Use Of Synthetic Cannabinoid Receptor Agonists Research Articles

Investigating selectivity and bias for G protein subtypes and β-arrestins by synthetic cannabinoid receptor agonists at the cannabinoid CB1 receptor

The cannabinoid CB1 receptor (CB1) is a G protein-coupled receptor (GPCR) with widespread expression in the central nervous system. This canonically G⍺i/o-coupled receptor mediates the effects of Δ9-tetrahydrocannabinol (THC) and synthetic cannabinoid receptor agonists (SCRAs). Recreational use of SCRAs is associated with serious adverse health effects, making pharmacological research into these compounds a priority. Several studies have hypothesised that signalling bias may explain the different toxicological profiles between SCRAs and THC. Previous studies have focused on bias between G protein activation measured by cyclic adenosine monophosphate (cAMP) inhibition and β-arrestin translocation. In contrast, the current study characterises bias between G⍺ subtypes of the G⍺i/o family and β-arrestins; this method facilitates a more accurate assessment of ligand bias by assessing signals that have not undergone major amplification. We have characterised G protein dissociation and translocation of β-arrestin 1 and 2 using real-time BRET reporters. The responses produced by each SCRA across the G protein subtypes tested were consistent with the responses produced by the reference ligand AMB-FUBINACA. Ligand bias was probed by applying the operational analysis to determine biases within the G⍺i/o family, and between G protein subtypes and β-arrestins. Overall, these results confirm SCRAs to be balanced, high-efficacy ligands compared to the low efficacy ligand THC, with only one SCRA, 4CN-MPP-BUT7IACA, demonstrating statistically significant bias in one pathway comparison (towards β-arrestin 1 when compared with G⍺oA/oB). This suggests that the adverse effects caused by SCRAs are due to high potency and efficacy at CB1, rather than biased agonism.

Synthetic cannabinoid receptor agonists are monoamine oxidase-A selective inhibitors.

Synthetic cannabinoid receptor agonists (SCRAs) are one of the fastest growing classes of recreational drugs. Despite their growth in use, their vast chemical diversity and rapidly changing landscape of structures make understanding their effects challenging. In particular, the side effects for SCRA use are extremely diverse, but notably include severe outcomes such as cardiac arrest. These side effects appear at odds with the main putative mode of action, as full agonists of cannabinoid receptors. We have hypothesized that SCRAs may act as MAO inhibitors, owing to their structural similarity to known monoamine oxidase inhibitors (MAOI's) as well as matching clinical outcomes (hypertensive crisis) of 'monoaminergic toxicity' for users of MAOIs and some SCRA use. We have studied the potential for SCRA-mediated inhibition of MAO-A and MAO-B via a range of SCRAs used commonly in the UK, as well as structural analogues to prove the atomistic determinants of inhibition. By combining in silico and experimental kinetic studies we demonstrate that SCRAs are MAO-A-specific inhibitors and their affinity can vary significantly between SCRAs, most notably affected by the nature of the SCRA 'head' group. Our data allow us to posit a putative mechanism of inhibition. Crucially our data demonstrate that SCRA activity is not limited to just cannabinoid receptor agonism and that alternative interactions might account for some of the diversity of the observed side effects and that these effects can be SCRA-specific.

Characterisation of AMB-FUBINACA metabolism and CB1-mediated activity of its acid metabolite

PurposeAMB-FUBINACA is a synthetic cannabinoid receptor agonist (SCRA) which is primarily metabolised by hepatic enzymes producing AMB-FUBINACA carboxylic acid. The metabolising enzymes associated with this biotransformation remain unknown. This study aimed to determine if AMB-FUBINACA metabolism could be reduced in the presence of carboxylesterase (CES) inhibitors and recreational drugs commonly consumed with it. The affinity and activity of the AMB-FUBINACA acid metabolite at the cannabinoid type-1 receptor (CB1) was investigated to determine the activity of the metabolite.MethodsThe effect of CES1 and CES2 inhibitors, and delta-9-tetrahydrocannabinol (Δ9-THC) on AMB-FUBINACA metabolism were determined using both human liver microsomes (HLM) and recombinant carboxylesterases. Radioligand binding and cAMP assays comparing AMB-FUBINACA and AMB-FUBINACA acid were carried out in HEK293 cells expressing human CB1.ResultsAMB-FUBINACA was rapidly metabolised by HLM in the presence and absence of NADPH. Additionally, CES1 and CES2 inhibitors both significantly reduced AMB-FUBINACA metabolism. Furthermore, digitonin (100 µM) significantly inhibited CES1-mediated metabolism of AMB-FUBINACA by ~ 56%, while the effects elicited by Δ9-THC were not statistically significant. AMB-FUBINACA acid produced only 26% radioligand displacement consistent with low affinity binding. In cAMP assays, the potency of AMB-FUBINACA was ~ 3000-fold greater at CB1 as compared to the acid metabolite.ConclusionsCES1A1 was identified as the main hepatic enzyme responsible for the metabolism of AMB-FUBINACA to its less potent carboxylic acid metabolite. This biotransformation was significantly inhibited by digitonin. Since other xenobiotics may also inhibit similar SCRA metabolic pathways, understanding these interactions may elucidate why some users experience high levels of harm following SCRA use.

