Acute pharmacological effects of 2C-B in humans: An observational study

Psychedelics are commonly classified by chemical class or primary mechanism into serotonergic indolamines (for example psilocybin, LSD) and phenylethylamines (for example mescaline). The 2C-series are novel phenylethylamine-derived psychoactive substances that have emerged in recent decades; 2C-B (2,5-dimethoxy-4-bromophenethylamine) is among the oldest and most widely used of these compounds. Preclinical work indicates that 2C-B interacts with monoaminergic systems and acts at serotonin 5-HT2A/2B/2C receptors, but human data on its acute pharmacology and pharmacokinetics are sparse and have largely come from poison-centre reports, surveys and case reports rather than controlled measurement. Souza and colleagues set out to characterise the acute subjective and physiological effects of oral 2C-B and to obtain preliminary pharmacokinetic information using oral fluid (saliva) samples. The study aimed to describe time courses of cardiovascular and subjective effects, measure 2C-B and cortisol concentrations in saliva over 24 hours, and provide an initial human dataset to inform future controlled investigations.

This was a prospective, non-controlled observational study of 16 healthy, experienced recreational drug users (eight males, eight females) who had used 2C-B at least once previously. Exclusion criteria included serious medical or psychiatric disorders, drug dependence (except nicotine), chronic medication use, and prior serious adverse reactions to 2C-B. Participants were recruited via word-of-mouth through a harm-reduction association, provided informed consent, and received financial compensation. Baseline urine drug screens were negative. Each participant attended a single session in a private home setting and self-administered a capsule they had obtained themselves; capsules of the same type tested elsewhere by a drug-checking service were reported to contain 2C-B at approximately 95% purity and were screened by GC/MS for common adulterants. Participants selected one of three dose options (10, 15 or 20 mg) based on prior experience; actual mean dose taken was 15.94 ± 4.17 mg (four took 10 mg, five 15 mg, seven 20 mg). Subjects were instructed to abstain from other drugs 48 hours prior and from alcohol/caffeine for 24 hours. Assessments occurred at baseline and repeatedly up to 6 hours after ingestion (vital signs at baseline and 1, 2, 3, 4, 6 h; subjective measures at baseline and 2 h, with a 0–6 h maximum-effect report at 6 h). Subjective instruments comprised visual analogue scales (VAS, 100 mm), the Addiction Research Center Inventory (ARCI), the VESSPA-SSE questionnaire (six subscales), and the Hallucinogenic Rating Scale (HRS, completed at 6 h). Saliva (oral fluid) was collected with Salivette tubes at baseline and 1, 2, 3, 4, 6, 16, and 24 h to quantify 2C-B (GC-MS) and cortisol (fluorescence polarisation immunoassay); cortisol was measured in a subset of eight participants. Pharmacokinetic parameters from oral fluid (Cmax, tmax, AUC0–24, elimination constant Ke, and t1/2) were calculated using pharmacokinetic functions in Excel. Statistical analysis initially tested dose and gender effects with two-way ANOVA but, because only marginal interactions were found, subsequent analyses pooled across dose and gender. Paired t-tests compared Emax values to baseline; repeated-measures one-way ANOVA with Dunnett post hoc tests examined time effects on vital signs and subjective measures across time points (baseline, 2 h, 6 h). A significance threshold of p < 0.05 was used with adjustment for multiple comparisons.

