DMT

Expectancy Effects in Psychedelic Trials

Abstract

Clinical trials of psychedelic compounds like psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltrptamine (DMT) have forced a reconsideration of how nondrug factors, such as participant expectations, are measured and controlled in mental health research. As doses of these profoundly psychoactive substances increase, so does the difficulty in concealing the treatment condition in the classic double-blind, placebo-controlled trial design. As widespread public enthusiasm for the promise of psychedelic therapy grows, so do questions regarding whether and how much trial results are biased by positive expectancy. First, we review the key concepts related to expectancy and its measurement. Then, we review expectancy effects that have been reported in both micro- and macrodose psychedelic trials from the modern era. Finally, we consider expectancy as a discrete physiological process that can be independent of, or even interact with, the drug effect. Expectancy effects can be harnessed to improve treatment outcomes and can also be actively managed in controlled studies to enhance the rigor and generalizability of future psychedelic trials.

Section snippets

Placebo Response, Placebo Effect, and Expectancy

Expert consensus distinguishes the placebo response from the placebo effect (6,7). The placebo response includes all health changes that result after administration of an inactive treatment, which includes behavior related to being observed, i.e., the Hawthorne effect (8), regression to the mean (9), and other nonspecific effects of clinical care (10).

The placebo/nocebo effect refers to the changes that are specifically attributable to placebo mechanisms and can be defined as the difference

Unblinding and Its Relationship to Expectancy

Unblinding occurs when patients recognize their treatment allocation in a randomized controlled trial (RCT). Usually, unblinding is captured by asking patients at the end of the trial to guess their treatment. If this treatment guess/perceived treatment matches the actual treatment at a higher than chance rate, then the trial has weak blinding integrity.

Most psychiatric trials have not assessed blinding integrity; it has been estimated that in this domain, only 2% to 7% of trials report

Changing Expectancy

Expectancy is not a static trait; rather, it changes dynamically according to new information and experiences (27). The ViolEx model has been proposed to account for both how expectancies change and why they are sometimes maintained even when contradictory information is obtained (27). For example, consider the fact that many psychedelic treatments include more than 1 psychedelic drug session. It is reasonable to assume that patients change their expectations in-between drug sessions as a

Measuring Expectancy and Blinding Integrity

Studies that assess expectancy often use a self-constructed questionnaire rather than a standardized and validated measure, which hinders generalization. To help overcome this issue, here we list validated expectancy measures. The most popular one is the Credibility and Expectancy Scale, which has been shown to have good psychometric properties (34). Alternative measures are the Stanford Expectations of Treatment Scale (35), which focuses on perceived benefits and risks of treatments; the

Macrodose Trials

Blinding integrity has been found to be poor in psychedelic macrodose RCTs that measured it (42, 43, 44). For example, Holze et al. noted that only 1 patient of 20 mistook lysergic acid diethylamide (LSD) for a placebo (95% correct guess rate) (45). Similarly, Bogenschutz et al. reported that 90 of 95 treated patients correctly guessed their treatment allocation (94% correct guess rate), showing that blinding integrity was almost nonexistent in these trials (4).

Expectancy has only been measured

Separating Expectancy and Drug Effects

Attempts to conceal treatment allocation in psychedelic studies often involve incomplete disclosure of the study design. In some nontherapeutic studies, investigators inform participants that they may receive one among many psychoactive substances, although the actual study design may only involve a limited number of drugs and doses (61,62). For example, in an LSD microdose trial, de Wit et al. told patients that they might receive a hallucinogen/cannabinoid/opioid/stimulant/sedative or placebo

Drug-Placebo Interactions

Most trials consider the observed treatment effect to be the sum of the placebo and the drug effect. However, this simple arithmetic may not apply to all circumstances, for example where interactions exist between drug and placebo effects, i.e., the total treatment effect may be less or more than the sum of the drug and placebo effects (79). Such drug × placebo interactions can be demonstrated in balanced placebo designs; for example, Hammami et al. (80) used a crossover variant of the balanced

