Psychedelic-assisted psychotherapy: where is the psychotherapy research?

RATIONALE: Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and depression. Current models of PAP emphasize the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical investigation of the "psychotherapy" in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered. OBJECTIVES: As clinical trials for psychedelic compounds continue the transition from safety- and feasibility-testing to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and inform cost-effectiveness. RESULTS: The present paper first reviews the current status of psychotherapy in the PAP literature, starting with recent debates regarding "psychotherapy" versus "psychological support" and then overviewing published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments (e.g., publish treatment manuals, establish eligibility criteria for providers), identifying mechanisms of change (e.g., measure established mechanisms in psychotherapy), and optimizing clinical trial designs (e.g., consider dismantling studies, comparative efficacy trials, and cross-lagged panel designs). Throughout this review, the need for increased research into the psychotherapeutic components of treatment in PAP is underscored. CONCLUSIONS: PAP is a distinct, integrative, and transdisciplinary intervention. Future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration.

Psychedelic substitution: altered substance use patterns following psychedelic use in a global survey.

Introduction: Recent research suggests that psychedelics may have potential for the treatment of various substance use disorders. However, most studies to date have been limited by small sample sizes and neglecting to include non-North American and European populations. Methods: We conducted a global, cross-sectional online survey of adults (n = 5,268, 47.2% women) self-reporting past or current psychedelic use and investigated whether psychedelic use was associated with changes in use of other substances. Results: Nearly three-quarters (70.9%; n = 3,737/5,268) reported ceasing or decreasing use of one or more non-psychedelic substances after naturalistic psychedelic use. Among those with previous use, 60.6% (n = 2,634/4,344) decreased alcohol use, 55.7% (n = 1,223/2,197) decreased antidepressant use, and 54.2% (n = 767/1,415) decreased use of cocaine/crack. Over a quarter of the sample indicated that their decrease in substance use persisted for 26 weeks or more following use of a psychedelic. Factors associated with decreased use included a motivation to either decrease one's substance use or self-treat a medical condition. Importantly, 19.8% of respondents also reported increased or initiated use of one or more other substances after psychedelic use, with illicit opioids (14.7%; n = 86/584) and cannabis (13.3%; n = 540/4,064) having the highest proportions. Factors associated with increased substance use included having a higher income and residing in Canada or the US. Discussion: Although limited by cross-sectional study design, this large observational study will help inform future studies aiming to investigate the relationship between substance use patterns and psychedelic use.

Effects of Ayahuasca on Gratitude and Relationships with Nature: A Prospective, Naturalistic Study.

Qualitative studies and anecdotal reports suggest that experiences with ayahuasca, a psychedelic brew found in Central and South America, may be followed by individuals enduringly feeling more grateful and connected to nature. Yet, to date, these changes have been understudied. Here, participants (N = 54) completed validated surveys related to gratitude, nature relatedness, and nature appreciation one-week before, one-week after, and one-month after attending an ayahuasca retreat center. Compared to baseline, there was a significant increase in gratitude, nature relatedness, and nature appreciation at the one-week and one-month follow-ups. Ratings of mystical-type experiences and awe, but not ego dissolution, during participants' ayahuasca sessions were weakly-to-moderately correlated with these increases. The number of ayahuasca ceremonies attended at the retreat was not related to change in outcomes, underscoring the importance of the quality rather than the quantity of the experiences in post-acute change. Lastly, participant age was negatively related to the occurrence of mystical-type experiences and awe, supporting literature indicating blunted psychedelic effects with increased age. In the context of study limitations, the results suggest that mystical-type experiences and awe occasioned by ayahuasca may be linked to prosocial changes in gratitude and relationships with nature that may be beneficial to mental health.

Eye-size effects in the dot-probe task: Greater sclera exposure predicts delayed disengagement from fearful faces.

Fearful facial expressions are nonverbal and biologically salient signals of potential threat that automatically hold, capture, and direct observers' attention. They are characterized by enlarged eye whites and dilated pupils, and fearful eyes alone are sufficient to capture attention. The morphological properties of the eye region, such as sclera exposure, are thought to play an important role in nonverbal communication. Specifically, increased sclera exposure associated with fearful expressions has been shown to moderate how observers' shift their attention toward the direction of another's gaze. Yet, the extent to which variability in sclera exposure possibly impacts the capture and hold of attention by fearful faces is untested. To address this, a sample of 249 adults completed a dot-probe task of selective attention with fearful and neutral faces. The results suggested that (1) fearful faces were prioritized over neutral faces (i.e., they captured and held attention), (2) greater sclera exposure at target locations facilitated reaction times, and (3) attention was held by greater sclera exposure of fearful faces at task irrelevant locations resulting in delayed disengagement. Collectively, the results indicate that fearful facial expressions and sclera exposure modulate spatial attention through independent and interactive mechanisms. Sclera exposure appears to be an important facilitator of nonverbal communication and perhaps represents an understudied variable in social cognition more broadly.

