Psychedelic Medicines for Mood Disorders

Current Evidence and Clinical Considerations

Jerome Sarris; Diego Pinzon Rubiano; Kimberley Day; Nicole L. Galvão-Coelho; Daniel Perkins

Curr Opin Psychiatry. 2022;35(1):22-29.

Abstract and Introduction

Abstract

Purpose of Review: Despite advances in treatment modalities for mood disorders over recent decades, further therapeutic options are still required. Increased research is occurring, with the pursuit of psychedelic-based pharmacotherapies for a range of mood disorders and other conditions.

Recent Findings: Serotonergic psychedelics have been found to modulate brain networks underlying various psychiatric disorders, as well promoting neurogenesis and neuroplasticity. Randomized placebo-controlled trials have found psilocybin with psychological support effective at treating depression, including treatment-resistant depression; with emergent research also signalling N,N-dimethyltryptamine/ayahuasca also as a potential option for the treatment of depression. Lysergic acid diethylamide has been found to have anxiolytic effects, whereas 3,4-methylenedioxymethamphetamine (MDMA) has been used effectively to treat post-traumatic stress disorder (PTSD), with Phase III clinical trial evidence. Microdosing of psychedelics is a growing phenomenon that has shown benefits in some preclinical data; however, a recent self-directed controlled trial reported no evidence of improved mood.

Summary: Current research with medicinal psychedelics, usually as an adjunct to psychotherapy, has shown encouraging results in treating mood disorders. However, there are challenges regarding blinding and sample sizes remain small, and there have been no definitive Phase III studies (aside from MDMA for PTSD). Further work exploring novel formulations, interface with pharmacogenomics and the microbiome, and inflammatory pathways can be advised.

Introduction

Ancient preindustrial cultures have used psychoactive plants to facilitate a process akin to psychotherapeutic healing, with archaeological evidence suggesting use of psychoactive plants by humans for milenia.^[1] In Western culture, from the early 1950s to the mid-late 1960s psychedelic substances were used in psychiatry, with encouraging signs of therapeutic potential.^[2] However, the prohibition of these substances from the 1960s halted scientific research in the areas of medical and life sciences.^[3] One of the consequences of this ban was the lack of innovation with new medicines in this area. Nevertheless, the past decade has seen a rebirth of research with psychedelic substances.^[4]

There are currently over 70 clinical trials being conducted across the world using psychedelic-based pharmacotherapies for mood disorders.^[5] One of the main areas of research has been the use of 'classical' psychedelics, which modulate the serotonergic pathway. These include compounds such as psilocybin, N,N-dimethyltryptamine (DMT; usually in the form of the South American plant-based preparation 'ayahuasca') and lysergic acid diethylamide (LSD), which have their primary pathway of action via the 5-HT2A receptors. The compound 3,4-methylenedioxymethamphetamine (MDMA), while not a classical psychedelic, has also been increasingly studied for use as a psychoactive agent within the field. Classical psychedelics have a lower harm profile than many drugs both legal and illegal, and are considered not to create physical dependence, abuse, or withdrawal.^[6] However, they are contraindicated for people diagnosed or at risk of psychotic disorders.^[7] MDMA is rarely addictive, has a low potential for abuse, and no known neurotoxic effects at doses used clinically.^[8] The recent Australian Drug Harms Ranking Study, identified psilocybin and MDMA as among the five least harmful drugs out of 22 investigated, scoring 5 and 7, respectively. Alcohol was ranked as the most harmful, scored at 71, fentanyl 51, prescription opioids 30, and cannabis 17.^[9]

Our present aim is to summarize current research within the evolving field of medicinal psychedelics for use in mood disorders. We provide a concise review of the key mechanistic and clinical data for all major classical psychedelics (psilocybin, LSD, and DMT/ayahuasca), and MDMA. A review of the English language literature was conducted from inception up to September 2021, with clinical data being located and synthesized on major depressive disorder, post-traumatic stress disorder (PTSD), and social anxiety. No clinical trial data were found for other affective disorders in which these were the primary outcome measure (e.g., generalised anxiety disorder, panic disorder, dysthymia). Further, we provide a 'clinician friendly' table summarizing the data and suggested applications, in addition to a clinical considerations section.

