Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition

Classical psychedelics produce profound alterations in waking consciousness, affecting mood, cognition, and self-referential awareness via serotonergic mechanisms, principally 5-HT2A receptor agonism. Previous research has characterised psilocybin's acute subjective, cognitive, and autonomic effects and has suggested inter-drug differences may arise from variations in receptor binding profiles beyond 5-HT2A. 2,5-dimethoxy-4-bromophenethylamine (2C-B) is a phenethylamine analogue of mescaline that has gained popularity recreationally and shows 5-HT2A/2C selectivity plus secondary activity at other monoaminergic and trace amine receptors; observational data and surveys describe a blend of psychedelic and entactogenic effects but controlled human data are lacking. Mallaroni and colleagues set out to provide the first double-blind, placebo-controlled, within-subject comparison of the immediate acute subjective, cognitive, cardiovascular, and pharmacokinetic effects of oral 20 mg 2C-B versus 15 mg psilocybin in healthy, psychedelic-experienced volunteers. The study aimed to characterise similarities and differences in phenomenology, cognitive impact, autonomic changes, and serum concentrations, with the hypothesis that 2C-B would produce distinct emotional effects relative to psilocybin.

The investigators used a double-blind, placebo-controlled, crossover design with three acute sessions (placebo, 20 mg 2C-B, 15 mg psilocybin) and Latin-square counterbalancing of treatment order. Sessions were separated by a 14-day washout. Ethical approvals and regulatory permits for handling the compounds were obtained. Twenty-two healthy participants (11 female), aged 19–35 years (mean 25 ± 4), were recruited; inclusion required prior psychedelic experience (but not within the prior 3 months), BMI 18–28 kg/m2, no current medication, and absence of psychiatric, major medical or neurological disorders. Screening included medical examination, resting ECG and laboratory tests. Drugs were administered orally in a closed cup containing either placebo (bittering agent) or active compound powder; blinding integrity was assessed retrospectively. Participants attended a preparatory visit to familiarise with procedures and task training. Each dosing day lasted about 7 hours; participants abstained from recreational drugs, alcohol and caffeine/nicotine for specified intervals before sessions. A urine drug screen, breath alcohol test and pregnancy test (for females) confirmed eligibility on each session day. Subjective effects were assessed repeatedly using visual analogue scales (VAS) at baseline and multiple post-dose timepoints (up to +6 h), along with the Profile of Mood States (POMS), Clinician-Administered Dissociative States Scale (CADSS), Bowdle VAS (BVAS), Sensitivity to Drug Reinforcement Questionnaire (SDRQ), 5-Dimensional Altered States of Consciousness (5D-ASC), Hallucinogen Rating Scale (HRS), Ego Dissolution Inventory (EDI) and Interpersonal Reactivity Index (IRI). A computerised cognitive battery was administered during peak effects and included tasks measuring sensorimotor coordination (MCT), sustained attention (PVT), overall cognitive performance (DSST), executive function (Tower of London), spatial memory (immediate and delayed SMT), reflection impulsivity (MFFT) and empathy (MET). Blood pressure and heart rate were recorded hourly to compute rate pressure product. Venous blood samples at hourly intervals were analysed by LC-MS/MS to quantify serum 2C-B and psilocin concentrations. For analysis, peak changes from baseline (ΔEmax/ΔEmin) were calculated and baseline-adjusted Emax used for cardiovascular measures. Linear mixed models with drug condition as fixed effect and participant as random intercept were fitted using an AR1 covariance structure; Tukey adjustment handled pairwise comparisons and alpha was set at p < 0.05. Missing pharmacokinetic timepoints were handled with multiple imputation (MICE) after confirming data were missing completely at random; non-compartmental methods estimated AUC and half-lives. Duration of subjective effects was estimated from VAS "any drug effect" using a 10% on/off cut-off.

