This study (2017) reviews the human evidence regarding psilocybin as a potential treatment for substance use disorders (SUD). The authors conclude that the evidence thus far seems promising, but will need to be confirmed in future studies.

Abstract

“Introduction: Evidence based treatment for Substance use disorders (SUD) includes psychotherapy and pharmacotherapy. However, these are only partially effective. Hallucinogens, such as psilocybin, may represent potential new treatment options for SUD. This review provides a summary of (human) studies on the putative therapeutic effects of psilocybin, and discusses the receptor systems, brain regions and cognitive and emotional processes mediating psilocybin’s effects. Psilocybin’s chemical structure is similar to that of serotonin. Dysregulations in the serotonin system are associated with alterations in stress hormones, such as cortisol, and mood disorders. After psilocybin administration cortisol levels spike and activate the executive control network, with subsequent increased control over emotional processes, and relief of negative thinking and persistent negative emotions. Preliminary data of ongoing alcohol and smoking addiction studies in humans shows promising effects of psilocybin administration on substance use. Importantly, psilocybin has a low risk of toxicity and dependence and can be used safely under controlled clinical conditions.

Areas covered: This paper is a narrative review based on the search terms: psilocybin, substance use disorder, addiction, depression, serotonin. Literature on potential efficacy and mechanisms of action of psilocybin in SUD is discussed.

Expert commentary: Recent positive findings with psilocybin need confirmation in well-designed placebo controlled randomized trials employing a large sample size.”

Authors: Bas T. H. de Veen, Arnt F. A. Schellekens, Michel M. M. Verheij & Judith R. Homberg

Summary

The review of the putative therapeutic effects of psilocybin discusses the receptor systems, brain regions and cognitive and emotional processes mediating psilocybin’s effects. Psilocybin has a low risk of toxicity and dependence and can be used safely under controlled clinical conditions.

Rational and outline of this review

Current pharmacotherapies have limited success in treating substance use disorders, but hallucinogens have potential anti-craving properties and subsequently reducing substance use in SUD patients. Psilocybin has a shorter plasma half-life (6 h) and may have therapeutic potential in the treatment of substance use disorders.

Introduction

Substance use and addiction have been rather common for centuries. Several factors contribute to the risk of developing addiction, including socioeconomic factors, lifestyle, life events, and adverse life events.

Treatment of substance use disorders often involves psychological and pharmacological interventions, but about 50 – 60% of patients with drug and alcohol use disorders relapse within 6 – 12 months after treatment.

2.1. SUDs

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) provides 11 criteria for SUD, which are chronic disorders of brain reward, motivation, and memory processes that have gone awry.

2.1.1. Monoamines and SUD

The neurobiology of SUD involves multiple neurotransmitter systems, including the dopamine (DA), serotonin (5-HT) and corticotropin releasing factor (CRF) stress systems. Psilocybin is known to affect the DA, 5-HT and CRF systems, and may have other potential neuropharmacological mechanisms of action.

The reward system is at the basis of normal learning and decision-making through positive reinforcement by dopamine release. Long-term excessive substance use may be related with reduced sensitivity of dopamine D2 receptors, possibly resulting in downregulation of dopamine D2 receptors.

Serotonin levels are strongly modulated by 5-HT receptors in the reward system, and a deficit occurring upon chronic cocaine exposure may be associated with increased impulsivity, which also feeds addictive behaviors.

2.1.2. Neuropeptides and SUDs

Neuropeptides (like CRF) are also significantly involved in SUD, as reviewed by Koob [12]. CRF stimulates the release of adrenocorticotropic hormone (ACTH) in the blood, which in turn stimulates the secretion of cortisol by the adrenal cortex.

The HPA-axis plays an important role in substance use. It signals arousal and exerts rewarding effects involved in the initial behavioral response to drugs, and also plays a role in the maintenance phase of drug self-administration.

There are tight interactions between the 5-HT and CRF systems at various levels, including the central nucleus of the amygdala, which is implicated in compulsive substance use during later stages of SUD.

2.2. Psilocybin

LSD was extensively studied as an anti-SUD drug, but a lack of randomized, double-blind, placebo-controlled studies hamper researchers to draw firm conclusions concerning LSD’s efficacy in alcohol dependence. Psilocybin has gained popularity in neuropsychological research, and may be a valuable compound for the treatment of psychiatric conditions.

Similar promising findings have been observed in addiction research, where participants typically receive 0.3 – 0.4 mg/kg of psilocybin in two to three sessions. Psilocybin helped participants in quitting smoking, by changing their orientation toward the future, strengthening their beliefs, and changing their life priorities.

Psilocybin may have therapeutic potential for SUD treatment and relapse prevention. It is important to note that both studies did not assess the effect of psilocybin on relapse rates after a period of abstinence.

Current evidence suggests that psilocybin may support drug-dependent individuals in overcoming their SUD. Potential mechanisms are discussed.

Psilocybin is the main psychedelic ingredient of mushrooms of the genus Psilocybe. It was scheduled as a class I drug in 1970 and human experiments steadily terminated, but have revived since the late 1990s.

