This open-label study (n=20) in healthy volunteers found that a 20mg self-administered dose of 2C-B produced predominantly positive subjective effects, including euphoria and mild hallucinogenic states, reduced anger, and caused mild cardiovascular stimulation, while also increasing reactivity to negative emotional stimuli and impairing recognition of happiness, supporting its classification as an entactogen with psychedelic properties.
Background. 2C-B (Nexus) is one of the most widespread novel psychoactive substances. There is limited information about its pharmacological properties, and few studies in humans concern its acute and chronic effects. 2C-B has been classified as a stimulant, hallucinogen, entactogen, and/or empathogen.
Objectives. To evaluate the emotional, subjective, and cardiovascular effects of 2C-B.Methods. Twenty healthy recreational 2C-B users (12 women) self-administered a 20 mg dose of 2C-B. Evaluations included emotional (IAPS, FERT, and speech), subjective (visual analog scales, ARCI, VESSPA, HRS, and POMS questionnaires), and cardiovascular effects (blood pressure and heart rate).
Results. Positive subjective effects predominated with a reduction of anger under the influence of 2C-B. It did, however, increase reactivity to negative emotional stimuli and decrease the ability to recognize expressions of happiness. Augmented emotionality in speech could be appreciated by others. 2C-B induced euphoria and well-being, changes in perceptions, and slight hallucinogenic states. Mild sympathetic actions were observed.
Conclusions. The specific profile that 2C-B exerts on emotions suggests its classification as an entactogen with psychedelic properties.
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2C-B (4-bromo-2,5-dimethoxyphenethylamine, “Nexus”) is a phenylethylamine first synthesised by Alexander Shulgin in 1974 and has become one of the more widely used novel psychoactive substances (NPS) in Europe and Australia. Previous preclinical work suggests 2C-B modulates monoamine systems (inhibiting serotonin uptake and acting to a lesser extent on norepinephrine and dopamine transporters), alters dopamine metabolites in the nucleus accumbens, and produces dose-dependent effects on locomotion. Human data are limited and mixed: 2C-B has been variously classified as stimulant, hallucinogen, entactogen or empathogen, and it is frequently encountered as an adulterant of MDMA tablets. Its receptor profile is incompletely characterised, with reports of partial 5-HT-2A and 5-HT-2C activity and metabolism via monoamine oxidases and cytochrome P450 enzymes. This study aimed to characterise the acute emotional, subjective and cardiovascular effects of a single 20 mg oral dose of 2C-B in healthy recreational users, with particular interest in clarifying whether its effects fit an entactogenic profile, a psychedelic/hallucinogenic profile, or a mixture of both. González and colleagues set out to measure emotion processing (using validated picture and facial recognition tasks), spontaneous speech characteristics, a battery of subjective-effect questionnaires, vital signs and saliva concentrations over a 6-hour period after self-administration.
The study used an open, before–after design in which 20 healthy recreational 2C-B users (12 women) self-administered a single oral dose of 20 mg of 2C-B at approximately 14:00. Inclusion required prior 2C-B experience and abstinence from psychoactive substances for 48 hours; exclusion criteria included serious medical or psychiatric history, drug dependence (except tobacco), prior adverse reactions to 2C-B, and chronic medication. Ethical approval was obtained and participants provided informed consent; sessions were conducted in the home of an association member rather than a laboratory setting. Gas chromatography analysis by a harm-reduction NGO confirmed 95% purity of the material. Urine drug screens for common drugs were negative at baseline. Assessments occurred at baseline, at peak effects (approximately 1.5–3 h postdose, typically 1.5 h reported for peak neuropsychological testing) and at 6 h. The core neuropsychological/emotional measures were the International Affective Picture System (IAPS; 120 images in two counterbalanced sets, valence and arousal ratings), the Face Emotion Recognition Task (FERT; five emotions presented in graded intensity), and a 3-minute free-speech task (topics counterbalanced) recorded and later rated by five blinded psychologists on coherence, emotionality, depth and focus; syllable counts provided a measure of verbal fluency. Subjective effects were captured with multiple instruments: visual analogue scales (VAS), the Profile of Mood States (POMS), the Addiction Research Center Inventory (ARCI), the VESSPA-SEE questionnaire, and the Hallucinogenic Rating Scale (HRS) with timing as described above (some scales at 6 h summarised). Vital signs (heart rate and blood pressure) and saliva samples for 2C-B concentrations were taken at the same time points. Statistical analysis compared baseline versus peak (and baseline versus 6 h where applicable) using paired Student's t-tests for neuropsychological and questionnaire measures; vital signs were analysed with one-way repeated-measures ANOVA and Tukey post hoc tests. Independent-sample t-tests examined gender differences. Analyses were performed in SPSS 12.0 and significance was set at P < 0.05.
