Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders

Abstract

Classical psychedelics, primarily psilocybin and lysergic acid diethylamide (LSD), have been used and extensively studied in Western medicine as part of substance-assisted psychotherapy in the 1950s and 1960s. Modern clinical research is currently gaining momentum and provides new evidence for the safety and efficacy of classical psychedelics (primarily psilocybin, but also LSD and ayahuasca) in the treatment of different psychiatric conditions, including substance use and mood disorders.In this review article, we outline common pathological mechanisms of substance use disorders (SUD) and unipolar depression. Next, the current literature on the effects of psychedelics is summarized in order to generate hypotheses regarding their potential therapeutic mechanisms of action in treating these psychiatric conditions. Finally, we review and discuss clinical trials published since 2011 investigating the effects of psychedelics in SUD and depression.While results from those modern clinical trials are promising, most of them do not meet the methodological requirements to allow firm conclusions on the clinical efficacy of psychedelics. Larger, blinded, randomized controlled trials (RCT) with clearly defined patient groups and well-defined primary endpoints are needed. Additionally, the therapeutic mechanisms of classical psychedelics are currently unknown. This review presents hypotheses derived from preclinical and human studies that need to be tested in future trials to better understand the clinical potential of psychedelic substances in modern psychiatry.

A voice without a mouth no more: The neurobiology of language and consciousness

“…Thus, targeting inner speech core-periphery arrangements, the default mode network, and prefrontal selection processes with psychotherapy following the administration of psychedelics might permit less rigid word, meaning, and contextual associations. Indeed, this might underpin the promising results of psychedelic assisted psychotherapy (Mertens and Preller, 2021).…”

The Potential Role of Psychedelic Drugs in Mental Health Care of the Future

“…But here, too, it is still completely puzzling how the agonistic effect on a neurotransmitter receptor leads to profound changes in the perception of oneself, time, and space. It is also unclear how psychedelics exert their therapeutic effects in psychiatric disorders [20], which, at least in some patients, last a surprisingly long time even after a single administration [21,22]. Changes in self-experience, emotional processing, and social cognition may contribute to the potential therapeutic effects of psychedelics [23].…”

“…There are no large-scale quantitative implementation studies that regulators can draw on today. The field is still in an early stage of the regulatory process; phase II (psilocybin, LSD) and phase III studies (MDMA) are just underway and there is still remarkable ambivalence concerning the knowledge of treatment mechanisms of psychedelics and psychedelic therapies [20,23,[38][39][40]. Due to this situation, first conclusions for implementation must be drawn from Phase I-III studies and a qualitative analysis of non-clinical and traditional contexts in which psychedelics are used.…”

“…In current clinical studies, psychotherapeutic interventions range from manualized cognitive-behavioral strategies including third wave CBT concepts like ACT to marginally structured aftercare conversations with facilitators [20]. These studies using psilocybin or MDMA have built tailored curricula with minimal interventions for their therapists.…”

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“…What is the mechanism of action of psychedelics? The entire spectrum of psychological and biological processes that are triggered by psychedelics is the subject of the review by Mertens and Preller [7]. They discuss the current state of research using the example of 2 possible future therapeutic indications, affective and substance use disorders.…”