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Assessment of the Acute Effects of 2C‐B vs. Psilocybin on Subjective Experience, Mood, and Cognition

Authors:
Pablo Mallaroni at Maastricht University
Pablo Mallaroni
Natasha L Mason at Maastricht University
Natasha L Mason
Johannes Reckweg at Maastricht University
Johannes Reckweg
Riccardo Paci
Riccardo Paci
Riccardo Paci
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Abstract

2,5-dimethoxy-4-bromophenethylamine (2C-B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it's acute effects and distinctions from classical progenitors have yet to be characterised in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C-B (20 mg) in comparison to psilocybin (15mg) and placebo in a within-subjects, double-blind, placebo-controlled study of 22 healthy psychedelic-experienced participants. 2C-B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared to placebo, as indexed by the Digit Symbol Substitution Test (DSST), Tower of London (TOL) and Spatial Memory Task (SMT). Neither compound produced empathogenic effects on the Multifaceted Empathy Test (MET). 2C-B induced transient pressor effects to a similar degree as psilocybin. The duration of self-reported effects of 2C-B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorisation of 2C-B as a psychedelic of moderate experiential depth at doses given. Tailored dose-effect studies are needed to discern the pharmacokinetic dependency of 2C-B's experiential overlaps.
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Supplementary resources (2)

cpt2958-sup-0001-tables.xls
Data
June 2023
Pablo Mallaroni · Natasha L Mason · Johannes Reckweg · Riccardo Paci · Johannes G Ramaekers
cpt2958-sup-0002-supinfo.docx
Data
June 2023
Pablo Mallaroni · Natasha L Mason · Johannes Reckweg · Riccardo Paci · Johannes G Ramaekers
... In total, 19 publications between 1997 and 2023 reporting PK data after psilocybin administration were included (see Fig. 2) [14,20,21,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. The reported results originate from 12 distinct clinical datasets. ...
... Psilocybin was administered orally in all but one study, where it was administered orally and intravenously to six male healthy subjects [14]. Available specifics on oral formulations included the mention of capsules [14,20,32,36,[39][40][41], powder [29,31], purity [27,28,32,36,[38][39][40]42], excipients [14,20,27,37,38,42] or administration as psilocybin dihydrate [36,39,40]. Oral doses ranged from 7 to 59.2 mg and doses were often individualised within treatment groups, sometimes as the result of predefined weight-based doses [21,27,37,38,41,42]. ...
... Population weights (mean or median) were reported between 59.5 and 89.9 kg per studied dose level (minimum-maximum: 50-122 kg) [14,20,[33][34][35][36][37][38][39][40], yet body mass index was reported less, between 23 and 24 kg/m 2 (19-34 kg/m 2 ) [37,39,40]. Population age was reported between 23 and 43 years (19-61 years) [14,20,29,[31][32][33][34][35][36][37][39][40][41][42]. If reported, included sex was distributed fairly between both sexes with a median of 60% male individuals included [14,20,29,[31][32][33][34][35][36][37]39,40,42]. ...
Clinical Pharmacokinetics of Psilocin After Psilocybin Administration: A Systematic Review and Post-Hoc Analysis
Article
Full-text available
  • Jan 2025
  • CLIN PHARMACOKINET
Psilocybin is currently being extensively studied as a potential therapeutic agent for multiple psychiatric disorders. Here, a systematic literature review of all published pharmacokinetic data on the pharmacologically active metabolite of psilocybin, psilocin, is presented. The review includes clinical studies that reported pharmacokinetic data and/or parameters after psilocybin administration in humans. In addition, raw pharmacokinetic data from these studies was requested and/or extracted to further compare results across studies. In total, 309 publications were identified, of which 19 publications were ultimately included, which covered 12 unique clinical datasets. Except for one study that investigated intravenous psilocybin, all included studies administered psilocybin orally. Psilocybin acts as a pro-drug and is rapidly absorbed and transformed to psilocin after oral administration. In the majority of studies, unconjugated psilocin was measured while some also measured conjugated and total concentrations. Psilocin’s biphasic concentration–time profiles demonstrates fast and extensive disposition with an apparent distribution volume of 505–1267 L and a terminal half-life of 1.23–4.72 h. Only 1.5–3.4% of the dose is excreted as psilocin in urine. Psilocin is mainly transformed to 4-hydroxyindole-3-acetic acid and in less amounts to conjugated psilocin, where 4-hydroxyindole-3-acetic acid formation may occur prior to systemic psilocin absorption. Information on the absolute bioavailability of psilocin was limited, and estimated at 55% in one study. No covariates nor food effects have been reported, based on four studies with known fasting status. Overall, we found the pharmacokinetic parameters of psilocin to be consistent between studies. This review may guide the further clinical development of psilocybin-based therapies.
