Classic psychedelics as therapeutics for psychiatric disorders

This chapter (49, Handbook of Behavioural Neuroscience) reviews the use of classical psychedelics and the resurgence of research of them as therapeutics for psychiatric disorders.

Abstract

“Recently, there has been a resurgence of interest in the study of classic serotonergic hallucinogens, now widely referred to as classic psychedelics. These studies include fundamental molecular and cellular neuroscience and pharmacology, neuroimaging, and psychological experiments. In the early days of classic psychedelic research during the 1950s through the 1970s, classic psychedelics were examined for their therapeutic potential to treat disorders ranging from addiction to schizophrenia. After scheduling laws essentially halted classic psychedelic research worldwide for decades, beginning in the mid-2000s, a few select research groups were given regulatory approval to reinitiate clinical investigations with psilocybin. These studies demonstrated safety and allowed for the development of standardized methodology for conducting clinical trials with psilocybin and other classic psychedelics. There are now data from several clinical trials approved by the proper regulatory agencies in the United States, Europe, and elsewhere, suggesting safety and potentially profound efficacy to treat a variety of psychiatric disorders including anxiety, depression, and addiction.”

Authors: Charles D. Nichols & Peter S. Hendricks

Summary

I. EARLY HISTORY OF CLASSIC PSYCHEDELICS IN PSYCHIATRY

Classic psychedelics have been used by humans for many thousands of years, and in indigenous cultures, such use occurs in highly ritualized, sacramental, and healing contexts. Western science developed an interest in the potential clinical applications of classic psychedelics after Albert Hofmann discovered lysergic acid diethylamide (LSD) in 1943. However, most studies are inconclusive and yield promising data. In 2012, a meta-analysis of six randomized controlled trials conducted between 1966 and 1970 found that a single dose of LSD administered in the treatment of alcohol dependence reduced alcohol misuse relative to comparison conditions as long as 6 months after treatment. Classic psychedelics were associated with the countercultural revolution of the late 1960s, but recent clinical studies suggest that they may be safe and effective in the treatment of a number of mental health conditions.

A. Anxiety and depression

The first study of the effects of psilocybin on affect in the modern era was performed by Dr. Roland Griffiths and colleagues at Johns Hopkins University in 2006, and the results showed that psilocybin was associated with sustained positive well-being and attitudes toward life.

In 2011, Dr. Charles Grob at UCLA performed a double-blind, placebo-controlled crossover study in 12 patients with advanced cancer and reactive anxiety. Although no significant differences in depression and anxiety were identified between the psilocybin and niacin control groups, several trends were observed.

Gasser et al. (2014) reported on the use of LSD in patients with life-threatening diseases. The study found that the higher dose of LSD was associated with a statistically significant improvement in anxiety.

In 2016, a pilot study using psilocybin to treat treatment-resistant depression was conducted at Imperial College, UK. The results indicated that psilocybin was associated with antidepressant effects at 1 week and 3 months post treatment.

Several recent studies indicate that ayahuasca may be a safe and effective treatment for depression. These studies include an observational study of individuals participating in ayahuasca ceremonies, an open-label pilot trial of ayahuasca among hospitalized inpatients with recurrent Major Depressive Disorder, and a randomized clinical trial.

In two large scale studies, 51 patients with life-threatening cancer received psilocybin at either a high dose (w25 mg/70 kg) first or a very low dose (w2 mg/70 kg) first, followed by several post-session integrative meetings. They were assessed by several instruments prior to the treatment and at 1, 2, and 6 months after the treatment.

In both studies, high-dose treatments of psilocybin resulted in rapid and sustained antidepressant and anxiolytic effects. There were no adverse reactions, and patients were screened to exclude those at risk for potential reactions. In each of these studies, the subjective experience culminating in a “peak” or “mystical” transcendent experience was correlated with the antidepressant and anxiolytic effects of psilocybin, with mediator analyses indicating that such experience accounts for the efficacy of psilocybin treatment.

B. Addiction

A single-arm, open-label pilot trial of psilocybin for smoking cessation using established protocols and in conjunction with cognitive-behavioral therapy yielded biologically confirmed abstinence rates of 80% and 60% 6 months and 2.5 years after the quit date, respectively. A single-arm, open-label pilot trial of psilocybin in combination with motivational enhancement therapy produced pronounced reductions in alcohol consumption, and an observational study of ayahuasca-assisted therapy for addiction among First Nations individuals in Canada was associated with reductions in alcohol, tobacco, and cocaine use.

A. Biological/physiological

Increasing brain 5-HT levels treats depression by decreasing 5-HT1A autoreceptors, decreasing firing rates, and increasing cortical 5-HT release from afferents. This process is repeated over time, leading to an increase in 5-HT levels and antidepressant effects.

The 5-HT2A receptor is widely expressed in the brain postsynaptically on nearly every cell type, and is coupled to Gaq and its activation is considered excitatory. It has been suggested that reduction in 5-HT2A receptor function may be a mechanism underlying SSRI efficacy to treat depression.

Classic psychedelics can produce antidepressant effects in humans by activating the hypothalamicepituitaryadrenal (HPA) axis and by improving affect. These effects can last for several months and may be mediated by both psychological and biological mechanisms.

Classic psychedelics activate a small percentage of excitatory neurons, which leads to activation of inhibitory interneurons, astrocytes, and glia cells, with an overall activation of neural circuitry. These activations likely desynchronize neuronal activity and destabilize the Default Mode Network, and produce hyperconnectivity between brain regions.

Nichols et al. (2017) used ketamine receptor agonists to induce dendritic spine growth and density.

B. Drug abuse

Mesolimbic and basal ganglia pathways form the foundation of the brain’s reward circuitry, and 5-HT plays an important role in addiction both as a dopaminergic modulator and by direct action. 5-HT2A/C receptors are expressed in the ventral tegmental area (VTA) and nucleus accumbens (NAc) and modulate dopamine levels. 5-HT2A receptors increase DA levels by stimulating dopaminergic neurons in the VTA and NAc, while 5-HT2C receptors decrease DA levels by stimulating glutamatergic neurons in the PFC.

With respect to alcohol use, the amygdala is believed to substantially contribute to the development and maintenance of dependence. 5-HT2A receptors are expressed on glutamatergic pyramidal neurons and GABAergic interneurons of the basolateral amygdala and ventro-medial PFC.

Classic psychedelics have been shown to have therapeutic effects on addiction, similar to their effects on depression. This is likely because classic psychedelics activate both 5-HT2A and 5-HT2C receptors, and this activity overcomes the effects of 5-HT2A receptor activation to produce an overall net decrease of DA release. Psilocybin, a psychedelic drug, can activate 5-HT1A receptors in addition to 5-HT2 receptors, and may therefore be able to reduce alcohol consumption without altering taste perception.

Classic psychedelics have been shown to have anti-inflammatory effects, which may contribute to their efficacy to treat drug addiction at the cellular level.

C. Awe

Hendricks (2018) proposed that the discrete emotion awe may be responsible for effects of classic psychedelics. This hypothesis may be supported by the finding that awe is the quintessential binding emotion that drives social integration and cooperation, which are crucial to evolutionary success.