Sample characteristics: Twenty participants (12 women) mean age 34.65 years (SD = 5.25), BMI 22.14 (SD = 2.56); 60% had a university degree. Mean prior recreational 2C-B use was 6.5 occasions (SD = 7.0). All reported prior use of several illicit drugs; baseline urine screens were negative and no intoxication signs were present at baseline. Neuropsychological/emotional tasks: In the IAPS, 2C-B produced a statistically significant reduction in valence ratings for negative images (P = 0.037), interpreted as increased unpleasantness or discomfort in response to negative stimuli; arousal ratings did not change significantly except for a trend toward increased arousal for negative stimuli (P = 0.11). No gender differences were found for IAPS ratings. In the FERT, participants made significantly more errors recognising expressions of happiness after 2C-B (P = 0.027); under 2C-B, fear became the most readily detected emotion. Men made more errors detecting anger than women (men mean 5.75 (SD = 2.12) vs women 3.75 (SD = 1.06), P = 0.035). Free speech: Verbal fluency (syllable count) did not change (baseline 474.74, SD = 216.23; peak 479.11, SD = 152.09; P = 0.936). Speech was rated as significantly more emotional after 2C-B (P = 0.012), with higher emotionality ratings in women (men mean 4.36 (SD = 0.84) vs women 5.57 (SD = 1.12), P = 0.042). Two female participants cried during the task and one male laughed uncontrollably; that male's speech was unintelligible and he was excluded from the speech analyses, yielding n = 19 for that outcome. Subjective questionnaires: VAS scores increased significantly for positive effects, perceptual changes and mild visual hallucinatory experiences at peak and/or in the 0–6 h summary; no gender differences on VAS were observed. On the ARCI, significant increases occurred in euphoria (MBG), dysphoria/somatic effects (LSD), and the amphetamine-sensitive scales (BG and A); sedation (PCAG) did not change. The VESSPA showed significant increases across all subscales, with the highest scores for pleasure and sociability and the lowest for psychosomatic anxiety and psychotic symptoms; men scored higher than women on the activity and energy subscale at 6 h (men 9.88 (SD = 4.91) vs women 5.00 (SD = 4.51); P = 0.041). POMS showed a significant reduction in anger under 2C-B (P = 0.042); no effects were detected on vigor, depression, tiredness, tension or friendship overall, although men showed a reduction in tiredness (men 0.50 (SD = 0.535) vs women 3.75 (SD = 3.19); P = 0.011). On the HRS (6 h summary), high scores appeared particularly for volition, intensity and perception, while cognition scored lowest. Physiology and saliva: Small but statistically significant sympathetic effects were observed at peak (1.5 h): heart rate increased by approximately 6 beats/min, systolic blood pressure by about 5 mmHg and diastolic pressure by about 4 mmHg; values returned to baseline by 6 h. No gender differences in vital signs were reported. Saliva 2C-B concentrations were detectable at 1.5 h (6.8 ng/mL) and 6 h (2.3 ng/mL).