Emerging Challenges for Psychedelic Therapy.

This Viewpoint examines the benefits and challenges of psychedelic therapy using 4 fundamental questions.

Great Expectations: recommendations for improving the methodological rigor of psychedelic clinical trials.

RATIONALE: Psychedelic research continues to garner significant public and scientific interest with a growing number of clinical studies examining a wide range of conditions and disorders. However, expectancy effects and effective condition masking have been raised as critical limitations to the interpretability of the research. OBJECTIVE: In this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research. RESULTS: Although some challenges are shared with psychotherapy and pharmacology trials more broadly, psychedelic clinical trials have to contend with several unique sources of potential bias. The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition; the significant hype from positive media coverage on the clinical potential of psychedelics influences participants' expectations for treatment benefit; and participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects. Specific recommendations to increase the success of masking procedures and reduce the influence of participant expectancies are discussed in the context of study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, as well as the measurement of participant expectations and masking efficacy. CONCLUSION: Incorporating the recommended design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increases the ability to discern treatment-specific effects of psychedelic therapy.

Debunking the myth of 'Blue Mondays': No evidence of affect drop after taking clinical MDMA.

BACKGROUND: Incorporating 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy has shown promise in recent years for treating various mental health conditions, particularly those involving trauma. However, concerns about declines in mood and cognition during the days following dosing, also known as 'Blue Mondays', have been raised as limitations to its clinical use. Although these changes have been well-documented among recreational users, there are critical confounds to these reports that limit generalizability to clinically administered MDMA. AIMS: Here, we aimed to evaluate the evidence basis for the negative side effects associated with MDMA as well as inform our understanding of the drug's post-acute effects in a clinical context with an open-label study. METHODS: The current open-label study examined MDMA therapy for alcohol use disorder (AUD; N = 14) and measured mood, sleep quality, illicit MDMA consumption and anecdotal reports after the acute drug effects had worn off. RESULTS: Participants maintained a positive mood during the week following drug administration in a clinical context. Relative to baseline, self-reported sleep quality improved at the 3- and 6-month follow-ups. Finally, no participants reported using or desiring to use illicit MDMA, and the anecdotal reports indicated that they perceived the treatment favourably. CONCLUSION: The results support the overall safety and tolerability of clinically administered MDMA and, importantly, suggest that the 'come downs' previously associated with the substance may be explained by confounds in research relating to the illicit sourcing of the drug and specific environmental setting for recreational consumption.

Predicting Reactions to Psychedelic Drugs: A Systematic Review of States and Traits Related to Acute Drug Effects.

Psychedelic drugs are increasingly being incorporated into therapeutic contexts for the purposes of promoting mental health. However, they can also induce adverse reactions in some individuals, and it is difficult to predict before treatment who is likely to experience positive or adverse acute effects. Although consideration of setting and dosage as well as excluding individuals with psychotic predispositions has thus far led to a high degree of safety, it is imperative that researchers develop a more nuanced understanding of how to predict individual reactions. To this end, the current systematic review coalesced the results of 14 studies that included baseline states or traits predictive of the acute effects of psychedelics. Individuals high in the traits of absorption, openness, and acceptance as well as a state of surrender were more likely to have positive and mystical-type experiences, whereas those low in openness and surrender or in preoccupied, apprehensive, or confused psychological states were more likely to experience acute adverse reactions. Participant sex was not a robust predictor of drug effects, but 5-HT2AR binding potential, executive network node diversity, and rACC volume may be potential baseline biomarkers related to acute reactions. Finally, increased age and experience with psychedelics were individual differences related to generally less intense effects, indicating that users may become slightly less sensitive to the effects of the drugs after repeated usage. Although future well-powered, placebo-controlled trials directly comparing the relative importance of these predictors is needed, this review synthesizes the field's current understanding of how to predict acute reactions to psychedelic drugs.

Psychedelic drugs and perception: a narrative review of the first era of research.

