Synthetic Cannabinoid Toxicity Research Articles

Cannabis use in the intensive care setting: A scoping review

PurposeCannabis is the most used recreational drug worldwide, and is increasingly used for medicinal purposes, however little is known about its impact on patients in intensive care units (ICU). Our objective was to identify key themes in the literature surrounding cannabis in the ICU and identify future research priorities. MethodsFour databases were systematically searched for literature investigating the impact of cannabis, and evidence for its therapeutic use, in adult ICU patients. ResultsOf 2589 articles screened, 22 articles were included for analysis. Cannabis-associated admissions were primarily related to an outbreak of vaping associated lung injury, and synthetic cannabinoid toxicity. Studies on the impact of cannabis use on outcomes were mostly limited to trauma and burns populations, with an inconsistent mortality benefit, and a trend towards increased pain scores and analgesic requirements found. There is minimal research on its therapeutic uses in ICU, with two trials investigating the use of a synthetic cannabinoid in patients with severe traumatic brain injury, with ultimately no significant effect on intracranial pressure found. ConclusionsThere is a paucity of studies investigating the impact of cannabinoids or their therapeutic uses in critically ill patients, with further research in this area needed.

Toxicity of Synthetic Cannabinoids in K2/Spice: A Systematic Review.

(1) Background: Synthetic cannabinoids (SCs) are emerging drugs of abuse sold as 'K2', 'K9' or 'Spice'. Evidence shows that using SCs products leads to greater health risks than cannabis. They have been associated with greater toxicity and higher addiction potential unrelated to the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). Moreover, early cases of intoxication and death related to SCs highlight the inherent danger that may accompany the use of these substances. However, there is limited knowledge of the toxicology of Spice ingredients. This systematic review intends to analyze the toxicity of SCs compounds in Spice/K2 drugs. (2) Methods: Studies analyzing synthetic cannabinoid toxicity and dependence were included in the present review. We searched the PubMed database of the US National Library of Medicine, Google Scholar, CompTox Chemicals, and Web of Science up to May 2022. (3) Results: Sixty-four articles reporting the effects of synthetic cannabinoids in humans were included in our review. Ten original papers and fifty-four case studies were also included. Fourteen studies reported death associated with synthetic cannabinoid use, with AB-CHMINACA and MDMB-CHMICA being the main reported SCs. Tachycardia and seizures were the most common toxicity symptoms. The prevalence of neuropsychiatric symptoms was higher in third-generation SCs. (4) Conclusion: SCs may exhibit higher toxicity than THC and longer-lasting effects. Their use may be harmful, especially in people with epilepsy and schizophrenia, because of the increased risk of the precipitation of psychiatric and neurologic disorders. Compared to other drugs, SCs have a higher potential to trigger a convulsive crisis, a decline in consciousness, and hemodynamic changes. Therefore, it is crucial to clarify their potential harms and increase the availability of toxicology data in both clinical and research settings.

Subcutaneous Emphysema, Pneumothorax, Pneumomediastinum, and Pneumoperitoneum Following Synthetic Cannabinoid Toxicity in an Incarcerated Man.

Synthetic cannabinoids are a recreational drug that can cause toxicity with significant side effects. We report a 21-year-old incarcerated male with a delayed presentation of pneumothorax, pneumomediastinum, and pneumoperitoneum following synthetic cannabinoid use with altered mental status. This case not only highlights the need to consider pneumothorax when evaluating synthetic cannabinoid toxicity but it also emphasizes a vulnerable population (incarcerated individuals at risk for trauma, substance use disorders, and mental illness) who are at risk for delayed medical care and poor follow-up.

Adulteration of low-delta-9-tetrahydrocannabinol products with synthetic cannabinoids: Results from drug checking services.

