Acute dose-dependent effects of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) compared with 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin in a double-blind, placebo-controlled study in healthy participants

Psychedelics such as psilocybin and MDMA are being studied for several psychiatric disorders, but the acute effects of 2C-B remain less well characterised. The paper notes that 2C-B has a receptor profile that overlaps partly with psilocybin, through 5-HT2A receptor agonism, and with MDMA, through low-potency interaction with serotonin transporters in vitro. Earlier human studies suggested that 2C-B can produce both entactogenic and psychedelic-like effects, but they had only examined doses up to 20 mg and had compared 2C-B with psilocybin rather than MDMA. The authors therefore frame the main uncertainty as how 2C-B compares directly with prototypical doses of MDMA and psilocybin across a wider dose range. Arikci and colleagues set out to characterise the acute subjective, empathogenic, autonomic, and endocrine effects of 10, 20, and 30 mg 2C-B in healthy participants, and to compare those effects directly with 125 mg MDMA and 25 mg psilocybin. They also aimed to examine pharmacokinetics and the duration of subjective effects, using well-established measures sensitive to psychedelic and entactogenic drug effects. The study was intended to help with dose-finding for future 2C-B research and to provide a direct within-subject comparison with standard doses of MDMA and psilocybin.

The study used a double-blind, placebo-controlled, random-order, crossover design with six experimental sessions per participant: placebo, 10 mg 2C-B, 20 mg 2C-B, 30 mg 2C-B, 125 mg MDMA, and 25 mg psilocybin. Washout periods were at least 10 days. The study was conducted in accordance with ethical and good clinical practice requirements, and it was registered at ClinicalTrials.gov. Twenty-four healthy adults took part, with 12 women and 12 men, mean age 36 years, and mean body weight 68 kg. Participants were recruited through the University of Basel website and from volunteers interested in psychedelic research. The extracted text does not clearly list the detailed inclusion and exclusion criteria, referring instead to supplementary information. Participants provided written informed consent and were paid. Test days began at 8:00 AM and lasted about 10 h, with outcomes assessed repeatedly for 9 h after drug administration. The researchers measured subjective drug effects using visual analogue scales and mood questionnaires, including retrospective assessments of altered states of consciousness, psychedelic experience, and mystical-type effects at 9 h. Duration measures such as onset, peak, offset, and total effect duration were derived from the VAS item “any drug effect”. Autonomic outcomes included repeated blood pressure, heart rate, and body temperature measurements, plus ECG before and 2 h after dosing. Adverse effects were assessed with the List of Complaints before and 9 h after drug administration. Plasma samples were collected for drug concentration analyses and for oxytocin and neurophysin I, which were measured to explore endocrine effects relevant to empathy. Social cognition was assessed with the Multifaceted Empathy Test and Facial Emotion Recognition Task. Pharmacokinetic parameters were estimated by non-compartmental methods using validated liquid chromatography-tandem mass spectrometry, and the main repeated-measures analyses used rmANOVA with Tukey-corrected post hoc comparisons.

