We report the presence of a new substance detected in the hidden web as an adulterant of heroin, ocfentanil. It has short acting opioid-like effects, roughly the same potency as fentanyl, and can be injected, snorted or smoked. Severe side effects have been associated with its use, including one death. No discussion about this substance could be found in the Internet, which suggests this substance has not been sold as such. Available data about purities of drugs purchased in cryptomarkets suggest that adulteration is not a severe problem and this agrees with users' perceptions. However, this study suggests that adulteration is a real threat not only at the street level, but also for users that buy substances in cryptomarkets, and suggest the need for harm reduction initiatives in this setting.

Cannabinoid CB1 receptors (CBR) and serotonergic 2A receptors (5HTR) form heteromers in the brain of mice where they mediate the cognitive deficits produced by delta-9-tetrahydrocannabinol. However, it is still unknown whether the expression of this heterodimer is modulated by chronic cannabis use in humans. In this study, we investigated the expression levels and functionality of CBR-5HTR heteromers in human olfactory neuroepithelium (ON) cells of cannabis users and control subjects, and determined their molecular characteristics through adenylate cyclase and the ERK 1/2 pathway signaling studies. We also assessed whether heteromer expression levels correlated with cannabis consumption and cognitive performance in neuropsychological tests. ON cells from controls and cannabis users expressed neuronal markers such as βIII-tubulin and nestin, displayed similar expression levels of genes related to cellular self-renewal, stem cell differentiation, and generation of neural crest cells, and showed comparable Na currents in patch clamp recordings. Interestingly, CBR-5HTR heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively with age of onset of cannabis use. In addition, a negative correlation was found between heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CBR-5HTR heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.

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Since the emergence of these substances could prove to be the next step to the cat-and-mouse game existing between drug producers and legislation, further clinical and epidemiological research should be carried out in order to build evidence to support policy for public health issues.

Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulation, but difficulty in obtaining in vivo neurological tissue has limited its exploration. We investigated CB1R-5-HT2AR heteromer expression and functionality via intracellular pERK and cAMP quantification in olfactory neuroepithelium (ON) cells of SCZ patients non-cannabis users (SCZ/nc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZ/c). Results were compared vs healthy controls non-cannabis users (HC/nc) and healthy controls cannabis users (HC/c). Further, antipsychotic effects on heteromer signaling were tested in vitro in HC/nc and HC/c. Results indicated that heteromer expression was enhanced in both SCZ groups vs HC/nc. Additionally, pooling all 4 groups together, heteromer expression correlated with worse attentional performance and more neurological soft signs (NSS), indicating that these changes may be useful markers for neurocognitive impairment. Remarkably, the previously reported signaling properties of CB1R-5-HT2AR heteromers in ON cells were absent, specifically in SCZ/nc treated with clozapine. These findings were mimicked in cells from HC/nc exposed to clozapine, suggesting a major role of this antipsychotic in altering the quaternary structure of the CB1R-5-HT2AR heteromer in SCZ/nc patients. In contrast, cells from SCZ/c showed enhanced heteromer functionality similar to HC/c. Our data highlight a molecular marker of the interaction between antipsychotic medication and cannabis use in SCZ with relevance for future studies evaluating its association with specific neuropsychiatric alterations.