Synthesis and pharmacological evaluation of newly detected synthetic cannabinoid receptor agonists AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA, MDMB-4F-BUTINACA and their analogs.

Synthetic cannabinoid receptor agonists (SCRAs) continue to make up a significant portion new psychoactive substances (NPS) detected and seized worldwide. Due to their often potent activation of central cannabinoid receptors in vivo, use of SCRAs can result in severe intoxication, in addition to other adverse health effects. Recent detections of AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA and MDMB-4F-BUTINACA mark a continuation in the appearance of SCRAs bearing novel tail substituents. The proactive characterization campaign described here has facilitated the detection of several new SCRAs in toxicological case work. Here we detail the synthesis, characterization, and pharmacological evaluation of recently detected SCRAs, as well as a systematic library of 32 compounds bearing head, tail, and core group combinations likely to appear in future. In vitro radioligand binding assays revealed most compounds showed moderate to high affinity at both CB1 (pKi = < 5 to 8.89 ± 0.09 M) and CB2 (pKi = 5.49 ± 0.03 to 9.92 ± 0.09 M) receptors. In vitro functional evaluation using a fluorescence-based membrane potential assay showed that most compounds were sub-micromolar to sub-nanomolar agonists at CB1 (pEC50 = < 5 to 9.48 ± 0.14 M) and CB2 (pEC50 = 5.92 ± 0.16 to 8.64 ± 0.15 M) receptors. An in silico receptor-ligand docking approach was utilized to rationalize binding trends for CB2 with respect to the tail substituent, and indicated that rigidity in this region (i.e., 4-cyanobutyl) was detrimental to affinity.

Towards better understanding SCRAs and metabolites in recreational drug intoxications associated with 5F-MDMB-PICA use

Synthetic cannabinoid receptor agonists (SCRAs) pose a danger to public health. Historically, SCRA use has been associated with a multitude of adverse events, including neurotoxicity and cardiotoxicity. Numerous case reports are published on observed SCRA toxicity, however clear studies on the toxicity of SCRAs in humans are lacking because of obvious ethical reasons. This study focused on a unique cohort of patients experiencing recreational drug toxicity, who had used 5F-MDMB-PICA, to better understand the effects of SCRAs and their metabolites in humans. All patients were evaluated regarding vital signs, Glasgow Coma Scale (GCS) and clinical features. Liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) confirmed and quantified the presence of 5F-MDMB-PICA (and/or metabolites) as the only SCRA present in the serum of 71 patients (Janssens et al., Clinical Chemistry , 2022, in press, https://doi.org/10.1093/clinchem/hvac027 ). Cannabinoid activity was assessed in extracts from all serum samples by a cannabinoid receptor (CB1) bioassay, allowing to assess the relationship between serum concentrations and ex vivo human CB1 activation potential. Furthermore, a link with the clinical presentation was appraised. 5F-MDMB-PICA and metabolites were pharmacologically profiled in vitro to evaluate the theoretically possible contribution of active metabolites to overall cannabinoid activity. This revealed the presence of active in vivo metabolites M2 (oxidative defluorination) and M7 (ester hydrolysis) in serum. Serum levels of 5F-MDMB-PICA were correlated to the ex vivo cannabinoid activity, revealing a sigmoidal relationship. The latter could also be predicted based on the pharmacological characterization and an in-depth investigation of the bioassay outcome. Regarding the clinical presentation, the GCS showed a significant trend (decrease) upon increasing ex vivo cannabinoid activity. Trends for the occurrence of symptoms or an altered heart rate, blood pressure or body temperature were non-significant. Although high concentrations of 5F-MDMB-PICA metabolites (M2 and M7) were present in serum, a negligible contribution of these active metabolites to the overall cannabinoid activity in serum was anticipated, based on their in vitro CB1 receptor activation potential. Prediction of ex vivo cannabinoid activity was made possible by generating a mathematical formula based on the pharmacological characterization of reference standards of all compounds that were detected in serum. Including correction factors within this formula to account for incomplete recovery and matrix effects within the bioassay was necessary as – in contrast to the analytical method – no internal standard could be used due to retained CB1 activation potential of SCRA internal standards. The clinical presentation of 5F-MDMB-PICA-intoxicated patients was not unequivocally correlated to the ex vivo cannabinoid activity in their serum. On the one hand, the level of consciousness significantly correlated to the ex vivo cannabinoid activity that could be measured within extracts of their serum. This is in line with previous reports of SCRA misuse resulting in drowsiness or ‘zombie-like’ effects. The insignificance of other clinical trends, on the other hand, suggest that the clinical presentation regarding SCRA abuse cannot be deemed as clear-cut. This is the first study to evaluate in a large patient cohort the correlation between possible toxic effects of 5F-MDMB-PICA misuse and ex vivo cannabinoid activity. Pharmacological profiling and in-depth bioassay analysis allowed a better understanding of the contribution of 5F-MDMB-PICA and active metabolites to the total CB1 activity present in serum, suggesting a negligible contribution by metabolites of this specific SCRA despite the high concentrations in serum.