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... 2C-B is a less common psychedelic of the phenethylamine class that also activates 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors but has less affinity for 5-HT 1A receptors compared with psilocybin and has other activity including blocking serotonin transporters (29)(30)(31). 2C-B has some entactogenic effects (32)(33)(34), and at a dose with visual effects comparable to those of psilocybin, 2C-B has weaker mysticallike effects (35). By testing 2 psychedelics with differing chemistry, pharmacology, and phenomenology, we investigated whether effects on familiarity and other episodic memory processes may be common mechanisms across psychedelics. ...
... Procedures from this study have been described in detail elsewhere (35). A double-blind, placebo-controlled, repeatedmeasures design with 3 experimental arms was used. ...
... Prior to experimental sessions, participants completed a preparatory session that included a practice version of the memory task. During the first session of each arm, participants received a capsule containing placebo, 15 mg of psilocybin (Duchefa Farma B.V.), or 20 mg of 2C-B (THC Pharm GmbH) and completed the encoding phase of the memory task z185 minutes post-drug administration [other tasks were completed before drug administration (35)]. These doses are thought to be moderate and comparable with similar half-lives and durations of action, although psilocybin/psilocin may be slightly longer acting (1,(34)(35)(36). ...
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... Study design: Published single-blind or double-blind RCTs focusing on the efficacy, safety, and tolerability of adjunctive psilocybin in physically healthy patients with MDD. Studies focusing on patients with chronic and serious physical illnesses, such as cancer (38)(39)(40)(41), or healthy volunteers (42)(43)(44)(45)(46) were excluded. Only studies with the most complete data were included (8,17,18) when there were multiple publications based on the same dataset. ...
Psilocybin for major depressive disorder: a systematic review of randomized controlled studies
Article
Full-text available
  • Sep 2024
Objectives The purpose of this systematic review of randomized controlled trials (RCTs) was to evaluate the effectiveness, safety, and tolerability of psilocybin in adult patients with major depressive disorder (MDD). Methods A systematic search (up to September 14, 2023) was conducted for RCTs that examined the efficacy, safety, and tolerability of psilocybin in physically healthy adult patients with MDD. Three independent researchers extracted data from publications where the primary outcome was a change in depressive symptoms, and key secondary outcomes were changes in anxiety symptoms and suicidal ideation, discontinuation rates for any reason, and adverse drug reactions (ADRs). Results Five RCTs with 472 adult patients with MDD on psilocybin (n = 274) and controls (n = 198) were included. Two of the five RCTs (40%) reported mixed results, while the other three (60%) found that psilocybin had a beneficial effect on MDD treatment. Four RCTs (80%) assessing the anxiolytic effects of psilocybin for treating MDD found that psilocybin was significantly more effective than the control group in improving anxiety symptoms. Psilocybin was more effective than the control group in improving suicidal ideation in one out of five RCTs. Discontinuation rates were similar for any reason between the psilocybin group (2–13%) and the control group (4–21%) (P > 0.05). Four RCTs (80%) reported ADRs in detail. The most common ADR in both groups was headache. Conclusion Psilocybin was effective in improving depressive symptoms in over half of the included studies and reduced anxiety symptoms in patients with MDD. The long-term efficacy and safety of psilocybin for MDD treatment needs to be further investigated in large RCTs.
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... The hallucinogenic properties of 2C-B are mainly attributed to its interaction with the 5-HT2A receptor. The drug's effects are dose dependent, with a half-life of approximately 1.43 hours, and they typically last between six and 12 hours [12,13]. ...