Two participants withdrew after inclusion, one after a difficult psilocybin experience and one before the first session. The main subjective findings were dose dependent for 2C-B. The 10 mg dose produced only low but significant “any drug effects” versus placebo, while the 30 mg dose produced overall subjective drug intensity similar to MDMA but lower than psilocybin. Ratings of “good drug effects” and “high” were similar for 30 mg 2C-B, MDMA, and psilocybin. Only psilocybin produced significant increases in “bad drug effects” and “anxiety” versus placebo. Psychedelic-like effects increased with 20 mg and 30 mg 2C-B, MDMA, and psilocybin on measures such as visual change, auditory change, audiovisual synaesthesia, altered time perception, and ego dissolution. Psilocybin generally produced the strongest perceptual and altered-state effects, higher than 30 mg 2C-B on most of these measures and higher than MDMA. The 30 mg 2C-B dose produced more visual and synaesthetic effects than MDMA on some VAS items. On the 5D-ASC and related measures, 2C-B again showed a dose-response pattern, with 30 mg producing a psychedelic profile closer to MDMA in some respects but still weaker than psilocybin overall. MDMA produced mainly positive alterations of consciousness, whereas 30 mg 2C-B and psilocybin produced more complex profiles that also included perceptual changes; psilocybin additionally produced more distressing effects and spiritual-type ratings. In the social cognition tasks, MDMA and 30 mg 2C-B both increased explicit emotional empathy for positive images on the MET. Psilocybin, in contrast, reduced cognitive empathy for positive stimuli and tended to reduce it for negative stimuli as well. On the FERT, psilocybin reduced overall emotion recognition and particularly recognition of fearful faces, whereas 2C-B and MDMA did not significantly change emotion recognition. Only MDMA increased plasma oxytocin and neurophysin I compared with placebo, 2C-B, and psilocybin. In the blinding assessment, participants had difficulty correctly identifying 2C-B and psilocybin immediately after sessions, whereas MDMA and placebo were more often identified correctly. At study end, only 38% correctly identified the high-dose 2C-B condition and 52% correctly identified psilocybin. Autonomic effects also differed across drugs. 2C-B produced mild, dose-dependent blood pressure increases, but the 30 mg dose caused less cardiovascular stimulation than MDMA and psilocybin. Heart rate increased only with 30 mg 2C-B, and this increase was similar to psilocybin but lower than MDMA. Overall, MDMA produced the greatest cardiovascular stimulation, followed by psilocybin and then 2C-B. Psilocybin and the two higher doses of 2C-B increased body temperature, but none of the drugs affected QT time. Total acute adverse effect scores increased with all conditions except 10 mg 2C-B, and no severe adverse events were observed.

The authors interpret the findings as showing that 2C-B has mixed entactogenic and psychedelic properties that become clearer as the dose increases. They argue that 10 mg produced only very mild effects, 20 mg produced modest psychedelic-like changes, and 30 mg produced a stronger drug experience that was broadly similar to MDMA for overall intensity and positive effects, but still less psychedelic and less distressing than psilocybin. They emphasise that the highest dose of 2C-B produced meaningful psychedelic-type changes, yet with less perceptual disturbance and less negative affect than 25 mg psilocybin. Relative to earlier studies, the authors note that their work extends the dose range previously tested for 2C-B and is the first to compare 2C-B directly with both MDMA and psilocybin in the same within-subject study. They say their findings are consistent with prior reports that 2C-B can combine entactogenic and psychedelic features, while also helping to resolve how strongly it resembles each comparator at therapeutically relevant doses. They also note that 30 mg 2C-B may be the closest of the tested doses to the psychedelic profile of psilocybin, although still weaker overall. For social cognition, the authors interpret the MET and FERT results as suggesting that 2C-B can increase emotional empathy in a manner similar to MDMA, but without the broader impairment in emotion recognition seen with psilocybin. They suggest that the lack of change in oxytocin and neurophysin I with 2C-B implies that its empathogen-like effects are not critically mediated by circulating oxytocin. They also relate the lower recognition of negative emotions after psilocybin to earlier psychedelic research. The authors highlight that 2C-B showed relatively mild cardiovascular stimulation compared with MDMA and psilocybin, and that its shorter duration of action fits its shorter plasma half-life. They state that this shorter duration may be an advantage for clinical use. They also observe that 2C-B was comparatively well blinded, which they present as a methodological strength. Key limitations acknowledged by the authors are that the study was conducted only in healthy participants in a highly controlled setting, so effects and safety may differ in patients or in recreational contexts. They also note that higher doses of 2C-B were not tested, so the full upper range of its effects remains uncertain.

The authors conclude that 2C-B shows partly MDMA-like and partly psilocybin-like acute effects, especially at higher doses, indicating overlapping entactogenic and psychedelic properties. They state that 2C-B’s effect duration is shorter than psilocybin’s and is consistent with its shorter plasma half-life, and that its cardiovascular stimulation and psychological distress were lower than with the comparators at the doses tested. They suggest that these findings can inform future dose-finding research and provide a direct reference point against standard doses of MDMA and psilocybin.