Convulsant doses of abused synthetic cannabinoid receptor agonists AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA and JWH-018 do not elicit electroencephalographic (EEG) seizures in male mice.

Synthetic cannabinoid receptor agonists (SCRAs) are found in illicit smoking products, such as "K2" or "Spice." Convulsions are commonly reported adverse effects of SCRAs but are poorly understood. We determined convulsant effects of SCRAs AB-PINACA, and 5F-ADB-PINACA in adult male NIH Swiss mice, and then determined if convulsant effects of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 elicited seizure-like effects using EEG. Mice were administered SCRAs or pentylenetetrazole (PTZ) and placed in observation chambers where convulsant effects were scored. The capacity of the CB1R antagonist rimonabant, the benzodiazepine diazepam, or the non-specific CYP450 inhibitor 1-aminobenzotriazole (1-ABT) to attenuate convulsant effects was determined. Other mice were prepared with EEG headmounts to ascertain whether observed convulsions occurred concurrently with seizure-like effects by assessing root-mean-square (RMS) power, high amplitude EEG spike analysis, and videography. Mice receiving AB-PINACA or 5F-ADB-PINACA exhibited dose-dependent convulsant effects that were blocked by 10mg/kg rimonabant pretreatment but not by pretreatment with 10mg/kg diazepam; these convulsant effects were not altered in the presence of 100mg/kg 1-ABT. Repeated administration of 10mg/kg AB-PINACA and 3mg/kg 5F-ADB-PINACA produced partial tolerance to convulsant effects but did not lead to cross-tolerance to PTZ-induced convulsions. In EEG studies, convulsant doses of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 did not produce seizures concomitantly with convulsions. These data extend previous findings of convulsant effects of SCRAs and suggest that convulsant effects of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 are CB1R-mediated but are not associated with electroencephalographic seizures. These results further suggest that benzodiazepines may not effectively treat convulsions elicited by SCRA use in humans.

Does cannabis testing in the military drive synthetic cannabinoid use? Self-reported use motivations among justice-involved veterans