González and colleagues interpret the pattern of findings as consistent with an entactogenic profile that includes psychedelic and mild hallucinogenic properties. They argue that reductions in self-reported anger (POMS) together with increased well-being and sociability (VAS and VESSPA) reflect serotonergic actions typically associated with entactogens. At the same time, impairment in affective face processing—worse recognition of positive expressions and increased reactivity to negative images—does not support a straightforward empathogenic effect and points to a more complex influence on emotional processing. The authors situate these results relative to previous work: some similarities exist with MDMA in subjective prosocial and euphoriant effects, but 2C-B differed from MDMA and amphetamine in that it did not increase verbal fluency or the POMS dimensions of vigor and friendship. The unexpected increase in discomfort to negative stimuli contrasts with typical amphetamine or MDMA effects and with anxiolytic-like responses to other drugs; González and colleagues note that this pattern has analogies with findings in depression and with certain acute effects of selective serotonin reuptake inhibitors, and they discuss potential roles for serotonergic receptors beyond 5-HT-2A (including 5-HT-2C and 5-HT-1A) in mediating these emotional-processing changes. Several limitations are acknowledged: the uncontrolled before–after design lacking placebo or active comparator, assessment in a nonexperimental/home setting, a limited number of evaluation time points, and a sample of experienced users which may limit generalisability to naïve individuals. The study used a single fixed dose for all participants; menstrual phase of female participants was not recorded despite observed gender differences; standard urine screening could not detect other NPS; and saliva/plasma pharmacokinetic data remain sparse. The authors caution that, although adverse events were limited in this experienced sample, substances with similar pharmacology can cause severe medical or psychiatric reactions in susceptible users, and long-term health effects are unknown. They call for further research into 2C-B's pharmacology, toxicity and potential therapeutic applications.
A single 20 mg oral dose of 2C-B in experienced recreational users produced a mixed profile: increased feelings of well-being and sociability, reduced anger, altered perceptual and mild hallucinogenic experiences, heightened emotional expression in speech, but also greater reactivity to negative stimuli and impaired recognition of positive facial expressions. González and colleagues conclude that these effects together support classification of 2C-B as entactogenic with psychedelic properties. They suggest a potential, tentative psychotherapeutic application in disorders involving aggression or altered affective processing, but emphasise that safety, pharmacology and medium–long term consequences are insufficiently characterised and that caution and further controlled research are required.
The neuropsychological test scores were contrasted with paired Student's 𝑡-test (baseline versus peak effects). The results of the subjective effects scales were compared with paired Student's 𝑡-test (baseline versus peak effects and baseline versus 6 h, depending on the questionnaire). In the case of vital signs a one-way analysis of variance-ANOVA with repeated measures (baseline, peak effect (1.5 h), and 6 h) and a Tukey test post hoc comparison between times were performed. In order to observe intergender differences, an independent sample 𝑡-test was carried out with baseline and postdose measures for neuropsychological tests and POMS. Analyses were performed with the SPSS 12.0 program. 𝑃 value < 0.05 was considered statistically significant.
This study is the first to describe the emotional effects of 2C-B and one of the few that reports subjective and cardiovascular effects after its administration. Our results indicate that 2C-B has specific effects on emotional processing and mood states which permit its classification as an entactogenic substance with psychedelic and hallucinogenic characteristics. Entactogenic effects are characterized as an "open mind" state with properties including an increase in self-awareness, the sensation "to produce a touching within," introspection, elevated sensory perception, and enhanced prosocial effect. However, its influence with respect to the worsening of the affective perception of faces does not point to empathogenic qualities and, despite the slight effects observed in cardiovascular measurements, the result of the verbal fluency test is not typical of stimulants. Serotonin is an ancestral neuromodulator that modulates the control of violent impulses incited by provocation through a down-top regulation of emotional reactions. In this regard, the effects of 2C-B are characteristic of the activation of serotonergic receptors as a significant decrease of anger was observed in the POMS questionnaire. The increase in well-being in the VAS and sociability in the SOC subscale of the VESSPA reaffirms this result, given that the subscale was created to evaluate the typical effects of entactogenic substances, reflecting the pleasurable effect of feeling well with oneself and others. Such effects are similar to those induced by MDMAand 2C-Bas previously reported. Nevertheless, the effect of 2C-B on mood states reflected by the POMS differs substantially from that of MDMA and amphetamine, in spite of sharing a similar chemical structure, as these two substances tend to augment vigor and friendship. Oxytocin, liberated by MDMA, has been more strongly associated with the latter sentiment than serotonin. While the specific role of oxytocin with regard to the subjective effects of MDMA remains unclear, it is possible that this hormone does not