New insights into the clinical and nonclinical effects of psychedelic substances: An integrative review

This review (2022) explores the potential of psychedelics in treating mental health disorders, their short- and long-term effects on recreational users, and the neurological and cognitive processes responsible for their effects using the most up to date research. The positive findings of psilocybin for depression (MDD) and anxiety are highlighted. The mystical experience (MEQ) also plays a large role, but individual differences (for whom does it work) are still not well examined.

Abstract

“After decades of stagnation, research on psychedelic substances (such as lysergic acid diethylamide [LSD], psilocybin, or N,N-dimethyltryptamine [DMT]) has experienced a renaissance over the last 10 years, with various major research programs being conducted across Europe and the United States. This research primarily investigates the potential of psychedelics in the treatment of mental health disorders, their short- and long-term effects on recreational users, and the neurological and cognitive processes responsible for their effects. The present review provides a concise summary of the most recent insights gained from this research. We briefly outline the history of psychedelic research, the objective and subjective effects caused by these substances, the prevalence and socio-psychological correlates of their use, as well as their potential for harm. Subsequently, we review empirical research on the beneficial effects of psychedelics in clinical samples, focusing on their efficacy in the treatment of major depression, anxiety, and substance use disorders, and discuss research on the proposed neural and cognitive mechanisms behind these effects. We then review research on their effects on healthy subjects, focusing on psychological well-being as well as changes in personality, nature-relatedness, and creativity. Finally, we review empirical evidence regarding the long-term effects of single experiences with psychedelics and conclude with a summary and outlook.”

Authors: Matthias Forstmann & Christina Sagioglou

Summary

After decades of stagnancy, research on psychedelic substances has experienced a renaissance over the last 10 years. This review summarizes the most recent insights gained from this research, including the history of psychedelic research, the objective and subjective effects caused by these substances, and their potential for harm.

In 1971, most commonly-used psychedelic substances were classified as Schedule 1 substances by the UN Convention on Psychotropic Substances, which effectively stopped scientific inquiries into their effects on humans. However, with a changing political landscape and new safety protocols in place, research on these substances saw a resurgence.

Classic psychedelic substances include LSD, psilocybin, and DMT, and are characterized by their affinity to the serotonin 2A receptor (5-HT2A).

Psychedelics are naturally occurring alkaloid found in various plants that are traditionally used in South American shamanic rituals. They have pronounced acute effects on perception, affect, and cognition, and can induce a mystical-type experience, characterized by feelings of internal unity, external unity, and a special sense of sacredness. In the US, 32 million people have used psychedelic substances, and 9.7% of adults between 16 and 34 have used LSD. In Europe, the numbers are less conclusive.

EU surveys estimate that 0.1% to 5.4% of 15-34-year-old adults use LSD and 0.3% to 8.1% use psilocybin, and newer research attests to the relative safety and tolerability of classic psychedelic substances. While no adverse long-term side-effects were observed across more than 2000 participants in psychedelic research studies as of 2016, acute emotional distress can occur when using these substances.

In controlled laboratory studies, acute negative effects are relatively common, even with psychedelics. However, in clinical applications, the emergence of negative affective states may actually contribute to the therapeutic efficacy of psychedelics. Some case studies suggest that psychedelics may cause a type-2 hallucinogen persisting perception disorder (HPPD), a presumably chronic condition characterized by visual snow, afterimages, and corresponding difficulties concentrating. The prevalence of HPPD is unknown, but likely not specific to the use of psychedelic substances.

People seek out psychedelic substances in hope of gaining spiritual insights, getting new perspectives on life, or dealing with psychological distress and trauma. Clinical trials of psychedelic substances involve administering a psychedelic substance to thoroughly-screened participants in a controlled and comfortable setting under the guidance of trained professionals. These trials are typically embedded within a psychotherapeutic context, and focus on patients suffering from mood disorders.