All 22 participants completed every condition and no serious adverse events occurred. Blinding was imperfect: placebo was correctly identified by 95.5% of participants, while 2C-B and psilocybin were each correctly identified by 63.6%; 36.4% of 2C-B sessions were misidentified as psilocybin and 31.8% of psilocybin sessions were misclassified as 2C-B. Subjective effects: Both 2C-B and psilocybin produced significant and generally equivalent increases versus placebo on multiple VAS measures of drug intensity ("any drug effect", "good drug effect", "drug liking", "drug high"). 2C-B elevated "bad drug effect" relative to placebo but not relative to psilocybin. Self-reported effects resolved within 6 hours for 86.3% of participants after 2C-B compared with 63.6% after psilocybin. Ratings of happiness and creativity increased under both drugs versus placebo without differences between them. Psilocybin induced greater maximal reductions in concentration versus placebo; time perception was slowed under both drugs but psilocybin produced larger increases in perceived speed of time compared with 2C-B and placebo. On multidimensional mood measures (POMS), psilocybin produced larger increases across negative mood subscales (total mood disturbance, tension, anger, fatigue, depression, confusion) versus placebo, and depression scores were higher for psilocybin than for 2C-B. In contrast, 2C-B produced significant rises in positive affect markers (vigour, elation, friendliness) versus placebo, and its summary positive mood elevation exceeded that observed under psilocybin. Both drugs increased drug liking and wanting on SDRQ relative to placebo. Measures of dissociation and perceptual change were elevated for both drugs versus placebo: CADSS total and subscales (depersonalisation, derealisation, amnesia) increased under both, with derealisation showing the largest change. BVAS internal and external perception scores were similarly increased. Retrospective 5D-ASC scores showed that 2C-B produced a smaller total alteration in waking consciousness than psilocybin. Psilocybin yielded larger increases than 2C-B on several 5D-ASC subscales including oceanic boundlessness and anxious ego dissolution, as well as auditory alterations, vigilance reduction, changed meaning of percepts, and impaired control and cognition. Both drugs increased EDI scores (ego dissolution) to similar extents. On the HRS, both increased four of five dimensions (excluding volition), with psilocybin producing larger increases on the affect and cognition scales. Neither compound produced clear immediate changes in trait empathy on the IRI or empathogenic effects on the MET. Cognitive performance: Both active drugs produced comparable impairments on measures of global cognitive function. On the DSST, reductions in number of attempted and correct responses and longer reaction times were observed for both drugs versus placebo, while overall accuracy was not significantly affected. Immediate and delayed spatial memory (SMT) recall were significantly reduced under both compounds. No main drug effects were observed for sensorimotor coordination (MCT), sustained attention (PVT overall, though delayed reaction times occurred selectively), planning (TOL accuracy), reflection impulsivity (MFFT) or empathy (MET). Delayed reaction time increases relative to placebo were present for DSST and TOL for both drugs and for PVT selectively under psilocybin. Cardiovascular effects: Both 2C-B and psilocybin produced modest acute pressor effects (systolic and diastolic blood pressure) versus placebo. Systolic hypertension (>140 mmHg) occurred in n=5 for 2C-B, n=8 for psilocybin, and n=2 for placebo. Tachycardia (>100 BPM) was observed in n=2 for 2C-B and n=2 for placebo; overall heart rate differences were not statistically clear despite a main drug effect. Rate pressure product was higher after 2C-B versus placebo but did not differ significantly between the two active drugs, suggesting similar myocardial workload. Pharmacokinetics: Mean Cmax values were reported as 3.31 ng/mL (range 1.63–7.58, n=21) for 2C-B and 10.81 ng/mL (range 5.26–25.47, n=21) for psilocin. The investigators note shorter half-life and smaller AUC for 2C-B compared with psilocin, consistent with briefer subjective effects. Body weight did not influence serum concentrations for either compound.

Mallaroni and colleagues interpret their findings as the first controlled, within-subject clinical comparison of 2C-B and psilocybin, showing that fixed doses of 20 mg 2C-B and 15 mg psilocybin produce broadly similar peak intensities on acute drug effect ratings while differing in experiential depth. Specifically, 2C-B elicited psychedelic-like alterations in consciousness but of lesser overall profundity than psilocybin, whereas both drugs produced comparable cognitive slowing and modest cardiovascular stimulation. The authors emphasise that 2C-B generated perceptual changes, dissociative symptoms and positive affective markers, but psilocybin more strongly produced affective qualities of altered self-experience (for example oceanic boundlessness and anxious ego dissolution) and greater negative mood lability. Possible explanations discussed include differences in pharmacodynamics beyond 5-HT2A agonism — for example 5-HT1A/2C interactions and secondary monoaminergic activity — or pharmacokinetic distinctions such as shorter duration and lower exposure for 2C-B. The authors note that imperfect blinding and partial misclassification between active drugs could reflect overlapping phenomenology and marginal unmasking. Cognitive impairments are described as reflecting slowed information processing rather than gross loss of accuracy, consistent with prior psilocybin work; spatial memory deficits and delayed reaction times are highlighted as reproducible effects for both compounds. Key limitations acknowledged by the study team include the use of single fixed doses rather than dose–response assessment, cognitive testing at fixed timepoints that may not perfectly align with individual pharmacokinetic peaks, and the 6-hour pharmacokinetic sampling window that truncated full characterisation of psilocybin's longer duration. The controlled laboratory setting and homogeneous, psychedelic-experienced volunteer sample limit generalisability to other populations or therapeutic contexts. The authors suggest future work should include ascending dose studies, extended pharmacokinetic sampling, broader cognitive paradigms (for example set-shifting), and clinical-pathfinding to evaluate whether 2C-B's apparently "clearer" subjective state and reduced dysphoria could have utility in therapeutic models or preparatory exposures.

In summary, the study supports categorising 2C-B as a psychedelic with some entactogenic properties that produces an intermediary experiential depth relative to psilocybin. Acute subjective, cognitive and pressor effects are compatible with primary 5-HT2A-mediated action, but 2C-B shows a shorter duration, lower exposure and a subjective profile that emphasises positive affect and perceptual changes while showing less affective lability than psilocybin. The authors recommend further work on brain functional effects, emotional processing and persisting outcomes to clarify relative harms and potential clinical utility.