Human behavioral pharmacology of psychedelics

This commentary (2021) provides an overview of the human behavioural pharmacology of the classic psychedelic; psilocybin, LSD and DMT. Special considerations when conducting human research with psychedelics are discussed as well as the subjective, physiological, and clinical effects of these substances.

Abstract

“The past decade has witnessed a rapid growth of research on the basic science and clinical understanding of psychedelics. This chapter provides an overview of the human behavioural pharmacology of psychedelics focusing on three prototypic classic psychedelics—psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT). A brief historical overview of the classic psychedelics and naming and drug classification is first specified. Next, special considerations in the conduct of human behavioural pharmacology work with psychedelics is described including the role of set and setting, mystical experience measurement, the use of effective blinding and placebos, and the abuse liability of psychedelics. Following, a description of the subjective, physiological, and clinical effects of psilocybin, LSD, and DMT is provided. This body of work clearly documents a unique and complex collection of subjective effects following psychedelic use, both during acute drug administration and as related to long-term behaviour change following use. Clinical research demonstrates potential therapeutic utility with early phase clinical trials showing positive and enduring effects in many difficult-to-treat conditions including treatment-resistant depression, alcohol use disorder, and cigarette smoking. Future work in this newly reemerged field is needed to reveal mechanisms of behaviour change in psychedelic drug action. Behavioural pharmacology is ultimately well served to provide this direction answering questions at the intersection of environment and pharmacology.”

Authors: Justin C. Strickland & Matthew W. Johnson

Summary

In the past decade, there has been a rapid growth of research on the basic science and clinical understanding of psychedelics. This chapter provides an overview of the human behavioral pharmacology of psychedelics focusing on three prototypic classic psychedelics.

1. Introduction

Psychedelics are a collection of psychoactive compounds that act as agonists or partial agonists at the serotonin 2A receptor (5-HT2AR). They have been studied for their potential as clinical therapeutics.

During the mid-20th century, scientific evaluation of psychedelics was described in some of the leading medical and scientific journals, and clinical applications were evaluated to include the treatment of addictive behaviors by psychedelics.

Human laboratory and clinical research on psychedelics largely came to a halt in the early 1970s due to increasing marginalization, regulatory changes surrounding FDA scheduling, halted production of LSD, and association with counter-culture movements.

In the 1990s, human subjects research began anew with the use of psychedelics. Since then, researchers have established and closely followed safety guidelines for administering psychedelics, including careful screening and preparation before drug administration sessions, close monitoring during these sessions, and follow-up care.

This chapter will provide a summary of the human behavioral pharmacology of psychedelics, including psilocybin, LSD, and dimethyltryptamine. It will also describe some of the special considerations and current challenges when conducting human behavioral pharmacology research with psychedelics.

2. Classic psychedelics

The term psychedelic, first coined by Humphrey Osmond in 1957, is considered preferred by many given its suggestion of a class of compounds that produce more general, non-ordinary forms of consciousness and/or altered states of self upon use.

Classic psychedelics are indoleamines and phenylalkylamines, which are agonists at the 5-HT2AR. Atypical psychedelics include ketamine, salvinorin A, and 3,4-methylenedioxymethamphetamine (MDMA), but their primary mechanisms of action and distinct constellation of subjective effects set them apart from the classic psychedelics.

3.1 Set and setting

Psychedelic science has long recognized that the subjective experience of 5-HT2AR compounds is greatly influenced by the intention or expectancy surrounding the event as well as the context in which the person may use the substance.

The notion of set and setting is not dissimilar to other work in behavioral pharmacology describing the role of expectancy on drug effects. For example, research has shown that the environment in which a substance is used can influence drug effects.

It is thought that set and setting may be relevant for psychedelics, with white walls, medical equipment, and other “sterile” stimuli increasing the likelihood of negative drug effects. However, music played during psilocybin sessions for smoking cessation did not directly impact subjective experience or long-term clinical outcomes.

3.2 The mystical experience

The majority of human laboratory and clinical work involving psychedelics has operationalized and measured mystical experiences. The Mystical Experience Questionnaire (MEQ-30) is a widely used, validated, and modern scale of these experiences.