Sixteen participants completed the study; mean age was 33.25 ± 3.71 years (range 27–39), mean weight 63.81 ± 11.59 kg, and mean BMI 21.69 ± 2.49 kg/m2. Lifetime reported 2C-B use averaged three occasions (range 1–20). All had recreational experience with multiple other drugs; 12 were current tobacco smokers. Baseline urine tests were negative. Cardiovascular outcomes showed modest sympathomimetic effects. Maximum changes (Emax) versus baseline were +19 mmHg for systolic blood pressure (SBP), +13 mmHg for diastolic blood pressure (DBP), and +13 beats per minute for heart rate (HR). Compared with baseline, SBP was significantly elevated between 1 and 4 h, and DBP and HR showed significant increases from 1 to 3 h. Median tmax for SBP and HR ranged from 1 to 4 h, while DBP tmax ranged from 1 to 2 h. Authors note the time course of vital sign changes was similar to the time course of oral fluid 2C-B concentrations. Subjective measures indicated robust mood and perceptual effects with greater prominence of euphoria and activation than frank hallucinations. On the VAS, the largest mean increases (>50 mm from baseline) were observed for intensity, feeling high, good effects, and different body feeling. Moderate increases (>25 mm) were seen for changes in distances, colours, shapes and lights; smaller changes (<15 mm) occurred for scales measuring hallucinations and unreal surroundings. Statistically significant differences from baseline were detected for most VAS items except for bad effects, some hallucination items (seeing animals/people, hearing voices), dizziness, fear, and sadness. Five participants reported clear hallucinatory effects on VAS. On the ARCI, all subscales increased significantly except PCAG (sedation), with the largest rises on MBG (euphoria) and the amphetamine-sensitive A scale; modest increases occurred on LSD and BG subscales. The VESSPA-SSE showed significant increases across all subscales, most notably in pleasure/sociability, activity/energy and sedation subscales. HRS scores were highest for intensity, volition and affect; overall HRS scores were lower than those reported for several classical psychedelics in experimental settings but similar to recreational 2C-B reports. Pharmacokinetic data from oral fluid showed rapid absorption with mean Cmax 4.19 ± 1.86 ng/ml reached at a tmax of about 1 h. The AUC0–24 was 19.54 ± 4.72 ng·h/ml and the mean elimination half-life in oral fluid was 2.48 ± 3.20 h. Detectable oral fluid concentrations persisted up to 24 h in approximately half of participants. One participant's pharmacokinetic data were excluded as an outlier due to suspected analytical error. Cortisol measured in eight subjects had a baseline mean of 0.64 ± 0.46 µg/dl and reached a mean Cmax of 1.13 ± 0.23 µg/dl at 3 h; the authors report this cortisol increase as very small and not statistically significant. Where reported, peak subjective scores at the 6 h maximum-effect report were sometimes slightly lower than the 2 h ratings, a difference the authors attribute potentially to memory bias.

Souza and colleagues interpret their findings as showing that oral 2C-B in the 10–20 mg range produces a mixed psychedelic and psychostimulant subjective profile in experienced recreational users, with relatively prominent mood-enhancing and sociability effects and only infrequent, generally mild hallucinations. Physiological effects were moderate increases in blood pressure and heart rate that were smaller than those typically observed with MDMA or amphetamines in controlled trials; cardiovascular changes emerged by 1 h, persisted for several hours, and trended back toward baseline by 6 h. The time course of effects corresponded with oral fluid 2C-B concentrations, which peaked rapidly and declined over the first 6 h but could be detected at low levels up to 16–24 h in some participants. The authors emphasise that oral fluid sampling is a non-invasive, feasible approach for preliminary pharmacokinetic characterisation of 2C-B, though they caution that interpretation of oral fluid concentrations is difficult without paired plasma data. Cortisol increases after 2C-B were small and not significant, unlike larger cortisol responses reported for some other serotonergic psychedelics. Several limitations are acknowledged: the open-label, naturalistic design without placebo control meaning expectancy effects cannot be excluded; a small, self-selected sample of experienced users limiting generalisability; a narrow and participant-chosen dose range biased toward low–moderate doses; reliance mainly on subjective measures with few objective endpoints; potential setting effects from the non-clinical session environment; absence of plasma pharmacokinetics; and the 6 h maximum-effect report not necessarily capturing true peak subjective experience. The authors conclude that their results are preliminary and hypothesis-generating rather than definitive.

The authors present these data as a preliminary characterisation of acute physiological, subjective and oral fluid pharmacokinetic effects of oral 2C-B. They suggest oral fluid may be a suitable matrix to detect recent 2C-B use and conclude that, in experienced users at low–moderate recreational doses in a non-controlled setting, 2C-B produces a constellation of psychedelic and psychostimulant-like effects. Souza and colleagues state that further experimental research under controlled clinical conditions is required to compare 2C-B's human pharmacology directly with that of classical serotonergic drugs.