This article (2020) reviews the current evidence regarding the psychopharmacology of psychedelics and their promise as treatments for a variety of forms of addictions or substance use disorder (SUD).
Abstract
“Classical psychedelics are a group of drugs characterized by their activation of the serotonin-2A (5-hydroxytryptamine-2A; 5-HT2A) receptor and the unique hallucinogenic and mystical-type experiences that result. After a substantial period of restrictions limiting investigations into the therapeutic potential of psychedelics, a relatively recent recommencement of interest has sparked the burgeoning possibility for these drugs to play a part in the treatment of a wide array of psychopathologies. One of the most promising is in the study of addiction. Evidence has emerged that psychedelic agents may provide a novel avenue for the clinical treatment of patients dealing with substance use disorders (SUD). These serotonergic hallucinogens have displayed remarkable and enduring positive outcomes in this area, even when administered as one or two doses. The neural targets for these psychedelics are varied and underlie a complex mechanism of action—modulating multiple neural networks. It is believed that these agents allow for the reorganization of disordered neural pathways in the default mode network and attenuate maladaptive signaling in mesolimbic reward circuitry. The aim of this review is to examine the current standing of evidence regarding psychedelic psychopharmacology and to provide an overview of the use and effectiveness of these drugs in the treatment of SUD, alcohol use disorder, and for smoking cessation.”
Authors: Alec J. DiVito & Robert F. Leger
Summary
Classical psychedelics are characterized by their activation of the serotonin-2A (5-hydroxytryptamine-2A; 5-HT2A) receptor and the unique hallucinogenic and mystical-type experiences that result. They may be used to treat a wide array of psychopathologies, including substance use disorders, alcohol use disorder, and smoking cessation.
Introduction
Psychedelic drugs alter perception, cognition, and consciousness, and are often associated with mystical or awe-inspiring personal experiences. Recent research has implicated the 5-HT2A receptor as a novel target for the treatment of substance use disorder, alcohol use disorder, and smoking cessation.
The number of deaths in the United States attributable to drug overdoses has substantially increased over the past two decades to staggering numbers. In 2017, there were 142 deaths per day in the United States, and 8.9% of Americans reported illicit drug use. Current treatment modalities vary in terms of their effectiveness, and there is a dire need for improved treatments for psychostimulant abuse, especially given that no medications in the United States are approved for the treatment of other drugs of abuse such as cocaine, methamphetamines, and cannabis.
The current renaissance in psychedelic research has opened the door for these agents to potentially fill this much needed role in the treatment of SUD. However, the state of current research remains lacking, with most studies consisting of small-scale observational studies and open-label trials with few RCTs.
The mesolimbic pathway
Psychedelic drugs are believed to affect the mesolimbic pathway, which is associated with reward and the cravings, compulsive use, and depression seen during withdrawal. The mesolimbic dopaminergic system is believed to play the largest role in models of psychostimulant abuse, and is also involved in the acute reinforcing effects of these drugs, as well as some drug-seeking behaviors during withdrawal, and a lack of motivation for nondrug-related stimuli.
5-HT2A receptors are located on mesolimbic structures such as the ventral tegmental area (VTA) and nucleus accumbens (NAc). Serotonin can affect NAc activity and can be used to prevent or reverse the switch from a drug-nave to a drug-dependent motivational states.
Serotonergic neurotransmission in the mesolimbic pathway is complicated by variations in response based on serotonin receptor subtypes. Psychedelic agents are active at both the 5-HT2A and 5-HT2C receptors, and both receptors have been shown to affect dopamine release. Psychedelics may act therapeutically in part due to their ability to induce rapid tolerance to serotonergic input in this pathway. This tolerance may be due to the downregulation of the pathological response pathway that 5-HT2A receptors play in facilitating addictive behaviors in the setting of SUD.
The highest density of 5-HT2A receptors is in the cortex, but the therapeutic effect of psychedelics likely extends beyond mesolimbic areas.
Cortical pathways
The 5-HT2A receptor is found in the claustrum and all laminae of the neocortex, particularly excitatory layer V pyramidal cells, and is implicated in memory, attention, perceptual awareness, thought, and consciousness.
The 5-HT2A receptor contributes to multiple complex processes in the neocortex by way of multiple cellular mechanisms. It is known to interact with the glutamate receptor in the neocortex, and the mGluR2/3 are known to attenuate psychedelics’ effects on the 5-HT2A receptor.