Emerging Illicit Drug “2C”: A Case Report on Its Hallucinogenic and Stimulant Properties
Article
Full-text available
  • Sep 2024
“2C,” formally known as 4-bromo-2,5-dimethoxyphenethylamine, is an illicit drug that combines elements of ketamine, MDMA (ecstasy), methamphetamine, cocaine, and opioids. This report highlights the emergence of 2C compounds, a new class of illicit drugs recognized for their distinctive blend of hallucinogenic and stimulant properties. We present the case of a 22-year-old female who was admitted to the psychiatric emergency department with a history of bipolar I disorder and recent use of various illicit substances, including the drug known as 2C. The patient exhibited symptoms such as visual hallucinations, euphoria, and an increased heart rate. Laboratory tests and toxicology screens were performed to confirm the presence of the components associated with the 2C compound. Her management involved admission to an acute inpatient psychiatric unit for medication stabilization. This case underscores the critical need for healthcare providers to recognize the signs and symptoms of 2C compound intoxication and to provide timely, appropriate intervention. With the rise in recreational use of such substances, further research and public health initiatives are essential to address the associated risks.
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... The time course of the subjective quality of the psychedelic experience was assessed by tracking mean scores on ASC questions during the dosing session (Fig. 3). This time course was comparable to previous studies with psilocybin [55], peaking about 2 h after psilocybin administration (Fig. 3A). Participants administered higher doses of midazolam did not experience a reduction in the magnitude or the duration of elevated ASC scores. ...
Co-administration of midazolam and psilocybin: differential effects on subjective quality versus memory of the psychedelic experience
Article
Full-text available
  • Sep 2024
Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience. Furthermore, midazolam dose and memory impairment tended to associate inversely with salience, insight, and well-being induced by psilocybin. These data suggest a role for memory in therapeutically relevant behavioral effects occasioned by psilocybin. Because midazolam blocks memory by blocking cortical neural plasticity, it may also be useful for evaluating the contribution of the pro-neuroplastic properties of psychedelics to their therapeutic activity.
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... If these substances facilitate the recall and emotional processing of such memories, it raises the question of whether this is inherently therapeutic or whether, in some cases, it could cause harm or distress. There is hope, however, that since psychedelics generally heighten emotionality and cause a positive affective bias in mood, behavior, and emotion recognition (Griffiths et al. 2006;Kometer et al. 2012;Kraehenmann et al. 2015;Mallaroni et al. 2023), the retrieval of emotional memories, particularly positive ones, could be amplified. Understanding these aspects-both the potential for therapeutic benefits and the risk of harm-could help inform how autobiographical memory is approached in psychedelic therapy, guiding the creation of safe and effective therapeutic settings. ...
Psychedelics and autobiographical memory – Six open questions
Preprint
  • Sep 2024
Since the earliest LSD research, psychedelics have been claimed to enhance autobiographical recall. Revisiting and processing autobiographical memories has further been suggested to be a major component of the therapeutic action of psychedelics. However, modern psychedelic research has largely neglected autobiographical elements of psychedelic experiences, and many vital questions remain unanswered. We present and discuss six open questions related to psychedelics and autobiographical memory: 1. Do psychedelics enhance autobiographical recall? 2. Is recall and processing of significant autobiographical (e.g., traumatic) memories a common part of psychedelic experiences? 3. Do psychedelics promote the development of false or inaccurate memories? 4. How do autobiographical memories change if they are recalled and re-consolidated under the effects of psychedelics? 5. What are memories of psychedelic experiences like? 6. Are autobiographical experiences under psychedelics of particular importance for their therapeutic effects? We present the rationale and current limited state of evidence for each question and provide suggestions on how future studies could best address them. We argue that, besides advancing basic research, answering these pressing questions is highly relevant for the possible therapeutic use of psychedelics, both in terms of developing and optimizing new interventions and for avoiding iatrogenic harms. Ideally, future psychedelic-assisted interventions could harness the possible synergies between the effects of psychedelics and existing memory-based therapies.
