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Background and Objectives: Synthetic cannabinoids (SCs) are new psychoactive substances associated with acute intoxications. Experimental data obtained under controlled and comparable conditions remain limited for this category of compounds. This descriptive, hypothesis-generating screening study aimed to characterize the acute toxicity profile of three SCs, JWH-007, AM-694, and MAB-CHMINACA. Materials and Methods: Acute toxicity was evaluated in female Swiss Albino mice, in accordance with the OECD 423 guideline, following oral and intraperitoneal administration. Animals were monitored for 14 days for behavioral and clinical signs of toxicity. At the end, histopathological examination was performed to describe organ-level changes. Serum concentrations of the tested compounds were quantified by LC-ESI-MS/MS 24 h after intraperitoneal administration. Results: The three compounds were associated with distinct behavioral, clinical, and histopathological observations. JWH-007 was associated with transient behavioral depression and histopathological changes in peripheral organs. AM-694 was associated with histopathological changes in systemic organs and limited behavioral manifestations. MAB-CHMINACA was associated with acute behavioral toxicity and central nervous system lesions, including neuronal vacuolization, necrosis, oedema, and inflammatory changes. Conclusions: These preliminary findings describe compound-specific in vivo toxicity patterns and may inform the design of future confirmatory studies on SCs’ toxicity. The observed behavioral and histopathological changes should be interpreted as hypothesis-generating and require statistical validation before conclusions can be drawn regarding comparative toxicity, structural class effects, or predictive value for risk stratification.

ADB-FUBINACA and AMB-FUBINACA are two synthetic indazole-derived cannabinoid receptor agonists, up to 140- and 85-fold more potent, respectively, than trans-∆9-tetrahydrocannabinol (∆9-THC), the main psychoactive compound of cannabis. Synthesised in 2009 as a pharmaceutical drug candidate, the recreational use of ADB-FUBINACA was first reported in 2013 in Japan, with fatal cases being described in 2015. ADB-FUBINACA is one of the most apprehended and consumed synthetic cannabinoid (SC), following AMB-FUBINACA, which emerged in 2014 as a drug of abuse and has since been responsible for several intoxication and death outbreaks. Here, we critically review the physicochemical properties, detection methods, prevalence, biological effects, pharmacodynamics and pharmacokinetics of both drugs. When smoked, these SCs produce almost immediate effects (about 10 to 15 s after use) that last up to 60 min. They are rapidly and extensively metabolised, being the O-demethylated metabolite of AMB-FUBINACA, 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamide)-3-methylbutanoic acid, the main excreted in urine, while for ADB-FUBINACA the main biomarkers are the hydroxdimethylpropyl ADB-FUBINACA, hydroxydehydrodimethylpropyl ADB-FUBINACA and hydroxylindazole ADB-FUBINACA. ADB-FUBINACA and AMB-FUBINACA display full agonism of the CB1 receptor, this being responsible for their cardiovascular and neurological effects (e.g., altered perception, agitation, anxiety, paranoia, hallucinations, loss of consciousness and memory, chest pain, hypertension, tachycardia, seizures). This review highlights the urgent requirement for additional studies on the toxicokinetic properties of AMB-FUBINACA and ADB-FUBINACA, as this is imperative to improve the methods for detecting and quantifying these drugs and to determine the best exposure markers in the various biological matrices. Furthermore, it stresses the need for clinicians and pathologists involved in the management of these intoxications to describe their findings in the scientific literature, thus assisting in the risk assessment and treatment of the harmful effects of these drugs in future medical and forensic investigations.

Purpose MDA-19 or BZO-HEXOXIZID ( N ′-[(3Z)-1-(1-hexyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-benzohydrazide), in a more recent nomenclature, was first synthesized in 2008 as a selective type-2 cannabinoid receptor (CB2) agonist due to its potential to treat neuropathic pain. In Brazil, this substance was identified in a series of 53 apprehensions between September 2021 and February 2022. Nevertheless, what intrigues toxicologists is that BZO-HEXOXIZID does not exert significant type-1 cannabinoid receptor (CB1) agonism—which is responsible for the well-known psychoactivity of Δ-9-tetrahydrocannabinol. Thus, the objective of this work is to report the first apprehension and identification of BZO-HEXOXIZID in Brazil and to discuss pharmacologically the possible reasons why a CB2 agonist has been incorporated to the illicit market. Methods Suspected seized samples were sent to the Laboratory of the Scientific Police of the State of Sao Paulo. After the screening, samples were confirmed for the presence of BZO-HEXOXIZID using chromatography gas—mass spectrometry, Fourier-transform infrared spectroscopy and nuclear magnetic resonance techniques. Results Of the 53 samples analyzed, 25 contained only BZO-HEXOXIZID and 28 with mixtures, of which 11 with the CB1 agonist ADB-BUTINACA. Other substances were found in association such as cocaine and caffeine. Conclusions BZO-HEXOXIZID was detected in a series of seized materials for the first time in Brazil. Nevertheless, there are still unanswered questions regarding the use of this selective CB2 agonist as a drug of abuse.

