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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 Nutmeg’s Curse: Parables for a Planet in Crisis

In this ambitious successor to The Great Derangement, acclaimed writer Amitav Ghosh finds the origins of our contemporary climate crisis in Western colonialism’s violent exploitation of human life and the natural environment.

A powerful work of history, essay, testimony, and polemic, Amitav Ghosh’s new book traces our contemporary planetary crisis back to the discovery of the New World and the sea route to the Indian Ocean. The Nutmeg’s Curse argues that the dynamics of climate change today are rooted in a centuries-old geopolitical order constructed by Western colonialism. At the center of Ghosh’s narrative is the now-ubiquitous spice nutmeg. The history of the nutmeg is one of conquest and exploitation—of both human life and the natural environment. In Ghosh’s hands, the story of the nutmeg becomes a parable for our environmental crisis, revealing the ways human history has always been entangled with earthly materials such as spices, tea, sugarcane, opium, and fossil fuels. Our crisis, he shows, is ultimately the result of a mechanistic view of the earth, where nature exists only as a resource for humans to use for our own ends, rather than a force of its own, full of agency and meaning.

Writing against the backdrop of the global pandemic and the Black Lives Matter protests, Ghosh frames these historical stories in a way that connects our shared colonial histories with the deep inequality we see around us today. By interweaving discussions on everything from the global history of the oil trade to the migrant crisis and the animist spirituality of Indigenous communities around the world, The Nutmeg’s Curse offers a sharp critique of Western society and speaks to the profoundly remarkable ways in which human history is shaped by non-human forces.

The Great Derangement: Climate Change and the Unthinkable

Are we deranged? The acclaimed Indian novelist Amitav Ghosh argues that future generations may well think so. How else to explain our imaginative failure in the face of global warming? In his first major book of nonfiction since In an Antique Land, Ghosh examines our inability—at the level of literature, history, and politics—to grasp the scale and violence of climate change.

The extreme nature of today’s climate events, Ghosh asserts, make them peculiarly resistant to contemporary modes of thinking and imagining. This is particularly true of serious literary fiction: hundred-year storms and freakish tornadoes simply feel too improbable for the novel; they are automatically consigned to other genres. In the writing of history, too, the climate crisis has sometimes led to gross simplifications; Ghosh shows that the history of the carbon economy is a tangled global story with many contradictory and counterintuitive elements.

Ghosh ends by suggesting that politics, much like literature, has become a matter of personal moral reckoning rather than an arena of collective action. But to limit fiction and politics to individual moral adventure comes at a great cost. The climate crisis asks us to imagine other forms of human existence—a task to which fiction, Ghosh argues, is the best suited of all cultural forms. His book serves as a great writer’s summons to confront the most urgent task of our time.

Plant spirit

Visionary Plant Consciousness explores how the “vegetable mind” can affect the human condition. Twenty-three leading ethnobotanists, anthropologists, medical researchers and cultural and religious figures present their understandings, including the late Terence McKenna, Dr. Andrew Weil, Wade Davis, Michael Pollan, Alex Grey, Jeremy Narby and Kat Harrison. They reveal that these plants may help us access the profound intelligence in nature—the “mind of nature”—that we must learn to understand in order to survive our eco-logically destructive way of life.

Lifetime experience with (classic) psychedelics predicts pro-environmental behavior through an increase in nature relatedness

In a large-scale (N = 1487) general population online study, we investigated the relationship between past experience with classic psychedelic substances (e.g. LSD, psilocybin, mescaline), nature relatedness, and ecological behavior (e.g. saving water, recycling). Using structural equation modeling we found that experience with classic psychedelics uniquely predicted self-reported engagement in pro-environmental behaviors, and that this relationship was statistically explained by people’s degree of self-identification with nature. Our model controlled for experiences with other classes of psychoactive substances (cannabis, dissociatives, empathogens, popular legal drugs) as well as common personality traits that usually predict drug consumption and/or nature relatedness (openness to experience, conscientiousness, conservatism). Although correlational in nature, results suggest that lifetime experience with psychedelics in particular may indeed contribute to people’s pro-environmental behavior by changing their self-construal in terms of an incorporation of the natural world, regardless of core personality traits or general propensity to consume mind-altering substances. Thereby, the present research adds to the contemporary literature on the beneficial effects of psychedelic substance use on mental wellbeing, hinting at a novel area for future research investigating their potentially positive effects on a societal level. Limitations of the present research and future directions are discussed.

Entheogenic rituals, shamanism and green psychology

Psychedelic or consciousness-expanding drugs have been studied by Western scientific researchers as adjuncts to psychotherapy while their plant-based equivalents are used in traditional ceremonial context for healing and spiritual practice. Plant extracts from tobacco, coca, coffee and cannabis, used as sacraments in indigenous cultures have become recreational drugs in contemporary society. Research with consciousness-expanding or entheogenic substances such as MDMA, LSD and psilocybin has focused on their value as adjuncts to psychotherapy. The worldwide underground culture has adopted the use of hallucinogenic plants and fungi, such as psilocybe mushrooms, ayahuasca, iboga and peyote, in small group hybrid therapeutic-shamanic ceremonies as well as large scale events such as raves. Core elements of such hybrid rituals are: the structure of a circle, a ritual space and altar of some kind, the presence of an experienced elder or guide, the use of eye-shades or semi-darkness and the cultivation of a respectful, spiritual attitude.

Dreams and Psychedelics: Neurophenomenological Comparison and Therapeutic Implications

Background: A resurgence of neurobiological and clinical research is currently under-way into the therapeutic potential of serotonergic or ‘classical’ psychedelics, such as the prototypical psychedelic drug lysergic acid diethylamide (LSD), psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), and ayahuasca – a betacarboline- and dimethyltryptamine (DMT)-containing Amazonian beverage. The aim of this review is to introduce readers to the similarities and dissimilarities between psychedelic states and night dreams, and to draw conclusions related to therapeutic applications of psychedelics in psychiatry. Methods: Research literature related to psychedelics and dreaming is reviewed, and these two states of consciousness are systematically compared. Relevant conclusions with regard to psychedelic-assisted therapy will be provided. Results: Common features between psychedelic states and night dreams include perception, mental imagery, emotion activation, fear memory extinction, and sense of self and body. Differences between these two states are related to differential perceptual input from the environment, clarity of consciousness and meta-cognitive abilities. Therefore, psychedelic states are closest to lucid dreaming which is characterized by a mixed state of dreaming and waking consciousness. Conclusion: The broad overlap between dreaming and psychedelic states supports the notion that psychedelics acutely induce dreamlike subjective experiences which may have long-term beneficial effects on psychosocial functioning and well-being. Future clinical studies should examine howtherapeutic outcome is related to the acute dreamlike effects of psychedelics.

Functional neuroimaging of psychedelic experience: An overview of psychological and neural effects and their relevance to research on creativity, daydreaming, and dreaming

The neural correlates of the psychedelic experience are increasingly being investigated with noninvasive functional neuroimaging methods. This research has now provided a preliminary understanding of the neural substrates of various stages and contents of psychedelic experience, elucidating how various stages differ from one another, and also relate to kindred “altered” states of consciousness such as dreaming and creative thinking. Several conclusions can be gleaned from this review. First, psychedelic experiences involving strong visual hallucinatory components activate the same brain areas as “natural” altered states involving high rates of visual imagery, most notably daydreaming and nighttime dreaming. Second, peak psychedelic experiences involving loss of the sense of the self or “ego-dissolution” involve deactivation or disintegration of brain networks, most notably the default mode network, that are widely thought to maintain and subserve an internal stream of thoughts and a coherent sense of self.

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