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... There have not yet been any well-controlled 2C-B drug-drug interaction clinical trials published in the medical literature. In one comparative trial it appeared 2C-B duration of subjective effects was about an hour shorter than psilocybin, but any medications that inhibit MAO and relevant P450 enzymes may increase the peak and duration of 2C-B effects and further research will be necessary to quantify the impact of these potential drug-drug interactions (Mallaroni et al. 2023). ...
Toxicology and Pharmacological Interactions of Classic Psychedelics
Chapter
  • Jul 2024
As psychedelics are being investigated for more medical indications, it has become important to characterize the adverse effects and pharmacological interactions with these medications. This chapter will summarize what is known about the toxicology and drug–drug interactions for classic psychedelics, such as LSD, psilocybin, DMT, 5-MeO-DMT, mescaline, 2C-B, Bromo-DragonFLY, and 25X-NBOMe.
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... The results showed noticeable subjective effects and altered EEG rhythms (a decreased power in the theta band), and even a mild cognitive impairment. Mallaroni et al. (2023) conducted a study on the most prevalently used novel serotonergic hallucinogen to date, 2,5-dimethoxy-4-bromophenethylamine (2C-B), a hallucinogenic phenethylamine derived from mescaline. Considering the potential impact of subjective experience, they did not use a placebo control, but rather the more "classical" psilocybin. ...
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Global Trends and Disparities in Substance Use Disorders: Decades of Challenges amid Emerging Threats and the COVID-19 Impact (1990-2021)
Preprint
Full-text available
  • Oct 2024
Aims To provide a comprehensive analysis of the global epidemiology of substance use disorders (SUDs) from 1990 to 2021, highlighting trends, disparities, and public health implications. Design An analytical study leveraging data from the Global Burden of Diseases (GBD) to explore prevalence, distribution, and determinants of SUDs. Settings Global analysis with a focus on geographic disparities and socio-economic impacts across different regions. Participants Data includes global populations affected by substance use disorders as captured by the GBD database from 1990 to 2021. Measurements Examination of Age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR), and age-standardized disability-adjusted life years rate (ASDR) and analysis of trends in substance use, particularly opioid use, across different regions and economic groups. Findings There has been a 16.9% reduction in the overall ASPR since 1990. However, significant geographic disparities exist, with high-income regions of North America experiencing the greatest burden and Western Sub-Saharan Africa the lowest. The study identifies a rise in opioid use and emphasizes the socio-economic impacts of SUDs. Conclusions The study demonstrates the ongoing severity of SUDs and the need for cohesive and integrated health policies, especially given the influence of emerging psychoactive substances and the COVID-19 pandemic. It highlights pathways for targeted interventions and informs global health strategies.
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Cognitive functioning associated with acute and subacute effects of classic psychedelics and MDMA - a systematic review and meta-analysis
Article
Full-text available
  • Jun 2024
Classic psychedelics and MDMA have a colorful history of recreational use, and both have recently been re-evaluated as tools for the treatment of psychiatric disorders. Several studies have been carried out to assess potential long-term effects of a regular use on cognition, delivering distinct results for psychedelics and MDMA. However, to date knowledge is scarce on cognitive performance during acute effects of those substances. In this systematic review and meta-analysis, we investigate how cognitive functioning is affected by psychedelics and MDMA during the acute drug effects and the sub-acute (“afterglow”) window. Our quantitative analyses suggest that acute cognitive performance is differentially affected by psychedelics when compared to MDMA: psychedelics impair attention and executive function, whereas MDMA primarily affects memory, leaving executive functions and attention unaffected. Our qualitative analyses reveal that executive functioning and creativity may be increased during a window of at least 24 h after the acute effects of psychedelics have subsided, whereas no such results have been observed for MDMA. Our findings may contribute to inform recommendations on harm reduction for recreational settings and to help fostering differential approaches for the use of psychedelics and MDMA within a therapeutic framework.