In the first open label studies investigating the potential of psychedelics in the treatment of MDD, ayahuasca reduced depressive scores by up to 82% on a variety of measures, and 5-MeO-DMT showed similar antidepressant effects. A separate line of research has focused on psilocybin as an especially promising candidate for the treatment of patients with mood disorders. Results showed that psilocybin reduced depressive symptoms and improved anxiety and anhedonia in 12 patients, with results lasting up to six months post-treatment.

In double blind, randomized, placebo-controlled studies, administration of psychedelic substances was found to be more efficient and safer than administration of the substances alone for the treatment of anxiety disorders in patients suffering from life-threatening medical conditions. Gasser (2014) reports that LSD reduces trait anxiety in participants with life-threatening diseases, with no adverse side-effects.

In the 70s, psilocybin was used to treat tobacco dependence. More recently, psilocybin was used to treat alcohol dependency, and a survey study found that naturalistic use of psychedelic substances outside of treatment settings predicted subsequent reduction in self-reported alcohol use amongst people who struggled with dependency. Other research programs investigate the usefulness of psilocybin assisted therapy in the treatment of various substance use disorders, such as opioid dependence. However, more rigorously controlled studies are necessary to make more conclusive statements. The neural underpinnings of the psychedelic experience are not yet fully understood, but it is speculated that psychedelics can inhibit amygdala reactivity and decrease resting-state connectivity within the default mode network, thereby attenuating the elevated levels of threat processing that are associated with depression. In many studies investigating the effects of psychedelics on depression and anxiety, subjective qualities of the experience predicted therapeutic efficacy of the treatments. Other analyses suggest that a sense of connectedness, insights gained from the experience, and emotional breakthrough contribute to the effects of psychedelic substances.

Psychedelics can be used to treat substance use and dependence disorders. Higher doses of psychedelics are associated with greater mystical experiences and subjective insights gained from the experience.

Many people who use psychedelics do so outside of a clinical setting, yet multiple double-blind crossover studies have found that these substances can reliably induce dose-dependent mystical-type experiences with pronounced personal significance in healthy participants.

Several studies have shown that mystical-type experiences can have positive effects on people’s subjective well-being and quality of life, trait openness to experience, mindfulness, and prosocial attitudes and behaviors. A large-scale field study found that recent use of psychedelics was positively associated with self-reported transformative experiences and positive mood. It was also found that lifetime use of classic psychedelics was positively linked to nature relatedness and thereby to ecological behavior.

Research into the effects of psychedelic substances on creativity has been conducted, but convincing evidence for a causal relationship between psychedelic substance use and nature relatedness is still lacking. Although correlational in nature, evidence suggests a link between lifetime use of psychedelics and creative problem solving, with additional correlational evidence provided by Davis and colleagues (2020). However, no rigorous placebo-controlled studies have been conducted, and a causal link remains scarce.

Although longitudinal data are lacking, results from the first studies on psilocybin and MDD suggest that the therapeutic efficacy of psychedelics is long lasting, and that patients suffering from life-threatening cancer report increased life satisfaction six months after treatment. Although small sample sizes make it difficult to make conclusive statements regarding potential long-term effects, a meta-analysis of eight clinical studies found that psychedelics may contribute to a rapid improvement of depressive symptoms for up to six months.

The researchers found that psychedelic treatment can improve depression, but some studies require patients to abstain from their antidepressant medication. Multiple studies report that participants rated their psychedelic experience as one of the five most meaningful experiences of their lives, and that the effects of psilocybin continued to have an effect on their mental well-being 14 months post treatment.

Psychedelic substances have been shown to have positive effects on MDD, anxiety, and substance use disorders. This is in stark contrast to established medications for these conditions, which bring with them a host of unwanted and potentially burdensome side-effects. Studies on healthy subjects revealed promising findings, suggesting a relationship between use of psychedelics, transformative experiences, mood, creativity, and feelings of connectedness with oneself, others, and nature.

Studies on psychedelic substances have shown that they may have unique positive effects on people’s well-being and their relationships with others and the world around them. However, more studies are needed to determine the full potential of these substances.