Psychedelics may affect gene expression and induce long-term neuronal changes through the agonism of the 5-HT2A receptor. This may explain some of the long-term substantive changes in behavior and cognition observed following psychedelic administration.
Evidence of psychedelic effects on the neocortex is complex, with observations of both globally increased cortical excitation and decreased mPFC activity. It has been hypothesized that psychedelics cause a reduction of top-down control and increase in bottom-up information transfer, leading to ego dissolution and mystical experiences.
The default mode network
The default mode network (DMN) is a group of connected brain structures that govern processes related to self-directed thought.
The DMN consists of the ventromedial prefrontal cortex, dorsomedial prefrontal cortex, posterior cingulate cortex, inferior parietal lobule, lateral temporal cortex, and hippocampal formation. It is believed to mediate many behavioral elements of addiction and withdrawal. Investigations of the DMN have shown decreased activity in areas of the DMN, as well as increases in global functional connectivity, following administration of psychedelic agents. These areas correspond to areas of high 5-HT2A receptor density and have been implicated in cognitive processes such as self-reflection, self-awareness, autobiographical memory retrieval, and out of body experiences.
Psychedelic medications appear to restructure the personality in a positive way, which is enduring over time. This is reflected in neuroimaging data, where increased connectivity of high-order cognitive networks occurs subsequent to the acute time period of administration.
The exact implications of these findings require further investigation, but they may align with hypotheses that psychedelics enable the brain to “reset” pathological connectivity in states such as addiction and return to more normalized functioning.
Psychedelics may modulate the corticotropin releasing factor/brain stress system, which is known to be upregulated during withdrawal, enabling persistent positive ideas of self-reference to form, counteracting the maladaptive ideation present in addiction which leads to drug-seeking behaviors.
Mystical experiences and microdosing
Psychedelic drugs have been found to cause mystical-type experiences and a sense of openness and boundlessness, which may be a nidus for substantial psychological change. However, the importance of these self-reported mystical experiences for the therapeutic potential of these drugs is unclear. Separate investigations have suggested efficacy of “microdosing” psychedelics for treating conditions such as depression, anxiety, pain, and addiction. Although research in this emerging topic is quite new and far from robust, evidence suggests that self-administered microdoses of psychedelics have positive effects on addiction, as well as depression and anxiety, in the absence of any profound psychedelic experiences. A controlled clinical setting and objective measures were used to assess effects of microdosed psychedelics. The results showed that microdosed LSD was able to reproduce some findings seen in normal doses of psychedelics.
At small doses, psychedelic agents may act more selectively on mesolimbic pathways than on thalamocortical circuits, suggesting that psychedelic modulation of the DMN may occur at lower doses.
Microdosed psychedelics have limited activity to realize the full effects of these drugs appreciable at larger doses. This may be because of the lack of cortical glutamatergic potentiation at low doses.
Treatment effects in substance and alcohol use
In recent years, there has been increased interest in using psychedelics to treat psychiatric illness, including SUD and AUD. However, the concept is well-established, with the first studies of psychedelics and addiction being conducted in the 1950s demonstrating positive results using LSD for OUD and AUD.
Psychedelics have been shown to be effective in the treatment of substance use disorders and alcohol use disorders. Using psychedelics in combination with motivational enhancement therapy has shown significant reductions in abstinence from alcohol and substance use disorders.
Treatment effects in tobacco use
Although more research is needed to investigate the use of psychedelics for adjunctive smoking cessation therapy, current findings show that psilocybin has the potential to yield superior results with only a single administration, versus current typically used medications which have abstinence rates generally ranging from 35% to 28%.
Evidence supports the claim that psychedelics ease the process of smoking cessation in patients relative to other methods, with many subjects remaining tobacco abstinent after taking a psychedelic for more than 25 years.
Conclusion
Psychedelics are a group of serotonergic drugs that have profound impacts on the human brain. They have recently been used to treat substance use disorder, and more research is being done into their potential benefits. Psychedelics have been shown to produce significant and enduring positive changes in the management of patients suffering from substance use disorder.
The positive effects of psychedelics in the treatment of substance use disorder are due to the modulation of multiple distinct brain networks. These effects are supported by the high densities of the 5-HT2A receptor found in nodes of these discrete neural networks.
Future research is needed to more carefully parse how psychedelics function to produce the observed behavioral results in patients with disordered use of tobacco, alcohol, and other substances.