Several studies have demonstrated a positive relationship between greater mystical experiences and improved therapeutic outcomes following psychedelic-assisted treatment, but debate exists about the extent to which these kinds of subjective experiences are necessary for therapeutic drug effects.

3.3 Blinding and placebos

Several different placebo conditions have been used in laboratory work and clinical designs using psychedelics to effectively blind psychedelic administration. However, debate about the integrity of these blinding procedures is evident, and limited data on the integrity of such blinding attempts emphasizes possible concerns.

A solution to blinding and placebos for psychedelic studies awaits further investigation. However, embracing the difficulty of designing an effective placebo could encourage exploration of innovative clinical trial designs.

3.4 Abuse-related effects of classic psychedelics

Before reviewing the subjective and clinical data surrounding psychedelics, it is important to understand their unique status as drugs of abuse. Psychedelics have been used in religious or spiritual rituals for centuries and are also used for casual, unsupervised experimentation. Psychedelics such as psilocybin and LSD do not show overt signs of dependence and do not reliably self-administer in non-human animals. The majority of participants reported no change in their psilocybin use following use in laboratory settings, while some reported a decreased consumption. Other factors, therefore, may motivate continued use.

In the following sections, we review human laboratory and clinical work involving three classic psychedelics, psilocybin, LSD, and DMT. We focus on psilocybin given its larger breadth of research as the most widely used of these compounds in the modern era of psychedelic human behavioral pharmacology and clinical psychopharmacology.

4. Psilocybin

Psilocybin is an active constituent present in a variety of mushroom species. It has been used by indigenous people for religious and healing ceremonies for centuries, and has been evaluated in human laboratory settings for its unique profile of subjective effects characteristic of classic psychedelics.

4.1 Subjective and physiological effects

Psilocybin and its active metabolite psilocin exhibit low toxicity and are physiologically well-tolerated. In fact, psilocybin is associated with the lowest toxicity of 20 psychoactive compounds when compared to commonly used doses.

Human data have shown that psilocybin has a broadly safe physiological profile. Minor adverse physiological effects include dizziness, nausea, vomiting, muscle twitching, and transient headaches of mild to moderate severity.

In the late 1990s, studies of the effects of psilocybin on healthy adults showed that the 5-HT2AR receptor mediates these effects. Further studies have replicated this role of the 5-HT2AR in psychedelic effects.

In another study, healthy participants received psilocybin, MDE, or d-methamphetamine and experienced dose-dependent increases in perception and affect. These effects were rated as positive during acute drug experience and in retrospective reflection in long-term follow-up.

A double-blind, active comparator study evaluated the acute and long-term effects of higher doses of psilocybin compared to methylphenidate in psychedelic-na ve adults and found that psilocybin produced higher subjective drug effects and a greater likelihood of ascribing personal meaning to the session at long-term follow-up.

Psilocybin has been shown to have positive effects on subjective well-being in studies conducted with healthy participants. These effects were dose-orderly with the highest observations of mystical experiences observed at the two highest doses.

A secondary analysis of 10 studies conducted at Johns Hopkins University School of Medicine between 2001 and 2018 found that body weight was not a major factor influencing the subjective effects of psilocybin across a range of populations and dosing structures.

Studies have compared psilocybin to non-classic psychedelics, including the non-competitive NMDA receptor antagonist dextromethorphan (DXM), and found that psilocybin produced dose-orderly effects on cognitive tasks, with similar effects observed for DXM on psychomotor performance, working memory, episodic memory, associative learning, and visual perception. A secondary analysis of these data found that both psilocybin and DXM produced effects greater than placebo, but that DXM ratings were significantly lower than those for the two highest doses of psilocybin on most items.

4.2 Clinical research

Recent clinical trials have tested the potential positive clinical benefit of psilocybin for a variety of indications, including depression and anxiety related to cancer and other life-threatening illness, major depressive disorder, smoking cessation, and alcohol use disorder.

