after treatment, improvements which persisted in the one year follow-up. Shortly after, a similar study by Marcela Ot’alora replicated the results with 76% of patients not meeting the diagnostic criteria for PTSD one year after the treatment.
A Path Towards Regulation
Given these promising results, the FDA accelerated the approval process of MDMA with the Breakthrough Therapy designation in 2017 and allowed the early compassionate use of MDMA-assisted psychotherapy for treatment-resistant patients in 2020.
Two ongoing multi-site phase-3 trials sponsored by MAPS are currently assessing the efficacy of MDMA in around 200 participants from the US, Canada and Israel. Recently, MAPS’ interim analysis of the first phase-3 trial suggested that their results will probably reach statistical significance, and if nothing goes wrong, MDMA could be approved for the treatment of PTSD by mid-2022.
In the meantime, more phase-2 trials are starting to take place in Europe for PTSD and other conditions such as alcoholism. With the first psychedelic substance on the verge of approval, many questions remain in the air:

All these questions will require years of additional research, which needs to be done by current and future doctors, researchers and policy makers. But the direction and ambition of all this research is clear: to turn the hard facts of well-researched trials into a regulatory model, so that MDMA will be a legal future medication to help many.

Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin

Abstract

The aim of this systematic review was to examine the efficacy of MDMA, ketamine, LSD, and psilocybin for the treatment of posttraumatic stress disorder (PTSD). A search of four databases for English language, peer-reviewed literature published from inception to 18th October 2019 yielded 2,959 records, 34 of which were screened on full-text. Observational studies and RCTs which tested the efficacy of MDMA, ketamine, LSD, or psilocybin for reducing PTSD symptoms in adults, and reported changes to PTSD diagnosis or symptomatology, were included. Nine trials (five ketamine and four MDMA) met inclusion criteria. Trials were rated on a quality and bias checklist and GRADE was used to rank the evidence. The evidence for ketamine as a stand-alone treatment for comorbid PTSD and depression was ranked “very low”, and the evidence for ketamine in combination with psychotherapy as a PTSD treatment was ranked “low”. The evidence for MDMA in combination with psychotherapy as a PTSD treatment was ranked “moderate”.

Varker, T., Watson, L., Gibson, K., Forbes, D., & O’Donnell, M. L. (2021). Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin. Journal of psychoactive drugs, 53(1), 85–95. https://doi.org/10.1080/02791072.2020.1817639

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Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy

Abstract

The last two decades have seen a revival of interest in the entactogen 3,4-methylenedioxy-N-methylamphetamine (MDMA) as an adjunct to psychotherapy, particularly for the treatment of post-traumatic stress disorder. While clinical results are highly promising, and MDMA is expected to be approved as a treatment in the near future, it is currently the only compound in its class of action that is being actively investigated as a medicine. This lack of alternatives to MDMA may prove detrimental to patients who do not respond well to the particular mechanism of action of MDMA or whose treatment calls for a modification of MDMA’s effects. For instance, patients with existing cardiovascular conditions or with a prolonged history of stimulant drug use may not fit into the current model of MDMA-assisted psychotherapy, and could benefit from alternative drugs. This review examines the existing literature on a host of entactogenic drugs, which may prove to be useful alternatives in the future, paying particularly close attention to any neurotoxic risks, neuropharmacological mechanism of action and entactogenic commonalities with MDMA. The substances examined derive from the 1,3-benzodioxole, cathinone, benzofuran, aminoindane, indole and amphetamine classes. Several compounds from these classes are identified as potential alternatives to MDMA.