Psychedelic drugs are well-known for transiently altering perception, and in particular, for their visual effects. Although scientific interest into the substances' effects on perception increased during the first era of psychedelic research during the early to mid-20th century, there is currently no source where these findings have been synthesized. In addressing this gap, the current narrative review found that psychedelics were examined for their influences across all levels of the visual system (e.g., retinal, cortical, subcortical, simple visual processing, complex imagery, hallucinations). Psychedelics were also shown to affect auditory discrimination/generalization, neural correlates of auditory processing, and led to auditory hallucinations in subsets of participants. Several studies demonstrated that psychedelics can distort representations of body schema and time perception. Concerns regarding methodological standards of this era are a limitation to the findings and are discussed. Collectively, this review preserves and increases the accessibility of the work done by pioneering psychedelic/perception researchers, synthesizes findings, and critically analyzes areas of discrepancy to inform future studies.

Psychedelics and virtual reality: parallels and applications.

Psychedelic drugs and virtual reality (VR) each have the capacity to disrupt the rigidity and limitations of typical conscious experience. This article delineates the parallels among psychedelic and VR states as well as their potential synergistic applications in clinical and recreational settings. Findings indicate that, individually, psychedelics and VR are used in analogous ways to alter sensory experience and evoke awe. They are also both used in tandem with traditional therapies to treat a variety of mood disorders; their shared capacity to transiently alter perspective and disrupt rigid patterns of mental experience may underly their analogous and transdiagnostic therapeutic uses. In terms of their combined applications, a number of recreational users currently utilize psychedelics and VR together to enhance their experience. We propose that VR may be a useful tool for preparing hallucinogen-naïve participants in clinical trials for the sensory distortions experienced in psychedelic states. Given the critical role of "setting" in psychedelic treatment outcomes, we also detail how VR could be used to optimize the environment in psychedelic sessions. Finally, we provide considerations for future studies and detail how advancements in psychedelic and VR research can inform one another. Collectively, this article outlines a number of connections between psychedelics and VR, and, more broadly, is representative of growing scientific interest into the interactions among technology, psychopharmacology, and mental health.

Meditation alters representations of peripersonal space: Evidence from auditory evoked potentials.

Meditation commonly gives rise to the feeling that the self and the surrounding world are no longer separate, as if the boundary between them has dissolved. We propose this may occur due to alterations in representations of peripersonal space (PPS), the reachable space surrounding the body which is integral to a sense of where one's bodily "self" is located in space. Thirty-one participants completed an auditory oddball paradigm before and after a guided meditation, during which we measured their P3 evoked potential, a marker of attentional salience. Pre-meditation, participants exhibited an enhanced attentional response to stimuli presented within PPS, relative to beyond PPS. Post-meditation, this PPS attentional enhancement was negated, with no distinction between responses to stimuli within versus beyond PPS. The results suggest that meditation leads to a constriction of PPS boundaries, even in novice meditators, elucidating one potential cause of the perceptual changes associated with meditation.

Long-term effects of psychedelic drugs: A systematic review.

Research into the basic effects and therapeutic applications of psychedelic drugs has grown considerably in recent years. Yet, pressing questions remain regarding the substances' lasting effects. Although individual studies have begun monitoring sustained changes, no study to-date has synthesized this information. Therefore, this systematic review aims to fill this important gap in the literature by synthesizing results from 34 contemporary experimental studies which included classic psychedelics, human subjects, and follow-up latencies of at least two weeks. The bulk of this work was published in the last five years, with psilocybin being the most frequently administered drug. Enduring changes in personality/attitudes, depression, spirituality, anxiety, wellbeing, substance misuse, meditative practices, and mindfulness were documented. Mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were related to these long-term changes in psychological functioning. Finally, with proper screening, preparation, supervision, and integration, limited aversive side effects were noted by study participants. Future researchers should focus on including larger and more diverse samples, lengthier longitudinal designs, stronger control conditions, and standardized dosages.

Slowhand: Does time perception change in peri-hand space?

A variety of attentional and perceptual changes occur in peri-hand space, including increases in visual temporal acuity. These changes in cognition have been related to an increase in magnocellular visual processing. Other magnocellular-related processes have been shown to enhance temporal sensitivity and lead to time overestimation. We hypothesized that a similar slowing of time perception would occur in peri-hand space. To this end, we had participants complete either a temporal bisection task or a verbal time estimation task with their hands near to or far from the test stimuli. Contrary to our predictions, we found no differences in time perception in peri-hand space. We situate our findings within the context of a contemporaneous study by Qi, Wang, He, and Du (2019), which produced conflicting results when using a temporal reproduction task to investigate the same phenomenon. The disparate results might relate to the fragility of peri-hand effects and/or to the tasks tapping into different aspects of time perception. Further research will be needed to fully elucidate the nuances of peri-hand space and temporal processing.