Brain connectivity and neurological soft signs (NSS) are reportedly abnormal in schizophrenia and unaffected relatives, suggesting they might be useful neurobiological markers of the illness. NSS are discrete sensorimotor impairments thought to correspond to deviant brain development. Although NSS support the hypothesis that schizophrenia involves disruption in functional circuits involving several hetero modal association areas, little is known about the relationship between NSS and brain connectivity. We explored functional connectivity abnormalities of the default mode network (DMN) related to NSS in schizophrenia. A cross-sectional study was performed with 27 patients diagnosed with schizophrenia, 23 unaffected relatives who were unrelated to the schizophrenia subjects included in the study, and 35 healthy controls. Subjects underwent magnetic resonance imaging scans including a functional resting-state acquisition and NSS evaluation. Seed-to-voxel and independent component analyses were used to study brain connectivity. NSS scores were significantly different between groups, ranging from a higher to lower scores for patients, unaffected relatives, and healthy controls, respectively (analysis of variance effect of group F = 56.51, p < 0.001). The connectivity analysis revealed significant hyperconnectivity in the fusiform gyrus, insular and dorsolateral prefrontal cortices, inferior and middle frontal gyri, middle and superior temporal gyri, and posterior cingulate cortex [minimum p-family wise error (FWE) < 0.05 for all clusters] in patients with schizophrenia as compared with in controls. Also, unaffected relatives showed hyperconnectivity in relation to controls in the supramarginal association and dorsal posterior cingulate cortices (p-FWE < 0.05 for all clusters) in patients with schizophrenia as compared with in controls. Also, unaffected relatives showed hyperconnectivity in relation to controls in the supramarginal association and dorsal posterior cingulate cortices (p-FWE = 0.001) and in the anterior prefrontal cortex (42 voxels, p-FWE = 0.047). A negative correlation was found between left caudate connectivity and NSS [p-FWE = 0.044, cluster size (k) = 110 voxels]. These findings support the theory of widespread abnormal connectivity in schizophrenia, reinforcing DMN hyperconnectivity and NSS as neurobiological markers of schizophrenia. The results also indicate the caudate nucleus as the gateway to the motor consequences of abnormal DMN connectivity.

New psychoactive tryptamines may be a public health risk since they intend to mimic the hallucinogenic effects of regulated psychoactive drugs. Few studies describe uses and clinical effects of unregulated new psychoactive tryptamines. This study aims (1) to explore the presence of tryptamines classified as NPS among the substances delivered for analysis to a harm-reduction organization; (2) to describe the substances found in the samples after analysis; and (3) to compare analytical results of regulated vs. non-regulated tryptamines. Samples delivered and analyzed by gas chromatography-mass spectrometry from 2006 to 2015 were included. A descriptive study of results was conducted. From 25,296 samples that were delivered, 436 were tryptamines; from these 232 (53.21%) were non-regulated. The most delivered non-regulated tryptamine was 4-AcO-DMT. A search of the PubMed database in July 2016 revealed that no studies in humans have ever been carried out with 4-AcO-DMT. Unregulated tryptamines likely contained one unadulterated substance (p ≤ 0.001). The number of samples submitted which contained tryptamines increased during the course of the study, with significant differences in client expectations vs. analysis results between the controlled and uncontrolled groups. There is a need for further research in order to prevent the potential health risks associated with their use.

Synthetic cannabinoids (SCs) are one of the most frequent classes of new psychoactive substances monitored by the EU Early Warning System and World Health Organization. UR-144 is a SC with a relative low affinity for the CB1 receptor with respect to that for the CB2 receptor. As with other cannabinoid receptor agonists, it has been monitored by the EU Early Warning System since 2012 for severe adverse effects on consumers. Since data for UR-144 human pharmacology are very limited, an observational study was carried out to evaluate its acute pharmacological effects following its administration using a cannabis joint as term of comparison. Disposition of UR-144 and delta-9-tetrahydrocannibinol (THC) was investigated in oral fluid. Sixteen volunteers smoked a joint prepared with tobacco and 1 or 1.5 mg dose of UR-144 (n = 8) or cannabis flowering tops containing 10 or 20 mg THC (n = 8). Physiological variables including systolic and diastolic blood pressure, heart rate and cutaneous temperature were measured. A set of Visual Analog Scales (VAS), the Addiction Research Centre Inventory (ARCI)-49-item short form version and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) were administered to evaluate subjective effects. Oral fluid was collected at baseline, 10, 20, 40 min and 1, 2, 3 and 4 h after smoking, for UR-144 or THC concentration monitoring. Results showed significant statistical increases in both systolic and diastolic blood pressure and heart rate after both UR-144 and cannabis smoking. Both substances produced an increase in VAS related to stimulant-like and high effects, but scores were significantly higher after cannabis administration. No hallucinogenic effects were observed. Maximal oral fluid UR-144 and THC concentrations appeared at 20 and 10 min after smoking, respectively. The presence of UR-144 in oral fluid constitutes a non-invasive biomarker of SC consumption. The results of this observational study provide valuable preliminary data of the pharmacological effects of UR-144, showing a similar profile of cardiovascular effects in comparison with THC but lower intensity of subjective effects. Our results have to be confirmed by research in a larger sample to extensively clarify pharmacological effects and the health risk profile of UR-144.