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Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial
Article
Full-text available
  • Feb 2023
Background Psilocybin has been suggested as a novel, rapid-acting treatment for depression. Two consecutive doses have been shown to markedly decrease symptom severity in an open-label setting or when compared to a waiting list group. To date, to our knowledge, no other trial compared a single, moderate dose of psilocybin to a placebo condition. Methods In this double-blind, randomised clinical trial, 52 participants diagnosed with major depressive disorder and no unstable somatic conditions were allocated to receive either a single, moderate dose (0.215 mg/kg body weight) of psilocybin or placebo in conjunction with psychological support. MADRS and BDI scores were assessed to estimate depression severity, while changes from baseline to 14 days after the intervention were defined as primary endpoints. The trial took place between April 11th, 2019 and October 12th, 2021 at the psychiatric university hospital in Zürich, Switzerland and was registered with clinicaltrials.gov (NCT03715127). Findings The psilocybin condition showed an absolute decrease in symptom severity of −13.0 points compared to baseline and were significantly larger than those in the placebo condition (95% CI −15.0 to −1.3; Cohens' d = 0.97; P = 0.0011; MADRS) and −13.2 points (95% CI; −13.4 to −1.3; Cohens’ d = 0.67; P = 0.019; BDI) 14 days after the intervention. 14/26 (54%) participants met the MADRS remission criteria in the psilocybin condition. Interpretation These results suggest that a single, moderate dose of psilocybin significantly reduces depressive symptoms compared to a placebo condition for at least two weeks. No serious adverse events were recorded. Larger, multi-centric trials with longer follow-up periods are needed to inform further optimisation of this novel treatment paradigm. Funding The study was funded by the Swiss National Science Foundation, Crowdfunding, the Swiss Neuromatrix Foundation, and the Heffter Research Institute.
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Pharmacokinetics and Pharmacodynamics of Oral Psilocybin Administration in Healthy Participants
Article
Full-text available
  • Dec 2022
  • CLIN PHARMACOL THER
Psilocybin is being investigated as a potential treatment for psychiatric and neurological disorders. Only a few studies have evaluated the pharmacokinetics of psilocybin and have used body weight-adjusted dosing. Data on pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of fixed doses that are commonly used are unavailable. The present study characterized the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of 15, 25, and 30 mg of orally administered psilocybin in 28, 23, and 28 healthy subjects, respectively. Plasma levels of unconjugated psilocin (the psychoactive metabolite of psilocybin) and corresponding subjective effects were repeatedly assessed up to 24 h. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Mean (95% confidence interval) maximal psilocin concentrations were 11 ng/ml (10-13), 17 ng/ml (16-19), and 21 ng/ml (19-24) after the administration of 15, 25, and 30 mg psilocybin, respectively. Maximal concentrations were reached after an average of 2 h. Elimination half-lives were 1.8 h (1.7-2.0), 1.4 h (1.2-1.7), and 1.8 h (1.6-1.9) for 15, 25, and 30 mg psilocybin, respectively. Mean (± SD) durations of subjective effects were 5.6 ± 2.2 h, 5.5 ± 1.6 h, and 6.4 ± 2.2 h, and maximal effects ("any drug" effects) were 58% ± 25%, 73% ± 27%, and 80% ± 18% after 15, 25, and 30 mg psilocybin, respectively. Psilocin exhibited dose-proportional pharmacokinetics. The duration and intensity of subjective effects were dose-dependent. Body weight did not influence pharmacokinetics or the response to psilocybin. These data may serve as a reference for future clinical trials.