Though synthetic cannabinoid receptor agonists (SCRAs) were controlled after being introduced as a 'legal high,' SCRAs likely remain appealing to individuals subject to routine drug screens as not all testing programs consistently include SCRAs. Military populations have been linked to SCRAs due to the unconfirmed supposition that testing protocols led many to substitute SCRAs for cannabis. This study aimed to explore SCRA use prevalence, correlates, and use motivations among veterans, with a particular focus on whether United States military personnel substituted SCRAs for cannabis to subvert testing protocols.All veterans appearing in one of eight civilian criminal courts in three U.S. states were invited to answer questionnaire items related to military service, court functionality, and substance use. Of the 579 veterans eligible, 54.9% chose to participate, yielding a cross-sectional sample of 318 veterans charged with a criminal offense by civilian authorities.Sixty-five (21.3%) justice-involved veterans reported lifetime SCRA use. Use while within the military was reported by 15.0% of veterans enlisting after 2008. Only eight (12.3%) reported SCRAs were used as a substitute for cannabis. Boredom (36.9%), experimentation (27.7%), and social aspects of SCRA use (32.3%) were more commonly reported motives. Logistic regression models indicated that use of cannabis (aPR=2.06, p<.05), hallucinogens (aPR=2.50, p<.01), and SCRAs (aPR=2.49, p<.05) while in the military were risk factors for SCRA use after leaving the military, whereas older age at time of military exist was a protective factor (aPR=.87, p<.01) CONCLUSIONS: Drug testing programs within the military do not appear to have the unintended consequence of routing individuals to more risky drugs; however, SCRAs appear to have been an underappreciated problem within the military. Further, use extends beyond the military with many only initiating use after discharge, suggesting SCRA use may jeopardize the health of veterans post-service.

Including the multiply excluded: a mixed methods study exploring intragroup stigma towards people who use synthetic cannabinoid receptor agonists

People who use drugs are a highly stigmatized population. This study explored within-group stigma associated with the use of synthetic cannabinoid receptor agonists (SCRA) in a sample who accessed a support service in a large city in England. We used semi-structured interviews and a questionnaire that included two measures of stigma adapted for this population. Complete data were obtained from 42 participants (69.0% male, mean age 38.5 years). Increased contact with people who use SCRA (PWUS) was associated with reduced levels of stigma, and while qualitative data mirrored some stigmatizing views found in the wider population, mitigating factors such as the attribution of social and environmental influences on the use of SCRA were identified. While intersectional stigma was identified, for example between SCRA use, homelessness, or street activities such as begging, there was also evidence of mutual support within the service. Participants helped peers who were under the influence of SCRA, suggesting the role of safe environments in reducing harm for PWUS and for those who experience intersectional stigma. Aligned with intergroup contact and attribution theories, findings supported attempts to reduce SCRA-related stigma using peer educators, and the framing of substance use disorders from a viewpoint of social inequalities.

Forensic patients’ experiences of Synthetic Cannabinoid Receptor Agonists (SCRAs) within custodial settings

ABSTRACT There has been an enormous growth in New Psychoactive Substances (NPS), sometimes erroneously referred to as ‘legal highs’, over the past 15 years. There are currently at least 800 such compounds, and we lack adequate data on all their effects and harms. Synthetic cannabinoid receptor agonists (SCRAs), often referred to by the generic name ‘spice’, are particularly notable in this regard. There has been a lack of research on forensic patients’ experiences of SCRAs, their consumption, and any adverse impact they might have. This work qualitatively explored the experience of NPS and SCRA use in 19 male patients recruited from three secure forensic services in the South of England. The majority of participants discussed experiences of using SCRAs whilst in prison as opposed to their current forensic hospital admission. Three key themes emerged which describe participants experiences of SCRA use: (i) perpetuating cycle of drug use, mental ill-health, and crime; (ii) environmental injustices and consequences; and (iii) shame and stigma associated with SCRA use. The findings provide insights into the challenges faced by forensic patients as a result of SCRA use, as well as notable opportunities. A common call was for greater psychoeducation on drug harms and treatment opportunities.

Clinical withdrawal symptom profile of synthetic cannabinoid receptor agonists and comparison of effects with high potency cannabis