Beyond LSD: A Broader Psychedelic Zeitgeist during the Early to Mid-20th Century.

During the 1950s and 1960s, there was a tremendous surge in research into the effects of psychedelic drugs. When discussing this period of research, the discovery of the psychoactive properties of LSD in 1943 is often presented as the main, and sometimes only, driving force of the boom in research. This "Great Person," or "Great Chemical," historiographical lens fails to acknowledge other factors that were fundamental in setting the stage for the research. In particular, other psychedelic drugs, such as mescaline, were already being probed for their uses in psychotherapy and as models for psychosis before the effects of LSD had been discovered. Psilocybin and other classical psychedelics had also been discovered by Western researchers around the same time as the synthesis of LSD. Additionally, many of the dominant zeitgeists (e.g., pharmacological, psychoanalytic, and humanistic) in psychology during this period were congruent with psychedelic research. This article argues that while the discovery of LSD may have been a catalyst for psychedelic research in the 1950s and '60s, there was a broader psychedelic zeitgeist that deserves acknowledgement for setting the stage.

Temporal dynamics in attention bias: effects of sex differences, task timing parameters, and stimulus valence.

New methods of calculating indices from the dot-probe task measure temporal dynamics in attention bias or fluctuations in attention bias towards and away from emotional stimuli over time. However, it is unclear how task-specific parameters such as stimulus valence and stimulus onset asynchrony (SOA) as well as participant sex affect temporal dynamics in attention bias. To address this, male and female participants (N = 106) completed either a fearful or happy face dot-probe task with four levels of SOA (84 ms, 168 ms, 336 ms, and 672 ms). Results suggest that temporal dynamics in attention bias are (1) greatest at the longest SOA, (2) greater in females, and (3) insensitive to stimulus valence. These findings indicate that participant sex and task timing, but not stimulus valence, are related to temporal dynamics in attention bias and should be considered in future studies utilizing this approach.

Extended testing with the dot-probe task increases test-retest reliability and validity.

The dot-probe task is used to measure attentional biases toward threat. However, the test-retest reliability and validity of the task have been called into question. No studies to date have included an extended number of testing sessions or tailored the task to individual participants by incorporating self-relevant stimuli-doing so may improve reliability. Here, participants provided 10 words that caused them anxiety and 10 neutral words which were incorporated into a dot-probe task for 6 sessions. The test-retest reliability of their bias indices was stronger in bottom-target trials relative to top-target trials and stronger among later relative to earlier sessions. State and trait anxiety were moderately correlated with bias indices in later sessions, but not earlier sessions. Overall reaction time in each session was moderately correlated with state and trait anxiety. These results suggest that including extended testing may facilitate dot-probe task test-retest reliability and validity.

Neurotensin NTS1 and NTS2 receptor agonists produce anxiolytic-like effects in the 22-kHz ultrasonic vocalization model in rats.

Neurotensin is a neuropeptide neurotransmitter that interacts with multiple neurotransmitter systems, including those regulating amygdalar function, via NTS1 and NTS2 receptors. Both receptors are expressed in the amygdala and agonists for NTS1 or NTS2 receptors have exhibited anxiolytic effects in animal models. Systemic adminstration of NTS1 receptor agonist PD149163 was recently shown to reduce footshock conditioned 22-kHz ultrasonic vocalizations in rats, suggesting that PD149163 produced an anxiolytic effect. The effects that neurotensin may have or a selective NTS2 receptor agonist may have on 22-kHz vocalizations has yet to be examined. The current study evaluated the effects of intracerebroventricularly administered neurotensin (0.1-10.0µg), PD149163 (0.1-10.0ng), or the NTS2 receptor agonist JMV-431 (0.1-1.0µg) on footshock conditioned 22-kHz vocalizations in male Wistar rats. Neurotensin, PD149163, and JMV-431 all significantly reduced the number 22-kHz calls. No changes in call duration were found, suggesting that non-specific drug effects do not account for the reductions in 22-kHz calls. These data support anxiolytic effects produced by activation of NTS1 or NTS2 receptors, and suggest that neurotensin plays a natural role in the expression of conditioned USVs. These data suggest that both receptor subtypes are putative pharmacologic targets.