Lessons From the Pain Literature

Outsized placebo responses have been problematic for clinical trials of novel pain management drugs and interventions for decades and have contributed to the difficulty in developing novel analgesics despite an impressive array of novel molecular targets validated in animal models (82). Pain, as a sensory experience, can be quantified using various psychophysical measures, which allows for clear delineation of drug-induced relief. In contrast, depression, which is the subject of most

The Neurophysiological Basis of Expectancy

When placebo first appeared in medical dictionaries and texts from the 18th and 19th century, the term was generally defined as an inert substance whose primary value is to soothe, rather than benefit, the patient (61). Since the mid-20th century, most usages of the term preserved the distinction between true benefit and psychological benefit (62), perhaps reflecting the increasing emphasis across medicine and psychiatry that drug therapy could be explained primarily in terms of the drug’s

Conclusions

Expectancy effects are widely expected in psychedelic trials, but to date, only a few studies have assessed them. We distinguish between expectancy and unblinding and recommend treating these as separate but related concepts. A deeper understanding of these effects in psychedelic trials will require, first and foremost, a consistent effort across research groups to incorporate standardized measures of both expectancy and blinding integrity throughout the life cycle of these complex trials, as

The Open Hyperspace Traveler: A course handbook for the safe and responsible management of psychoactives

Welcome to the Open Hyperspace Traveler Course. If you are reading this, you presumably have an interest in entheogenic drugs – psychoactive compounds found in plants and fungi – often referred to as psychedelics or simply entheogens. In this manual we have tried to collect and provide unbiased information, backed by both experience and scientific evidence, on the various entheogens out there; on how they can be used safely, responsibly, and beneficially, what risks they present, and potential strategies to handle any problems that may surface when using them.

This manual is not meant to encourage the reader to use entheogens, which sadly are still illegal around the world and considered by many as far more dangerous than scientifice evidence indicates. Rather, it is meant to fill a void; a need for education and systematic approaches to these substances, in order to reduce the harm that can be caused by improper use and/or ignorance. In this respect (and many others), prohibition has failed. Entheogens are, and most likely always will remain, available and by making entheogens and other so-called drugs unavailable from reliable sources, prohibition has encouraged the distribution of unreliable products of questionable content and purity, potentially presenting severe health risks to the end user. Additionally, by legislating away reliable information concerning these substances, prohibition has propagated a great deal of misinformation, ranging from hearsay and myths to outright propaganda and lies. This has resulted in harm and trauma to people interested in exploring entheogens due to their ignorance of, generally speaking, avoidable issues.

The current situation clearly shows that prohibition is not effective at keeping people safe, and is even less effective at preventing them from exploring entheogens. The experiences of many explorers of these compounds as well as scientific studies indicate that much of the harm that we see resulting from the use of entheogens can be reduced, or even entirely avoided, by following a few basic steps concerning safety and planning. At the same time, more and more scientific studies indicate that people can actually benefit from using entheogens in certain situations – something that explorers of these compounds have been claiming for a long time. In order to prevent more harm and to help people benefit from using entheogens, this manual provides information that is easy to read and utilize, so that future explorers – also called travelers – can use these compounds safely and responsibly

Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings

Background: N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings.

Aims: Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. “set“ and “setting“), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings.

Methods: We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants.

Results: We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8–12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1–4 Hz) and gamma (30–40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band.

Conclusions: Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

Archiving Terence McKenna

The goal for this blog is to share the process of acquisition and research with you for the Terence McKenna Archives, to give you an insight into the process, as well as to share some of the interesting items encountered as part of the hunt. Please sign up to follow the blog and keep an eye out for new posts.

Serotonergic Psychedelics in Neural Plasticity

Psychedelics, compounds that can induce dramatic changes in conscious experience, have been used by humans for centuries. Recent studies have shown that certain psychedelics can induce neural plasticity by promoting neurite growth and synapse formation. In this review, we focus on the role of classical serotonergic psychedelics in neural plasticity and discuss its implication for their therapeutic potentials.