A pilot study in 2011 found that psilocybin reduced depression and anxiety severity in patients with cancer and other life-threatening illness, and later larger trials found immediate and sustained improvements in depression and anxiety at 5-week and 6-month follow-ups.

Our research group has similarly evaluated the role of psilocybin-assisted treatment in smoking cessation. Participants reported increased sense of interconnectedness, awe, and curiosity, as well as decreased smoking, after receiving psilocybin (20mg/70kg) on a target quit date.

Collectively, these findings underscore the potential clinical utility of psilocybin-assisted treatment for a variety of conditions. It is important to emphasize that these studies have been conducted with an underlying psychotherapy or other behavioral intervention supporting the therapeutic administration of psychedelics.

5. LSD

LSD was first synthesized in 1938 and has been shown to have psychoactive properties at the 5-HT2AR, dopaminergic and adrenergic receptors. It has a longer duration of action than psilocybin.

5.1 Subjective and physiological effects

A series of placebo-controlled, crossover design studies have evaluated the subjective and physiological effects of LSD in healthy adults. The effects were similar to those of psilocybin and were dose-orderly with greater increases with the 200mg dose.

A recent dose-response study was conducted with oral LSD in healthy adults. The duration of effect was dose-dependent and increased with higher LSD doses, although a possible ceiling effect was observed with no difference between 100 and 200mg doses.

A comparative pharmacology study found that LSD produced greater peak ratings on subjective measures of drug effect and mystical experience than MDMA or d-amphetamine and had a longer time course with overt effects lasting until 10 – 11h post administration.

Although not commonly used recreationally, studies with intravenous LSD administration have also been conducted with human participants. Results show that LSD produces marked changes in visual perception, positive mood, and personality, as well as increases in optimism and trait openness.

Other studies have evaluated the phenomenon of microdosing using laboratory designs. These studies found that self-reported well-being and reductions in anxiety/depression were observed following induction of a weekly microdosing regiment, but that these effects may be related to a placebo/expectancy response rather than a pharmacologically mediated one.

5.2 Clinical effects

From the 1950s to the early 1970s, researchers used LSD and mescaline to treat alcoholism, with non-significant trends favoring improved outcome for LSD. A meta-analysis of six studies found improvements in alcohol misuse in LSD groups with odd ratio effect sizes of approximately 2.

Research during this older era evaluated LSD in the context of opioid use and pain relief. It found that those receiving 300-450mg of LSD showed lower biologically confirmed heroin use compared to control groups up to 12-months post-treatment.

Modern therapeutic research with LSD is limited, but one trial evaluated LSD for patients with anxiety related to cancer and other life-threatening illness. Results showed that LSD reduced anxiety in the treated group.

6. DMT

Richard Manske synthesized DMT in 1931 and it is the psychedelic constituent of ayahuasca, a tea historically used by indigenous people of the Amazon basin and organized religious groups in sacramental ceremonies. DMT is short acting and agonist at 5-HT2AR, which is believed to be the primary site at which psychedelic drug effects are mediated.

6.1 Subjective and physiological effects

In the early 1990s, systematic studies were conducted to evaluate the effects of DMT in human participants. These studies observed that DMT causes significant increases in blood pressure and heart rate, as well as overwhelming feelings of euphoria intermixed with anxiety.

Other work has evaluated the subjective effects of DMT via oral dosing, most typical in the form of ayahuasca preparations. The effects were minimal via oral dosing, whereas smoked administration produced robust increases on a Hallucinogen Rating Scale.

The role of the 5-HT2AR in DMT effects has also been evaluated in a study of ayahuasca, where the 5-HT2AR antagonist ketanserin attenuated some of the subjective effects, although complete reduction was not observed.

6.2 Clinical effects

Experimental studies evaluating the clinical effects of DMT are limited to six patients with recurrent major depressive disorder and a larger sample of 17 patients. The most significant reductions in depressive symptoms were observed at the 7-day timepoint.

7. Conclusion

This chapter provided an overview of current and future directions in the human behavioral pharmacology of psychedelics. It emphasized the need for more information about the mechanisms of health change mediated by psychedelics.