Synthetic cannabinoid receptor agonists (SCRAs) may be used as an alternative to natural cannabis; however, they may carry a greater risk of problematic use and withdrawal. This study aimed to characterise the withdrawal symptom profile of SCRAs and compare their profile of effect with high-potency herbal cannabis. Global Drug Survey data (2015 and 2016) were used to access a clinically relevant sample of people reporting use of SCRAs >10 times in the past 12-months, a previous SCRA quit attempt, and lifetime use of high-potency herbal cannabis. Participants completed an 11-item SCRA withdrawal symptom checklist and compared SCRAs and high-potency herbal cannabis on their onset and duration of effects, speed of the development of tolerance, severity of withdrawal, and difficulty with dose titration. Participants (n = 284) reported experiencing a mean of 4.4 (95% CI: 4.1, 4.8) withdrawal symptoms after not using SCRAs for >1 day; most frequently reported were sleep issues (59.2%), irritability (55.6%), and low mood (54.2%). Withdrawal symptoms were significantly associated with frequency (>51 vs. 11–50 times per year: IRR = 1.43, 95% CI: 1.16, 1.77, p = 0.005) and quantity (grams per session: IRR = 1.13, 95% CI: 1.05, 1.22, p = 0.001) of SCRA use. Compared to high-potency herbal cannabis, SCRAs were rated as having a faster onset and shorter duration of effects, faster development of tolerance, and more severe withdrawal (p’s < 0.001). In conclusion, SCRA withdrawal symptoms are more likely to occur after greater SCRA exposure. The effects of SCRA indicate a more severe withdrawal syndrome and a greater risk of problematic use than natural cannabis.

Synthetic cannabinoid receptor agonists and their human metabolites in sewage water: Stability assessment and identification of transformation products.

Since their first appearance in 2008, synthetic cannabinoid receptor agonists (SCRAs) remain the most popular new psychoactive substances (NPS) in the EU. Following consumption, these drugs and their metabolites are urinary excreted and enter the sewage system enabling the application of wastewater-based epidemiology (WBE). Knowing the fate of target analytes in sewage water is essential for successful application of WBE. This study investigates the stability of several chemically diverse SCRAs and selected human metabolites under sewage conditions utilizing a combination of liquid chromatography-tandem mass spectrometry and high-resolution mass spectrometry (HRMS). Target analytes included SCRAs with indole (5F-PB-22, PB-22 pentanoic acid), indazole (AMB-FUBINACA, 5F-ADB, 5F-ADB dimethylbutanoic acid), carbazole (MDMB-CHMCZCA, EG-018), and γ-carboline (Cumyl-PeGaClone) chemical core structures representing most of the basic core structures that have occurred up to now. Stability tests were performed using wastewater effluent containing 5% activated sludge as inoculum to monitor degradation processes and formation of transformation products (TPs). The majority of investigated SCRAs, excluding the selected human metabolites, was recalcitrant to microbial degradation in sewage systems over a period of 29 days. Their stability was rather controlled by physico-chemical processes like sorption and hydrolysis. Considering a typical hydraulic in-sewer retention time of 24 h, the concentration of AMB-FUBINACA decreased by 90% thus representing the most unstable SCRA investigated in this study. Among the 10 newly identified TPs, three could be considered as relevant markers and should be included into future WBE studies to gain further insight into use and prevalence of SCRAs on the drug market.

The use and effects of synthetic cannabinoid receptor agonists by New South Wales cannabis treatment clients

IntroductionDespite decreasing consumption by general populations, use of synthetic cannabinoid receptor agonists (SCRAs) persists in some marginalised groups, including those who use other substances. This article explores SCRA consumption in an Australian cannabis treatment sample, comparing those who report ever using SCRAs with those who have never used SCRAs.MethodsA questionnaire orally administered in person to a convenience sample of 154 cannabis treatment service clients from New South Wales, Australia (71% male, median age 35) collected information regarding cannabis and SCRA use including motivations, effects and health-related consequences of use, demographics, other substance use and overall health. Demographic profiles and between-group differences were explored. McNemar tests compared effects of SCRA and cannabis. Logistic regression analysis determined predictors of SCRA use.ResultsHalf (53%) reported lifetime SCRA use; 20% reported previous-month use. The SCRA + cannabis group displayed greater polysubstance use and psychological distress. Reduced dependence on cannabis but higher levels of other substance use may predict SCRA use. Although curiosity motivated initial SCRA consumption, perceived psychoactive strength drove continued use. SCRAs appear to induce more negative side-effects than cannabis. Of the SCRA + cannabis group, 27% sought medical assistance for SCRA use. Most (90%) preferred cannabis to SCRAs, citing superior safety, effects and consistency of cannabis.ConclusionsAmong clients seeking treatment for cannabis use, SCRA use was relatively common, although not a preferred substance. Hazardous substance use and poor mental health characterised SCRA consumers, highlighting the need for continued monitoring by researchers and treatment providers of SCRA consumption in populations who use substances.

Synthetic Cannabinoid-Related Deaths in England, 2012-2019.