Transient reinforcing effects of phenylisopropylamine andindolealkylamine hallucinogens in rhesus monkeys

Relatively few studies have assessed the reinforcing effects of hallucinogenic compounds, and no such studies have attempted to engender contingent responding for these compounds in animals with behavioral histories that include experience with serotonergically mediated reinforcing effects. The objectives of the present study were to investigate the capacity of several hallucinogenic compounds to maintain self-administration behavior in rhesus monkeys with a previous history of 3,4-methylenedioxymethamphetamine (MDMA) self-administration, and to compare these effects across a range of doses of drugs from two structural classes (indolealkylamines and phenylisopropylamines). The results indicate that no compound generated reliable responding and that no subject ever self-administered 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI) at rates above those engendered by contingent saline. However, 3 out of 4 subjects did respond at rates between 0.75 and 3.0 responses/s in one or more sessions where N,N-dimethyltryptamine (DMT), mescaline or psilocybin were available. During some of these sessions in which self-administration was maintained, animals earned a majority of all available infusions and appeared intoxicated by the end of the session. This pattern of transient self-administration may indicate that these compounds have weak reinforcing effects, or mixed reinforcing and aversive effects.

Classic Psychedelic Use and Mechanisms of Mental Health: Exploring the Mediating Roles of Spirituality and Emotion Processing on Symptoms of Anxiety, Depressed Mood, and Disordered Eating in a Community Sample

A resurgence of research has begun to systematically examine the relationship between psychedelic use and mental health and well-being. Although preliminary findings examining the therapeutic value of these substances show promise, the mechanisms through which psychedelic use may predict reduced mental distress remain poorly understood. To this end, we surveyed a community sample of individuals (n = 159) who endorsed lifetime psychedelic use to examine relationships among psychedelic use and self-reported spirituality, difficulties in emotion regulation, and symptoms of mental health issues. Results revealed a pathway through which classic psychedelic use predicted greater spirituality, which in turn predicted better emotion regulation, ultimately predicting lower levels of anxiety, depressed mood, and disordered eating. These results contribute to our understanding of potential mechanisms of change with respect to psychedelics and mental health. They also add to the growing body of literature pointing to the healing effects of the cultivation of spirituality and emotion regulation as separate and related constructs.

The Relationship Between Psychedelic Use, Mystical Experiences, and Pro-Environmental Behaviors

Expanding on the work of Forstmann and Sagioglou, this study investigated the differences in personality and pro-environmental behavior (PEB) as a function of psychedelic-occasioned mystical experiences. A sample of 240 participants with prior psychedelic experience completed an online survey. Data were collected on participants’ psychedelic-occasioned mystical states, personality, and self-reported PEB. A measure of behavioral PEB was also included (Charity Task). The mean scores on self-reported PEB, openness and agreeableness of participants who met the criteria for a “complete” mystical state, were significantly higher than those who did not. Specifically, those who experienced a mystical state scored higher on the PEB types “eco-shopping and eating” and “one-off domestic conservation actions.” Participants who demonstrated PEB in the Charity Task scored higher on self-reported PEB than those who did not, supporting the task’s validity. Findings suggest that mystical experiences influence PEB. Future research with experimental designs could further illuminate potential causal relationships.

Pharmako/Gnosis: Plant Teachers and the Poison Path

This is the third and final volume of North Atlantic Books’ updated paperback edition of Dale Pendell’s Pharmako trilogy, an encyclopedic study of the history and uses of psychoactive plants and related synthetics first published between 1995 and 2005. The books form an interrelated suite of works that provide the reader with a unique, reliable, and often personal immersion in this medically, culturally, and spiritually fascinating subject. All three books are beautifully designed and illustrated, and are written with unparalleled authority, erudition, playfulness, and range.
Pharmako/Gnosis: Plant Teachers and the Poison Path includes a new introduction by the author and as in previous editions focuses on plant-based and derivative psychedelic “teachers” (including ayahuasca, peyote, LSD, and DMT) and on the “poison path” of substances such as belladonna, ketamine, and ibogaine. Each substance is explored in detail, not only with information on its history, pharmacology, preparation, and cultural and esoteric correspondences, but also the subtleties of each plant’s effect on consciousness in a way that only poets can do.The whole concoction is sprinkled with abundant quotations from famous writers, creating a literary brew as intoxicating as its subject.
The Pharmako series includes the predecessor volumes Pharmako/Poeia (which covers tobacco, alcohol, cannabis, opiates, salvia divinorum, and other substances) and Pharmako/Dynamis (focusing on stimulants and empathogens).

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