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Serotonin 5-HT2A, 5-HT2c and 5-HT1A receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twich response
Article
Full-text available
  • Oct 2022
  • BIOMED PHARMACOTHER
The psychedelic 5-HT2A receptor (5HT2AR) agonist psilocybin (or the active metabolite psilocin) has emerged as potential useful drug for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. However, the mechanisms responsible for such effects remain incompletely characterized. We aimed to study in vitro pharmacological profile and in vivo acute mechanism of psilocin/psilocybin. Competition binding studies with psilocin were performed in brain and cell cultures. The role of 5HT2AR, 5-HT2C receptors (5HT2CR) and 5-HT1A receptors (5HT1AR) on the psychosis–like head-twitch response (HTR) and on body temperature in mice after psilocybin administration were evaluated. Psilocin showed similar affinities for 5HT2AR (Ki: 120–173 nM), 5HT2CR (Ki: 79–311 nM) and 5-HT1AR (Ki: 152–146 nM) in human and mice brain. Psilocybin induced a dose-dependent HTR (maximal effect 17.07 ± 1.31 at 1 mg/kg i.p.) that was completely suppressed by the 5HT2AR antagonist MDL11939 (1 mg/kg). Higher doses of psilocybin (3 mg/kg) induced lower HTR (9.00 ± 0.53). The 5HT2CR antagonist SB242084 (0.1 mg/kg) increased HTR exerted by psilocybin (3 mg/kg). Psilocybin significantly raised core body temperature at low dose (0.125 mg/kg) (Emax=0.67 ± 0.15 °C), whereas a significant decrease was induced by doses over 1 mg/kg (Emax = −1.31 ± 0.16 °C). Pre-treatment with the 5HT1AR antagonist WAY100635 reversed the decrease of body temperature after psilocybin (1 mg/kg), causing hyperthermia (Emax = 0.94 ± 0.26 °C). The present work provides key findings on the 5HT2AR, 5-HT2CR and 5HT1AR involvement in the acute central effects of psilocybin. The results may be relevant for understanding the mechanism of action underlying the therapeutic effects and side effects of this psychedelic drug.
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The use patterns of novel psychedelics: experiential fingerprints of substituted phenethylamines, tryptamines and lysergamides
Article
Full-text available
  • Jun 2022
  • PSYCHOPHARMACOLOGY
Background Novel psychedelics (NPs) are an expanding set of compounds, presenting new challenges for drug policy and opportunities for clinical research. Unlike their classical derivatives, little is known regarding their use profiles or their subjective effects. Aims The purpose of this study was to compile usage patterns and adverse event rates for individual NPs belonging to each of three main psychedelic structural families. Targeting the most widely used representatives for each class, we expanded on their phenomenological distinctions. Methods A two-part survey was employed. We investigated the prevalence of novel phenethylamines, tryptamine and lysergamides in NP users ( N = 1180), contrasting the type and incidence of adverse events (AEs) using a set of logistic regressions. Honing in on 2–4-Bromo-2,5-dimethoxyphenyl)ethanamine (2C-B) (48.6%), 1-propionyl-lysergic acid diethylamide (1P-LSD) (34.2%) and 4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) (23.1%), we examined their phenomenological separability using a gradient boosting (XGBoost) supervised classifier. Results Novel phenethylamines had the highest prevalence of use (61.5%) seconded by tryptamines (43.8%) and lysergamides (42.9%). Usage patterns were identified for 32 different compounds, demonstrating variable dosages, durations and a common oral route of administration. Compared to phenethylamines, the odds for tryptamines and lysergamides users were significantly less for overall physical AEs. No significant differences in overall psychological AEs were found. Overall model area under the curve (AUC) stood at 0.79 with sensitivity (50.0%) and specificity (60.0%) for 2C-B ranking lowest. Conclusion NP classes may hold distinct AE rates and phenomenology, the latter potentially clouded by the subjective nature of these experiences. Further targeted research is warranted.
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Great Expectations: recommendations for improving the methodological rigor of psychedelic clinical trials
Article
Full-text available
  • Jun 2022
  • PSYCHOPHARMACOLOGY
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.
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Psychedelic Cognition—The Unreached Frontier of Psychedelic Science
Article
Full-text available
  • Mar 2022
Psychedelic compounds hold the promise of changing the face of neuroscience and psychiatry as we know it. There have been numerous proposals to use them to treat a range of neuropsychiatric conditions such as depression, anxiety, addiction and PTSD; and trials to date have delivered positive results in favor of the novel therapeutics. Further to the medical use, the wider healthy population is gaining interest in these compounds. We see a surge in personal use of psychedelic drugs for reasons not limited to spiritual enhancement, improved productivity, aiding the management of non-pathological anxiety and depression, and recreational interests. Notably, microdosing—the practice of taking subacute doses of psychedelic compounds—is on the rise. Our knowledge about the effects of psychedelic compounds, however, especially in naturalistic settings, is still fairly limited. In particular, one of the largest gaps concerns the acute effects on cognition caused by psychedelics. Studies carried out to date are riddled with limitations such as having disparate paradigms, small sample sizes, and insufficient breadth of testing on both unhealthy and healthy volunteers. Moreover, the studies are majoritarily limited to laboratory settings and do not assess the effects at multiple dosages within the same paradigm nor at various points throughout the psychedelic experience. This review aims to summarize the studies to date in relation to how psychedelics acutely affect different domains of cognition. In the pursuit of illuminating the current limitations and offering long-term, forward-thinking solutions, this review compares and contrasts findings related to how psychedelics impact memory, attention, reasoning, social cognition, and creativity.