Aim: To identify drug-related death trends associated with synthetic cannabinoid receptor agonists (SCRAs) reported to the National Programme on Substance Abuse Deaths (NPSAD) from England. Design: Case reports from NPSAD (England) where a SCRA was detected in post-mortem tissue(s) and/or implicated in the death were extracted, analyzed, and compared against non-SCRA-related deaths that occurred over the same time period (2012-2019). Findings: One hundred sixty-five death SCRA-related reports were extracted, with 18 different SCRAs detected. Following the first death in 2012, a subsequent sharp increase in reporting is evident. Acute SCRA use was the underlying cause of death in the majority of cases (75.8%) with cardiorespiratory complications the most frequently cited underlying physiological cause (13.4%). SCRA users were predominantly found dead (68.6%), with a large proportion of those witnessed becoming unresponsive described as suddenly collapsing (81.6%). Psychoactive polydrug use was detected in 90.3% of cases, with alcohol the most commonly co-detected (50.3%), followed by opioids (42.2%), benzodiazepines/Z-drugs (32.1%), stimulants (32.1%, [28.5% cocaine]), and cannabis (24.8%). Compared to all non-SCRA-related NPSAD deaths occurring over the same time period, SCRA-related decedents were more predominantly male (90.3% vs. 72.0%; p<0.01), and lived in more deprived areas (p<0.01). While a comparatively significant proportion of decedents were homeless (19.4% vs. 4.1%), living in a hostel (13.3% vs. 2.3%) or in prison (4.9% vs. 0.2%) at time of death (all p<0.01), the greatest majority of SCRA-related decedents were living in private residential accommodations (57.6%). Conclusions: This is the largest dataset regarding SCRA-related mortalities reported to date. Reporting of SCRA-related deaths in England have increased considerably, with polydrug use a specific concern. Lack of effective deterrents to SCRA use under current UK legislation, compounded by limited knowledge regarding the physiological impacts of SCRA consumption and their interaction with other co-administered substances are contributory factors to the occurrence of SCRA-related mortalities in an increasingly deprived demographic.

Characterizing Trends in Synthetic Cannabinoid Receptor Agonist Use from Patient Clinical Evaluations during Medical Toxicology Consultation

ABSTRACT Synthetic cannabinoid receptor agonists (SCRAs) are a new class of compounds with profound psychoactive effects and potential toxicity. This study characterizes patterns in SCRA abuse using qualitative interviews with individuals receiving medical toxicology consultation. Patients with suspected exposure to a new psychoactive substance were interviewed by medical toxicologists upon presentation for acute care. Investigators collected clinical and qualitative data including knowledge, attitudes, beliefs, and practices related to psychoactive substance use. Responses were categorized by identifying themes, and statistics were generated to describe patterns of use. Overall, 69% (86) of the 124 cases of novel psychoactive substance use entered into the registry were associated with exposure to SCRAs. Most patients (68.8%) had used SCRAs at least once before the presenting episode. 47.7% considered SCRAs to be very easy to obtain, and 44.2% reported paying for the substances while 32.6% acquired it for free. Nearly half (48.8%) of patients reported their primary reason for use was to get high; a small proportion used SCRAs to avoid testing positive on drug screening (6.9%) or as an alternative to marijuana (4.6%). Findings suggest an independent and stable culture is developing around the use of SCRAs separate from their appeal as an “undetectable” alternative to marijuana.

Synthetic cannabis: adverse events reported to the New Zealand Pharmacovigilance Centre

Introduction Synthetic Cannabinoid Receptor Agonists (SCRA) were legally available in New Zealand (NZ) prior to May 2014. During the period November 2012–November 2019, reports of adverse events associated with SCRA use from across the country were submitted to the New Zealand Pharmacovigilance Centre (NZPhvC). The purpose of this study was to investigate adverse reactions associated with SCRA reported to the NZPhvC. Methods The NZPhvC database was searched for adverse events involving SCRA. Cases were extracted and analysed for demographic information of users, reactions reported and SCRA involved. Summary statistics were performed using SAS 9.3. Results One hundred and thirteen cases were identified from 1 November 2012 to 31 November 2019, comprising 81 males (71.7%) and 32 females (28.3%), with a mean age of 28.4 ± 10.1 years. Ethnicity included European (51.3%, n = 58), Māori (39.8%, n = 45), Indian (1.8%, n = 2), and Polynesian (0.9%, n = 1). There were a total of 327 reactions recorded in these cases, and the majority were psychiatric (52%, n = 170), followed by nervous system (11%, n = 35), alimentary (7%, n = 24), and cardiovascular (7%, n = 23). Where the compounds could be identified, the majority of events involved AB-FUBINACA (n = 18), 5 F-PB-22 (n = 17), and PB-22 (n = 6). Conclusions This study found that young, male and European populations frequently were involved in SCRA adverse events. A disproportionate number of Māori were present in this group. Psychiatric reactions were of clinical significance, and possibly correlated to the high potency and efficacy of SCRA compared to cannabis. Pharmacovigilance is a useful tool to measure and monitor illicit drug use, and with appropriate infrastructure and capacity has the potential to contribute to drug policy at a national level.