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Table 1. Key clinical trials
Condition	Psychedelic agent/s	Methodology	Results	Comment
Major depressive disorder (and depressive symptoms)
Galvão-Coelho et al. 2021	Psilocybin, LSD, ayahuasca	Meta-analysis (psilocybin n= 8, LSD n= 3, ayahuasca n= 1)	Medium-term effects (2–7 days after treatment) in those with depression (measured on depression rating scales), with a large effect size (SMD = −0.841, P= 0.001) in favour of psychedelics in symptom reduction. In this cohort, moderate impact sizes were found in both acute (SMD −0.720, P= 0.003) and long-term outcomes (SMD −0.792, P < 0.001)	Significant antidepressant effects for all classic serotonergic psychedelics reviewed during acute effects, medium and long-term
Goldberg et al. 2020	Psilocybin	Meta-analysis (4 studies, 3 placebo-controlled RCTs) including depression and anxiety symptoms	Within-group statistically significant effects and a large effect size (Hedges g = 1.16–1.47). In placebo RCTs large effect was also found (Hedges g = 0.82–0.83)	Within-group effects at posttreatment and 6-month follow-up indicated considerable decreases in anxiety and depression symptoms
Carhart Harris et al. 2021	Psilocybin	Double-blind RCT: psilocybin vs. escitalopram	Mean (±SE) changes in the scores from baseline to week 6 were −8.0 ± 1.0 points in the psilocybin group and −6.0 ± 1.0 in the escitalopram group, for a between-group difference of 2.0 points. Outcome measure was nonstatistically significant	Secondary measures favoured psilocybin. Higher percentage of response and remission on those in the psilocybin group
Davis et al. 2021	Psilocybin	Double-blind RCT	Statistically significant reduction in depression scores at week-1 and week-5 after treatment. Effect sizes were large at week 5 and week 8 (Cohen's d = 2.5, 2.6, respectively). 54% of participants were in remission at week 4	Psilocybin with psychotherapy produced significant rapid and continuing antidepressant effects
Treatment-resistant depression
Carhart-Harris et al. 2016, 2018	Psilocybin	Open-label study	Significant and substantial reduction in depressive symptoms at week 1 (Cohen's d = 2.2) and week 5 (d = 2.3), largely maintained at 3 months (d = 1.5) and at 6 months (d = 1.4)	Psilocybin with psychological support was found to be highly efficacious in mitigating symptoms of TRD and even lead to remission in some patients
Palhano-Fontes et al. 2019	Ayahuasca/DMT	Double-blind RCT	Montgomery-Asberg Depression Rating Scale scores were significantly lower in the ayahuasca group compared with placebo at day 1, day 2 (P= 0.04), and at day 7 (P < 0.0001)	Evidence of rapid antidepressant effects on patients with TRD
PTSD
Mitchell et al. 2021	MDMA	Phase III double-blind RCT	MDMA was observed to elicit a significant and robust reduction in CAPS-5 score (P= 0.0001, d = 0.91) and a significant decrease in SDS total score (P= 0.0116, d = 0.43) when compared with placebo	MDMA-assisted therapy is highly effective in treating severe PTSD when compared with manualized therapy with an inert placebo. It's also safe and well tolerated, even in those with comorbidities
Social anxiety
Danforth et al. 2018	MDMA	Double-blind RCT	Improvement in LSAS scores from baseline to the primary endpoint was significantly greater for MDMA group compared with the placebo group (P= 0.037), and placebo-subtracted Cohen's d effect size was very large (d = 1.4). Change in LSAS scores from baseline to 6-month follow-up showed similar effect size (d = 1.1)	Fast and lasting improvement in social anxiety symptoms in autistic adults following MDMA-assisted psychotherapy

DMT, N,N-dimethyltryptamine; LSAS, Leibowitz Social Anxiety Scale; LSD, lysergic acid diethylamide; MDMA, 3,4-methylenedioxymethamphetamine; PTSD, post-traumatic stress disorder; RCT, randomized controlled trial; SDS, sheehan disability scale; SMD, standardized mean difference; TRD, treatment-resistant depression.