Psilocybin is rapidly dephosphorylated by alkaline phosphatase in the intestinal mucosa to psilocin, and is then glucuronidated by endoplasmic enzymes and excreted from the body by the kidneys, liver, and intestine. There have been two reported fatalities of psilocybin use.

2.2.3. 5-HT neuropharmacology of psilocybin

Psilocybin binds to 5-HT receptors with high affinity, and the neurophysiological action of psilocybin is dependent on 5-HT receptor distribution in different cell types. Psilocybin has the highest affinity for 5-HT2A receptors, and to a lesser extent at 5-HT1A receptors.

Hallucinogens interact with 5-HT2A receptors in animals, and this interaction contributes to behavioral effects such as lateral head weaving, hind limb abduction, backward locomotion, and lower lip retraction.

2.2.4. Neuroanatomical localization of 5-HT receptors

The neuroanatomical distribution of 5-HT receptors in cerebral cortical areas explains the behavioral effect of psilocybin, including memory, attention, perceptual awareness, thought, language, and consciousness as well as cognitive control.

The amygdala and ventral striatum both show high expression of 5-HT2A receptors, which may be involved in the associative processes in SUD through interactions between primary reinforcement, psychomotor activation, Pavlovian conditioning, and cue-induced drug seeking behavior.

5-HT1A receptors are found in the hippocampus, septum, neocortex, raphe nucleus, and amygdaloidal nuclei, which are involved in mediating cognitive and emotional processes.

2.3. Putative modes of action of psilocybin in SUD

Psilocybin may exert its anti-addictive properties by affecting brain regions containing high levels of serotonergic receptors, and by influencing negative emotional states and stress, as well as cognitive inflexibility and compulsivity, which are two key features displayed in patients with SUD.

2.3.1. Psilocybin: effects on negative emotional states and stress

Substance dependence is strongly associated with negative affect and stress, and may also be related to dysregulations in the emotional and stress systems. The amygdala is strongly innervated by serotonergic neurons, and the 5-HT1A and 5-HT2A receptors play a central role in these processes.

A recent study found that psilocybin treatment decreased amygdala reactivity and increased positive mood in healthy volunteers. This finding may be relevant to the normalization of amygdala hyperactivity in SUD patients.

Chronic stressful circumstances are represented by an increase in basal cortisol levels, and lower cortisol responses are associated with more behavioral and social problems in maltreated/bullied children. The HPA-axis is also activated by 5-HT receptor activation in the hypothalamus. A psilocybin-induced cortisol spike activates large-scale brain networks, including the default mode network (DMN), the executive control network (ECN), and the salience network (SN). The SN is important for dynamic switching between the DMN and ECN, and for shifting emotional biases away from negative during emotional processing.

Psilocybin administration leads to activation of the DMN, which leads to an introversive phase and the ECN, which leads to improved focused attention and working memory.

2.3.2. Role of 5-HT2A and 5-HT1A in cognitive inflexibility and compulsivity

Psilocybin and LSD increase behavioral flexibility by increasing reversal learning in rats and primates, and 5-HT2A receptor antagonism impairs behavioral flexibility by increasing perseveration. The prefrontal cortex, insula, basal ganglia, anterior cortex, and posterior parietal cortex are involved in behavioral flexibility.

The side effects of using psilocybin depend on the user’s expectations, the environment, and the drug itself. Proper education, a calm environment, and guidance by an experienced user can prevent dangerous behavior.

It has been shown that hallucinogenic substances may accentuate or trigger psychotic symptoms in patients suffering from depression, schizophrenia, or psychosis, but it is not likely that hallucinogenic substances cause psychiatric conditions in non-predisposed individuals.

Psilocybin appears to have very low risk of substance dependence or addiction. It does not cause craving or withdrawal in humans, and animals do not show high self-administration rates above placebo.

Summary and conclusion

We propose here that psilocybin may have therapeutic effects in the treatment of SUD. We specifically hypothesize two mechanisms of action of psilocybin that might mediate its anti-addictive properties.

We hypothesize that psilocybin may improve cognitive functioning and alleviate anxiety-related and depression-like symptoms associated with SUD. However, more extensive research is needed to address these and other issues before psilocybin can be implemented as a treatment option for SUD.

Expert commentary

Many studies have tested the potential of psychedelics for treating psychiatric disorders, including substance use disorder. However, many of these studies lacked a double-blind controlled design, which limits the level of evidence.

Psilocybin has shown positive results in several studies on alcohol and nicotine dependence. It remains to be clarified whether psilocybin’s efficacy is dependent on the type of SUD, whether 5-HT2A receptors modulate SN, DMN, and ECN activity, and whether preexisting trait characteristics such as anxiety and personality influence the efficacy. Studies are required to unravel the anti-addictive potential of psilocybin, which may include investigating whether psilocybin use may have preventive effects for the development of SUDs, and whether psilocybin can reduce relapse during 6-12 month follow-up measures.

Five-year view

The use of psychedelics has remained popular among younger adults since the 1960s, and marijuana has been legalized in several US states. It is possible that some individuals are using psychedelic drugs as a form of self-medication.

Psilocybin is a hallucinogen that acts predominantly through the 5-HT2A receptor, and to a lesser extend through the 5-HT1A receptor.