The use of synthetic cannabinoid receptor agonists (SCRAs) within the homeless population: motivations, harms and the implications for developing an appropriate response

Background Synthetic cannabinoid receptor agonists (SCRAs) have become increasingly associated with a range of physical, mental health and societal harms. In response, several countries have introduced legislation aimed at restricting their supply and use. While these legislative changes have led to a decrease in SCRA use within the general population, SCRAs remain popular within vulnerable populations, in particular the homeless. This article presents the findings from the first in-depth qualitative study of SCRA use within the homeless population. It makes an important and timely contribution to the current evidence base and discourse on how governments and service providers should respond to SCRA use within the homeless population. Methods The research on which this article is based was undertaken in Manchester, UK. Qualitative interviews were undertaken with 53 homeless users of SCRAs and 31 stakeholders. Results The motivations for SCRA use are broadly similar to those associated with traditional drugs; namely to escape from the reality of life on the streets, and to provide relief from the physical conditions of a street-based lifestyle. However, the combination of their low cost, the ease with which they can be accessed, their high potency, and their non-detectability explains their particular appeal to the homeless population. Alongside these motivations, the research identified a range of physical, mental health, and societal harms that were directly attributable to SCRAs. Conclusions The most appropriate way to address the continued use of SCRAs within the homeless population is through the development of a more appropriate service response rather than further legislative change.

Adding more "spice" to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists.

Synthetic cannabinoid receptor agonists (SCRAs) first appeared on the international recreational drug market in the early 2000s in the form of SCRA-containing herbal blends. Due to the cannabimimetic effects associated with the consumption of SCRAs, they have acquired an ill-informed reputation for being cheap, safe, and legal alternatives to illicit cannabis. Possessing high potency and affinity for the human cannabinoid receptor subtype-1 (CB1 ) and -2 (CB2 ), it is now understood that the recreational use of SCRAs can have severe adverse health consequences. The major public health problem arising from SCRA use has pressed legislators around the world to employ various control strategies to curb their recreational use. To circumvent legislative control measures, SCRA manufacturers have created a wide range of SCRA analogs that contain, more recently, previously unencountered azaindole, γ-carbolinone, or carbazole heterocyclic scaffolds. At present, little information is available regarding the chemical syntheses of these newly emerging classes of SCRA, from a clandestine perspective. When compared with previous generations of indole- and indazole-type SCRAs, current research suggests that many of these heterocyclic SCRA analogs maintain high affinity and efficacy at both CB1 and CB2 but largely evade legislative control. This review highlights the importance of continued research in the field of SCRA chemistry and pharmacology, as recreational SCRA use remains a global public health issue and represents a serious control challenge for law enforcement agencies.

Synthetic cannabinoid use among a sample of individuals enrolled in community-based recovery programs: Are synthetic cannabinoids actually preferred to other drugs?