have a strong influence on 2C-B effects. Contrary to our expectations, under the effects of 2C-B, emotional reactivity with respect to the negative stimuli in the IAPS task increased. This type of affective response is uncommon and has not been observed in other substances. It is well-known that with any kind of stimulus amphetamine augments valence and arousal. In the Multifaceted Empathy Test (MET), MDMA increased implicit empathy (arousal) particularly with positive valence stimuli. On the other hand, high doses of alcohol suppress the response to negative stimuli. In all of these cases there is some form of affective regulation that has been linked to heightened response as they either strengthen the impact of the positive stimuli or reduce the negative ones. In contrast, 2C-B does not appear to produce this type of response as greater discomfort with respect to negative stimuli at baseline was reported. It is noteworthy that, under the effects of 2C-B, affective perception deteriorated and the number of errors in recognizing positive expressions increased. A similar pattern has been observed in depressed patientswhich reverses with prolonged administration of SSRI antidepressants. Most studies, however, which examined the effect of SSRI on the affective processing of faces have found that an acute administration of a single dose helped recognition of expressions of fearwith a corresponding worsening at long term administration. In our study, in spite of not having observed significant differences in the recognition of expressions of fear, it did, nevertheless, become the emotion best detected under the effects of 2C-B. Some authors have reported an increase in the accuracy of detecting fear under the influence of MDMA followed by a significant decrease 4 days after ingestion. Most studies, however, have concluded that MDMA worsens recognition of negative emotional expressionsparticularly those of fear. Such results can be extrapolated to other substances that act upon the 5-HT-2A such as psilocybin, the effect being reversed when these receptors are blocked with ketanserin. A recent study has observed the role of the 5HT-1A receptors in the recognition of fear when the agonist buspirone was administered. It was found that the 5HT-1A and 5-HT-2A receptors are linked to the structural coding of this expression in a prior process, both receptors thus contributing to its reduced recognition. Notwithstanding the fact that 2C-B alters visual perception, our results underscore the issue that its unique profile in the affective processing of faces leads to further questions regarding the possible implications of other receptors, such as 5HT-2C, in this kind of process. In a similar manner to MDMA and in contrast to methamphetamineand d-amphetamine, verbal fluency did not increase under the effects of 2C-B: significant differences were not observed in the number of syllables uttered during the experiment. Differences were, however, reported in the emotionality and depth variables, particularly in the female participants. A recent study has demonstrated that under the effects of 1.5 mg/kg of MDMA discourse comes close to concepts such as "friend" and "support" and with 0.75 mg/kg to "empathy." However, speech under the effects of 20 mg of methamphetamine distances itself from concepts such as "compassion". Considering that two of the female participants cried whilst performing the free speech task, it appears that 2C-B influences emotionality, reflecting an entactogenic activity defined by Nicholsas "to produce a touching within." The intergender variable should be taken into account with respect to 2C-B effects. In the POMS questionnaire a reduction in tiredness was observed in men, but not in women. In addition, in the speech task the female participants had significantly higher scores in emotionality. These results show that 2C-B has similar effects to amphetamine in men and more entactogenic effects in women. A similar condition occurs with amphetamine, the effects of which depend not only on gender but also on the menstrual phase. Women barely experience stimulation during the luteal phase due to an increase in the plasmatic levels of progesterone. This fact draws attention to one of the limitations of the study as the menstrual phases of the female participants were not taken into consideration. Given the relevant influence of hormones in subjective emotional states such data should be included in future research. The 2C-B dose that was administered provoked minor alterations in the participant's vital signs, with a sympathomimetic stimulation similar to an average dose of MDMA. There are no available data regarding 2C-B concentrations in plasma and saliva. As occurs with weak bases, such as MDMA and methylphenidate, the saliva concentrations could be related to the plasma ones. Our study has some limitations related to its before-after design and lack of control (placebo or MDMA). In addition, subjects were assessed in a nonexperimental setting and the number of evaluations was limited. The use of the same dose for all subjects was a strength although few differences were observed with respect to gender. Whilst the standard rapid urine drug test employed prior to the session was negative for the most common drugs, it was naturally unable to identify any other possible NPS (e.g., synthetic cannabinoids or cathinones). The participants did not, however, present any signs of intoxication. With respect to tolerability and safety, all the volunteers had had previous positive experiences with 2C-B and other drugs. Nevertheless, taking into account the fact that substances with similar profiles can induce severe medical and psychiatric reactions, its consumption in naïve users or in subjects with less experience could produce side effects.
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