Psychedelic Drugs in Biomedicine

This review (2017) summarizes pre/clinical data pertaining to the effects of psychedelics and their pharmacological mechanisms of action and outlines future areas of translational research to investigate how synapse-related gene expression influences the disruption of established neural connectivity patterns, underlying therapeutic effects.

Abstract

“Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.”

Authors: Evan J. Kyzar, Charles D. Nichols, Raul R. Gainetdinov, David E. Nichols & Allan V. Kalueff.

Summary

Origins of Psychedelic Medicine

Humans have used psychedelic drugs for spiritual and religious purposes for centuries, if not millennia. The effects of psychedelic drugs were first characterized in humans before animals, and have since been studied in a wide range of animal models.

Psychedelic drugs were placed in the most restrictive drug categories in the late 1950s, and nearly all research into their underlying biology halted with the passage of the Controlled Substances Act of 1970. However, the appeal of psychedelic drugs did not completely abate during the 1980s through to the early 2000s. In the 1980s, the rigorous study of psychedelics in rodents began again in a few laboratories. The 5-HT2A receptor was identified as the key target for psychedelic-mediated behaviors, and the 5-HT2A receptor antagonist ketanserin was developed to block the psychedelic effects of both psilocybin and LSD clinically.

Clinical trials have shown preliminary efficacy in treating nicotine and alcohol addiction, depression, and end-of-life anxiety. Animal studies have shed light on the behavioral and physiological effects of psychedelics, and molecular, cellular, and circuitry levels have been investigated.

Effects of Psychedelic Drugs in Animal Models

Psychedelic drugs induce anxiolytic-like effects in rodents, enhance fear conditioning, facilitate faster extinction of fear memory, and increase impulsivity in a dopamine D2 receptor-dependent manner. The pharmacological mechanism of this later increase in dopaminergic activity has yet to be fully determined.

A commonly used rodent phenotype is the head twitch response (HTR), which is induced by psychedelic drugs and nonpsychedelics. HTR is also highly strain-dependent, and is absent in 5HT2A receptor knockout mice.

The gold standard for measuring psychedelic-related behavior is the two-lever drug discrimination assay, and rodent models of psychedelic exposure are also used to answer other complex mechanistic questions. Zebrafish and fruit flies are emerging as novel sensitive model organisms for translational psychedelic research and drug screening.

There are limitations to using animal models to study psychedelics, but they have allowed researchers to gather important data that has revealed important biological insights into the effects of psychedelics in humans.

Recent psychedelic research has systematically probed the subjective effects of psychedelics on cognition and behavior in humans. These studies have revealed that psychedelic drugs increase positive mood and visual imagery alterations, and moderately and transiently increase heart rate, blood pressure, body temperature, and plasma levels of hormones.

Effects of Psychedelic Drugs on Human Cognition and

Imaging studies have shown that psilocybin causes widespread alterations in blood flow and metabolism in the brain, which may contribute to the subjective effects of psychedelics. Psilocybin, ayahuasca and LSD increase resting state functional connectivity between brain regions that do not normally show significant functional association, and decrease resting state functional connectivity between established circuits in the brain, such as the default mode network (DMN).

Psychedelic drugs may prove a novel pharmacotherapy for patients who suffer from mild to moderate depression and anxiety. A single dose of psilocybin given in a program of psychotherapy is beneficial in patients with anxiety related to terminal cancer.

Psychedelic drugs have been tested for the potential to disrupt established patterns of addictive behavior. One small modern pilot study has examined the effects of a psychedelic drug on alcoholism, reporting increased abstinence and fewer drinking days several weeks after treatment. Psilocybin is promising for the treatment of nicotine and alcohol addiction, with 80% of patients remaining smoke-free after receiving two or three doses of psilocybin along with cognitive behavioral therapy.

Potential Neurobiological Mechanisms of Psychedelic Drugs

Psychedelic drugs have many effects on the brain, including agonism at the 5-HT2A receptor. These effects may help explain why psychedelics are beneficial for a number of etiologically varied psychiatric illnesses.

Only a few studies have investigated the effects of psychedelics on gene expression in the brain. These studies found that cFos, Ikb-a, Nor1, and Ania3 are all upregulated in the PFC of LSD-exposed rats, and that MAP kinase phosphatase 1, core/ enhancer binding protein B, and ILAD1 are also upregulated.

In a subsequent study, LSD and DOI upregulated genes of early growth response protein 1 (Egr1), 2 (Egr2), and Period-1 (Per1) in the mouse somatosensory cortex, but not in the hippocampus or thalamus. These changes may explain both acute behavioral changes and those that may persist long after the initial drug exposure.

Although psychedelics activate only small populations of excitatory neurons, they also activate a significant number of inhibitory GABAergic interneurons and non-neuronal cells in the medial prefrontal cortex and claustrum, which are then connected to other brain regions in a complex network.

Psychedelic drugs alter cerebral blood flow and functional connectivity in different ways, which may contribute to the visual hallucinations and other disturbances evoked by psychedelics. LSD exposure reduces the within-network stability of established brain networks and decreases the separateness between these networks. Psychedelic drugs may induce a state of entropic activity within the brain, whereby established resting state networks break down, and novel local connectivity hubs form between regions that show little connectivity in a baseline state. This may be one of the reasons why psychedelic drugs show promising efficacy in treating psychiatric illnesses.

Psychedelic drugs induce powerful experiences of a mystical/spiritual nature in patients. These experiences have a lasting effect on the patient and are related to therapeutic potential. Studies in healthy volunteers and patients with brain disorders have shown that psychedelics can induce an exceptionally meaningful experience and increase mindfulness, which may both contribute to the noted increases in wellbeing and mood following exposure to these drugs.

Although serious adverse reactions to psychedelic drugs have not been seen in modern, controlled-environment human trials, more research is needed to compare the effects of different doses and treatment schedules. The relationship between psychedelic effects and mystical experiences is unclear. It is possible that increased subjective ratings of the psychedelic experience reflect increased synaptic activity-related gene expression, which causes more robust entropic brain activity.

Beyond the Brain: Peripheral Effects of Psychedelics

Psychedelics inhibit inflammation in rat aortic smooth muscle cells, and in human cells in vitro. They may represent the first-in-class bioavailable small molecule TNF-a inhibitors that act to inhibit inflammation through intracellular mechanisms at relevant targets, rather than biologics on the market that act essentially to sequester TNF-a from circulation.

A study with radiolabeled 2,5-dimethoxy-4-bromoamphetamine (DOB) revealed that a substantial fraction was sequestered in the lungs of human volunteers. DOB prevented the development of asthma in a mouse model by suppressing T helper 2 cell recruitment, and production of several proinflammatory cytokines and chemokines. Psychedelics, including (R)-DOI, have been demonstrated to have antiasthmatic effects not only in mice but also in rats. These data suggest that psychedelics may be able to treat peripheral inflammation at sub-behavioral levels, which may have a far greater impact on human health than in the treatment of psychiatric disorders.

Concluding Remarks

We hypothesize that the induction of synapse-related gene expression in key neuronal populations identified by molecular studies and the robust alterations observed in neural circuits by imaging studies are highly interrelated processes. This puts the results of psychedelic research using animal models into a new context.

Clearly, many questions remain regarding the biology of these compounds and their use in the clinic. However, early phase clinical trials have shown promising results.