There 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). Patients 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. 128 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. Of 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.

Introduction About a decade ago, synthetic cannabinoids (SC) started to appear as recreational drugs on the new psychoactive substance (NPS) market. This report from the STRIDA project describes analytically confirmed intoxications involving MDMB-CHMICA (methyl-2-(1-(cyclohexylmethyl)-1 H -indol-3-ylcarbonylamino)-3,3-dimethylbutanoate), a SC that was first detected in 2014. Study Design This is an observational case series of patients from Sweden with suspected NPS exposure presenting in emergency departments and intensive care units. The results of retrospective serum and urine toxicological analysis were compared with clinical signs reported during consultation with the Poisons Information Centre and retrieved from medical records. Methods Clinical and bioanalytical data in nine acute intoxications associated with MDMB-CHMICA during 2014–2015 are presented. The patients were aged 23–62 (median 34) years, and eight were men. MDMB-CHMICA (parent compound) was analytically confirmed in serum samples, using a liquid chromatography–high-resolution mass spectrometry multi-component method. Results Of the nine MDMB-CHMICA-positive patients, eight had a Poisoning Severity Score (PSS) of 2 or 3, and five were monitored in the intensive care unit and all patients survived. Development of seizures and deep unconsciousness were common features. All cases except one also tested positive for other NPS and/or classical psychoactive compounds, hampering the possibility to establish a causal relationship between drug and toxic symptoms. MDMB-CHMICA was also identified in seven drug materials donated by the patients. Conclusions The association with severe adverse reactions in nine acute analytically confirmed intoxication cases involving MDMB-CHMICA is consistent with other reports of serious toxicity linked to this substance, suggesting that MDMB-CHMICA might be a particularly harmful SC.

Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used. Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential in vivo therapeutic effects in relation to cannabinoid receptors. From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity. Therefore, it is believed that discovering novel cannabinoids starting from studying the biodiversity of the species living on planet earth is an uncharted territory.

Introduction Despite 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. Methods A 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. Results Half (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. Conclusions Among 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.

Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at μ-opioid receptors and γ-aminobutyric acid-A (GABAA) or GABAB receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-d-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.

New psychoactive substances (NPS) are a heterogeneous group of substances. They are associated with a number of health and social harms on an individual and societal level. NPS toxicity and dependence syndromes are recognised in primary care, emergency departments, psychiatric inpatient and community care settings. One pragmatic classification system is to divide NPS into one of four groups: synthetic stimulants, synthetic cannabinoids, synthetic hallucinogens and synthetic depressants (which include synthetic opioids and benzodiazepines). We review these four classes of NPS, including their chemical structures, mechanism of action, modes of use, intended intoxicant effects, and their associated physical and mental health harms. The current challenges faced by laboratory testing for NPS are also explored, in the context of the diverse range of NPS currently available, rate of production and emergence of new substances, the different formulations, and methods of acquisition and distribution.

The synthetic cannabinoid receptor agonist (SCRA) market is undergoing important changes since the enactment of the 2021 class-wide generic SCRA ban in China, one of the most important source countries for new psychoactive substances (NPS). Recently, various compounds with new structural features, synthesized to bypass this legislation, have entered the recreational drug market. Certain monocyclic pyrazole-carrying “FUPPYCA” SCRAs have been sporadically detected since 2015 without gaining further popularity. However, as evidenced by their recent detection in Scottish prisons, 5F-3,5-AB-PFUPPYCA and 3,5-ADB-4en-PFUPPYCA have re-emerged, potentially triggered by the new legislative ban. The aim of this study was to characterize the in vitro intrinsic CB1 and CB2 receptor activation potential of 5F-3,5-AB-PFUPPYCA and 3,5-ADB-4en-PFUPPYCA, as well as 4 analogs (5F-3,5-ADB-PFUPPYCA, 3,5-AB-CHMFUPPYCA, 5,3-AB-CHMFUPPYCA and 5,3-ADB-4en-PFUPPYCA) using live cell β-arrestin 2 recruitment assays. Most analogs were essentially inactive at either CB1 or CB2, with only 3,5-AB-CHMFUPPYCA, 5,3-AB-CHMFUPPYCA and 5,3-ADB-4en-PFUPPYCA showing a limited activation potential at CB1. Furthermore, the importance of the position of the tail structure was demonstrated, with 5,3 regioisomers being more active than their 3,5 analogs. Moreover, all compounds exhibited antagonistic behavior at both receptors, which may be associated with their structural resemblance to cannabinoid antagonists and inverse agonists. Although the 3,5 regioisomers of these “FUPPYCA” SCRAs circumvent the Chinese ban, it is unlikely that these SCRAs will pose a major threat to public health, given the lack of pronounced CB receptor activity. [Display omitted] •Generic ban-evading pyrazole FUPPYCA SCRAs have been detected in Scottish prisons.•Activity at CB1 and CB2 receptor of 6 analogs was found to be limited.•All tested compounds show signs of antagonism.