Oeri H. E. (2021). Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy. Journal of psychopharmacology (Oxford, England), 35(5), 512–536. https://doi.org/10.1177/0269881120920420

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Psychedelic science in post-COVID-19 psychiatry

Abstract

The medium- to long-term consequences of COVID-19 are not yet known, though an increase in mental health problems are predicted. Multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of COVID-19. Preliminary evidence from the rapidly progressing field of psychedelic science shows that psilocybin therapy offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behaviour, notably depression, addiction and obsessive compulsive disorder. The COMPASS Pathways (COMPASS) phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (TRD) is underway to determine the safety, efficacy and optimal dose of psilocybin. Results from the Imperial College London Psilodep-RCT comparing the efficacy and mechanisms of action of psilocybin therapy to the selective serotonin reuptake inhibitor (SSRI) escitalopram will soon be published. However, the efficacy and safety of psilocybin therapy in conjunction with SSRIs in TRD is not yet known. An additional COMPASS study, with a centre in Dublin, will begin to address this question, with potential implications for the future delivery of psilocybin therapy. While at a relatively early stage of clinical development, and notwithstanding the immense challenges of COVID-19, psilocybin therapy has the potential to play an important therapeutic role for various psychiatric disorders in post-COVID-19 clinical psychiatry.

Kelly, J. R., Crockett, M. T., Alexander, L., Haran, M., Baker, A., Burke, L., … & O’Keane, V. (2020). Psychedelic science in post-COVID-19 psychiatry. Irish journal of psychological medicine, 1-6; 10.1017/ipm.2020.94

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Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies

Abstract

Introduction: Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders.

Objective: To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients’ accounts, and elucidating how these affect the treatment process.

Methods: We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP).

Results: Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses.

Conclusions: This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.

Breeksema, J. J., Niemeijer, A. R., Krediet, E., Vermetten, E., & Schoevers, R. A. (2020). Psychedelic treatments for psychiatric disorders: a systematic review and thematic synthesis of patient experiences in qualitative studies. CNS drugs, 1-22; 10.1007/s40263-020-00748-y

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The rise, fall, and possible rise of LSD

Abstract

LSD and other hallucinogens or psychedelics have been therapeutically used in psychiatry in the period between the Second World War and the late 1980s. In the past years renewed interest in the medical sciences for research and therapeutic use of these substances has evolved. AIM: A discussion of contemporary lsd research in the context of earlier research. METHOD: A systematic survey of the literature on the psychiatric use of lsd and the reactions towards lsd use in society. RESULTS: Since 1947 lsd has been therapeutically used in the treatment of anxiety, depression, addiction, post traumatic disorders, and other conditions. Since the early 1960s this use has been criticized because of the danger of evoking psychoses in patients, and because of the rise of a widespread non-medical use. However, there is no consolidated evidence-base for either the positive or the negative outcomes of lsd therapy. CONCLUSION: At this moment it is unpredictable whether lsd will make a comeback in psychiatry. Contemporary research attempts to evade all public controversy and to build up a solid evidence-base. Nevertheless it demonstrates a direct continuity with earlier research.

Snelders, S., & Pieters, T. (2020). The rise, fall, and possible rise of LSD. Tijdschrift Voor Psychiatrie62(8), 707-712.
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[Psychedelics in the treatment of substance use disorders and psychosis]

Abstract

After psychedelics were banned in 1968, the flourishing research on the use of psychedelics in patients with a mental disorder stopped abruptly. Recently, we see a renaissance of this research.<br/> AIM: To present an overview of what is known about the treatment of addiction and psychosis with psychedelics.<br/> METHOD: Literature study based on Medline en PubMed publications till December 2019.<br/> RESULTS: Studies on the effectiveness of psychedelics in the treatment of addiction and psychosis is still very limited in size and methodological quality. Nevertheless, most studies show positive effects of both classical and atypical psychedelics in a variety of addictions on motivation, craving, reduced consumption, and abstinence often following a single dose and with long-lasting benefits (3-24 months). Use of ketamine in patients with a psychosis stabilized on an antipsychotic might reduce negative symptoms.<br/> CONCLUSION: Before psychedelics can be used in standard clinical practice for the treatment of patients with an addiction or a psychosis, larger and methodologically better studies are needed. The use of psychedelics also creates an opportunity to better understand the shared underlying pathology of many different mental disorders.
van den Brink, W., Breeksema, J. J., Vermetten, E., & Schoevers, R. A. (2020). Psychedelics in the treatment of substance use disorders and psychosis. Tijdschrift Voor Psychiatrie62(8), 650-658., https://pubmed.ncbi.nlm.nih.gov/32816293/
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