Background: Over the past decade, availability and use of novel psychoactive substances such as synthetic cannabinoid receptor agonists (SCRA) have proliferated globally. However, the prevalence of SCRAs use remains uncertain, as does the degree to which individuals reporting SCRA use prefer SCRA to other drugs. Methods: In April 2017, a total of 500 anonymous surveys were completed by clients enrolled in a residential drug recovery program. Chi-square and t tests were used to examine significant differences between those who had ever used SCRA and those who had not. Logistic regression analysis was conducted in order to determine which other substances used within the past 12 months were significantly associated with past-12-month SCRA use. Results: About 69% (68.4%) of clients reported lifetime SCRA use. Those reporting SCRA use were predominantly younger ( = 32.5 vs. 40.7, P < .001), single (60.3% vs. 48.1%, P = .011), and white (87.1% vs. 77.7%, P = .008) and were more likely to have experienced past-12-month homelessness (6.5% vs. 3.2%, P = .004). This group had higher rates of probation/parole involvement (79.2% vs. 61.8%, P < .001) and incarceration (91.8% vs. 79.6%, P < .001). Individuals reporting SCRA use also showed extensive substance use histories and favored heroin, opioids, and amphetamines compared with SCRA. Only 5.2% of the SCRA-using group stated that SCRA was a preferred substance, and only 11.8% reported that they would try SCRA again. E-cigarettes (adjusted odds ratio [AOR] = 1.88), traditional cannabis (AOR = 3.87), amphetamines (AOR = 2.20), and synthetic cathinones (AOR = 3.51) were significantly associated with past-12-month SCRA use. Motivations for use included circumnavigating drug screens and peer influence. Approximately half of those who tried SCRA reported adverse effects associated with use. Conclusions: Prevalence of SCRA use among individuals with a history of substance misuse and criminal justice system involvement is high; however, SCRA are not indicated as a preferred drug.

Suspected synthetic cannabinoid receptor agonist intoxication: Does analysis of samples reflect the presence of suspected agents?

BackgroundThere has been a surge in synthetic cannabinoid receptor agonist (SCRA) exposures reported in recent years. The constituents of SCRA preparations are constantly evolving and rarely confirmed. We sought to characterize the constituents of reported SCRA exposures presenting to the emergency department (ED). MethodsPatients who presented to two academic EDs in Washington, DC with reported or suspected SCRA exposure from July 2015–July 2016 were enrolled at the discretion of the treating provider. Blood and/or urine samples were obtained as part of routine clinical care and sent to the DC medical examiner's office for identification of known SCRAs with liquid chromatography-mass spectrometry-mass spectrometry. Standard toxicology screens were additionally performed to determine the presence of other drugs of abuse. Results128 samples were analyzed. Seventy-one (55.5%) were positive for an SCRA. The most common SCRAs detected were AB-fubinaca (28, 39.4%), ADB-fubinaca (15, 21.1%), AB-chminaca 3-methyl-butanoic acid (15, 21.1%), ADB-chminaca (14, 19.7%), and 5-flouro-PB-22 (8, 11.3%). Fifty-seven (44.5%) samples were negative for an SCRA, of which 28 (21.9%) were positive for another substance, most commonly delta-9-tetrahydrocannabinol and phencyclidine. An additional 29 (22.7%) patients had both negative SCRA and toxicology screens. ConclusionsOf patients presenting with reported SCRA intoxication, 55.5% had detectable SCRAs on analytical testing. These results suggest that in a considerable proportion of cases, clinicians are mis-attributing the effects of other drugs or medical conditions to SCRA use. The individual SCRAs detected in our study differed from compounds detected in earlier studies, suggesting there has been a change in constituents.

Spicing it up - synthetic cannabinoid receptor agonists and psychosis - a systematic review

Synthetic cannabinoid receptor agonists (SCRAs) are suggested to have increased potential to induce psychosis compared to natural cannabis (NC). In this review we synthesise current knowledge about the association of SCRA use with psychotic symptoms. Following a literature search we identified 2 toxicology reports, 4 case-control studies, 3 cross-sectional studies and 15 case reports. In each of the case reports, we identified the presence or absence of symptoms based on the items of the Postitive and Negative Syndrome Scele (PANSS). The toxicology reports highlighted the main presenting features as being toxic psychosis and delirium (40%), agitation (10%) and hallucinations (4–7%). The median age was 25 years, and around 80% cases were male. Cross-sectional studies reported that SCRA use was present in approximately 10–13% patients presenting to acute psychiatric services, and was often the cause of their presentation, and that psychotic symptoms were present in 15% patients attending emergency departments following SCRA use. Case-control studies reported that SCRA use was significantly associated with psychotic symptoms and that SCRA users had higher levels of positive psychotic symptoms than NC users. The case reports supported the association of SCRA use with a wide range of positive and negative psychotic symptoms as well as with self-harm, agitation and aggressive behaviour. SCRA use is relatively prevalent in patients with psychosis and may lead to psychotic symptoms in individuals with no past psychiatric history. Further work is required to understand the long term risks of SCRA use and optimal management strategies.