therapy

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 therapeutic use of ayahuasca

Focusing on the potential of Ayahuasca in the treatment and management of various diseases and ailments. Presents a series of perspectives on the therapeutic potential and clinical use. Stimulates discussion on the methodological, ethical, and political aspects of research on psychedelics.

Studying Harms Is Key to Improving Psychedelic-Assisted Therapy—Participants Call for Changes to Research Landscape

Although psychedelic drugs generally have good safety profiles, a recent systematic review concluded that adverse events in psychedelic trials are poorly defined, not systematically assessed, and likely underreported. In the past year there have been multiple reports of serious adverse events (SAEs), and long-lasting harms to participants in clinical trials of psychedelic-assisted therapy (PAT) have emerged. We draw attention to a unique and overlooked category of risk in PAT stemming from the interactions between therapists and patients receiving high doses of psychedelics. In our view, the understudied therapeutic component of PAT presents the most serious risks. Addressing it requires interdisciplinary approaches by researchers free from conflicts of interests.

What Happens When Psychedelic Treatment for PTSD Turns Into a Bad Trip

I lay flat on my back, pouring sweat and heart racing, in a hotel room with a woman who had just overdosed me.

Let’s call her Sarah. To be clear: Neither of us was here to party. Sarah, in fact, was a therapist, a licensed clinician. Outside of her office hours, she offered patients like me psilocybin and MDMA, for PTSD and treatment-resistant depression. She did this at fairly extreme risk to her career, because, as she said, she believed in it. This was my second time trying a guided, high-dosage cocktail of psychedelics to address my ongoing PTSD, a result of my surviving the 2008 terrorist attack on the Taj Mahal Hotel in Mumbai.

The goal with such an experience is to “go inside” yourself, surrender the trappings of the ego, and through that process transcend or soothe damage caused by a fundamental trauma. The idea is fairly simple: By letting go of yourself (commonly known as ego loss, or ego death), you become one with everything else. Put another way, you can experience a sense of wholeness that transcends yourself, and that wholeness can be very healing. In conversations with underground practitioners, I learned this was achieved through taking a combination of “medicines.” (For example: MDMA, the main ingredient in what is commonly referred to as ecstasy, paired with psilocybin, otherwise known as magic mushrooms.) But equally important, they said, was the guided support for the experience itself, followed by integration (processing of the experience) with that same guide. My first trip had been very positive and had resulted in a sense of peace and calm with respect to the particular anguish I had been experiencing for years. Indeed, recent scientific research increasingly supports the potential for MDMA-assisted psychotherapy to be “an innovative, efficacious treatment” for PTSD.

Mendel Kaelen: Psychological & Neurophysiological Effects of Music in Combination with Psychedelics

Mendel Kaelen, PhD presents “The Psychological and Neurophysiological Effects of Music in Combination with Psychedelics” at Psychedelic Science 2017: A six-day global gathering of the international scientific community in Oakland, California to explore new research into the benefits and risks of MDMA, LSD, psilocybin, ayahuasca, ketamine, ibogaine, medical marijuana, and more. https://2017.psychedelicscience.org

Breakthrough for trauma treatment: Safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline

Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for Psychedelic Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD on the basis of pooled analyses showing a large effect size for this treatment. This review covers data supporting BTD. In this treatment, MDMA is administered with psychotherapy in up to three monthly 8-h sessions. Participants are prepared for these sessions beforehand, and process material arising from the sessions in follow-up integrative psychotherapy sessions. Comparing data used for the approval of paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated that MDMA-assisted psychotherapy constitutes a substantial improvement over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As MDMA is only administered under direct observation during a limited number of sessions, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation. BTD status has expedited the development of MAPS phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA approval in 2021.

The Pharmacology and Clinical Applications of Psychedelic Medicines Within Midwifery Practice

The research and use of psychedelic medicines to treat common mental health disorders has increased substantially in the past 2 decades. At the same time, knowledge is relatively uncommon among midwives regarding (1) the relative benefits of psychedelic-assisted therapy, (2) best practices associated with the delivery of psychedelic-assisted therapy, and (3) responsible integration of this potentially useful intervention into mental health treatment plans. The purpose of this review is to describe current applications of psychedelic medicines to treat common mental health disorders, to describe the current legal status of these medicines used in this context, and to explore the potential for midwifery practice in this area with further training. This article also addresses the disparities regarding LGBTQIA+ and BIPOC populations in relation to this topic and their historical exclusion from research and treatment access in this field.

Psychedelic Therapy’s Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective

Accumulating clinical evidence shows that psychedelic therapy, by synergistically combining psychopharmacology and psychological support, offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and/or maladaptive habitual patterns of emotion, cognition and behavior, notably, depression (MDD), treatment resistant depression (TRD) and addiction disorders, but perhaps also anxiety disorders, obsessive-compulsive disorder (OCD), Post-Traumatic Stress Disorder (PTSD) and eating disorders. Despite the emergent transdiagnostic evidence, the specific clinical dimensions that psychedelics are efficacious for, and associated underlying neurobiological pathways, remain to be well-characterized. To this end, this review focuses on pre-clinical and clinical evidence of the acute and sustained therapeutic potential of psychedelic therapy in the context of a transdiagnostic dimensional systems framework. Focusing on the Research Domain Criteria (RDoC) as a template, we will describe the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, traversing molecular, cellular and network levels. These levels will be mapped to the RDoC constructs of negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems. In summarizing this literature and framing it transdiagnostically, we hope we can assist the field in moving toward a mechanistic understanding of how psychedelics work for patients and eventually toward a precise-personalized psychedelic therapy paradigm.

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