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Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects
Article
Full-text available
  • Feb 2022
Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research. Trial registration: ClinicalTrials.gov identifier: NCT03604744
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The costs and benefits of psychedelics on cognition and mood
Article
  • Jan 2023
Anecdotal evidence has indicated that psychedelic substances may acutely enhance creative task performance, although empirical support for this claim is mixed at best. Clinical research has shown that psychedelics might have enduring effects on mood and well-being. However, there is no neurocognitive framework that ties acute changes in cognition to long-term effects in mood. In this review, we operationalize creativity within an emerging cognitive control framework and assess the current empirical evidence of the effects of psychedelics on creativity. Next, we leverage insights about the mechanisms and computations by which other psychoactive drugs act to enhance versus impair cognition, in particular to those that act on catecholamines, the neurophysiological consequences of which are relatively well understood. Finally, we use the same framework to link the suggested psychedelic-induced improvements in creativity with enduring psychedelic-induced improvements in mood.
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The neural basis of psychedelic action
Article
  • Oct 2022
Psychedelics are serotonin 2A receptor agonists that can lead to profound changes in perception, cognition and mood. In this review, we focus on the basic neurobiology underlying the action of psychedelic drugs. We first discuss chemistry, highlighting the diversity of psychoactive molecules and the principles that govern their potency and pharmacokinetics. We describe the roles of serotonin receptors and their downstream molecular signaling pathways, emphasizing key elements for drug discovery. We consider the impact of psychedelics on neuronal spiking dynamics in several cortical and subcortical regions, along with transcriptional changes and sustained effects on structural plasticity. Finally, we summarize neuroimaging results that pinpoint effects on association cortices and thalamocortical functional connectivity, which inform current theories of psychedelic action. By synthesizing knowledge across the chemical, molecular, neuronal, and network levels, we hope to provide an integrative perspective on the neural mechanisms responsible for the acute and enduring effects of psychedelics on behavior. Psychedelics are serotonergic drugs that have therapeutic potential. This Review article provides an integrative perspective on the basic neurobiology underlying the actions of psychedelics and highlights open questions in the field.
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The promises and perils of psychedelic pharmacology for psychiatry
Article
  • Mar 2022
Psychedelic drugs including psilocybin, N,N'-dimethyltryptamine (DMT) and lysergic acid diethylamide (LSD) are undergoing a renaissance as potentially useful drugs for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. Notably, phase II trials have shown that psilocybin can produce statistically significant clinical effects following one or two administrations in depression and anxiety. These findings have inspired a 'gold rush' of commercial interest, with nearly 60 companies already formed to explore opportunities for psychedelics in treating diverse diseases. Additionally, these remarkable phenomenological and clinical observations are informing hypotheses about potential molecular mechanisms of action that need elucidation to realize the full potential of this investigative space. In particular, despite compelling evidence that the 5-HT2A receptor is a critical mediator of the behavioural effects of psychedelic drugs, uncertainty remains about which aspects of 5-HT2A receptor activity in the central nervous system are responsible for therapeutic effects and to what degree they can be isolated by developing novel chemical probes with differing specificity and selectivity profiles. Here, we discuss this emerging area of therapeutics, covering both controversies and areas of consensus related to the opportunities and perils of psychedelic and psychedelic-inspired therapeutics. We highlight how basic science breakthroughs can guide the discovery and development of psychedelic-inspired medications with the potential for improved efficacy without hallucinogenic or rewarding actions.
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