Since late 2019, low‐delta‐9‐tetrahydrocannabinol (THC) preparations adulterated with synthetic cannabinoids (SCs) have been frequently observed in Switzerland. The unawareness of users concerning the presence of SCs and the typically higher potency and toxicity of SCs, when compared with THC, can result in increased health risks. In Switzerland, low‐THC (<1%) cannabis products, except hashish, are legal. These products can act as carrier materials for SCs. In this study, cannabis samples and user self‐reports received through three drug checking services were collected and analysed, to gain deeper insight into this new phenomenon. Samples were collected from January 2020 to July 2021. Liquid chromatography coupled with high‐resolution mass spectrometry was used for the qualitative screening and semi‐quantification of SCs, while gas chromatography with flame ionization detector was applied for the quantification of THC and cannabidiol levels. Reported adverse effects were compared between users who consumed adulterated (SC‐group) and non‐adulterated (THC‐group) products. Of a total 94 samples, 50% contained up to three different SCs. MDMB‐4en‐PINACA was most often detected. All adulterated cannabis flowers contained ≤1% THC. Adulterated hashish also typically presented low THC‐levels (median: 0.8%). The SC‐group was associated with higher numbers of adverse events (p = 0.041). Furthermore, psychologic (p = 0.0007) and cardiologic (p = 0.020) adverse effects were more profound in the SC‐group than in the THC‐group. Drug checking services enabled the timely detection and monitoring of new and potentially dangerous trends. Furthermore, due to user‐reports, additional valuable information was gained on adverse events associated with the consumption of novel SCs.

Near-Fatal Spice Intoxication of a Toddler

Synthetic cannabinoids are a heterogenous group of novel, legally regulated psychoactive substances that can result in broad, multisystemic, dangerous effects. Despite growing literature regarding synthetic cannabinoid toxicity, little is known about the extent of these effects in young children. Caregivers of drug-endangered children may not provide an accurate history of exposure when children present with symptoms of intoxication, and lack of swift detection on routine urine drug screens may further obscure and delay the diagnosis. Clinical recognition carries forensic relevance that may support interventions to aid in protecting vulnerable children. We describe a case of near-fatal child maltreatment due to supervisory neglect resulting from ingestion of an increasingly common synthetic cannabinoid. Furthermore, we highlight clinical findings that should increase a physician's index of suspicion for synthetic cannabinoid toxicity, even in the absence of a history of exposure.

Major Metabolites of the Synthetic Cannabinoid 5F‐ADB Retain High Affinity and Full Efficacy at CB1 Receptors; Potential Mechanism Contributing to Enhanced Toxicity?

Synthetic cannabinoids (SCs) are a large group of abused psychoactive compounds that elicit numerous toxic effects not observed with marijuana, including death. SCs are abused worldwide and metabolites of these drugs are often detected as a means of drug identification. SC metabolites resulting from Phase I metabolism have been shown to retain affinity and activity at cannabinoid receptors. However, whether these active compounds contribute to toxicity of SCs is unknown. 5-Fluoro-ADB (5F-ADB), also known as 5-Fluoro-MDMB-PINACA, is a commonly abused third-generation synthetic cannabinoid agonist based on an indazole-structure. Significantly, over 40 recent fatalities have been attributed to 5F-ADB overdose. A potential mechanism underlying 5F-ADB-induced mortality is drug-related dysrhythmia resulting in sudden death. Analysis of postmortem central and peripheral blood samples have revealed abnormally high concentrations of an ester-hydrolysis Phase I metabolite of 5F-ADB, identified as metabolite 7 (5F-ADB-M7). We propose that high concentrations of potent and efficacious active metabolites, such as 5F-ADB-M7 and others, accumulate with the parent drug 5F-ADB and produce additive and/or synergistic effects that possibly contribute to fatal intoxication following overdose. As a first step to test this hypothesis, in vitro studies were conducted to compare the affinity and activity of tetrahydrocannabinol (THC; the primary psychoactive component in marijuana), 5F-ADB, 5F-ADB-M7 and a second major metabolite, 5F-ADB-M2 at cannabinoid type-1 (CB1) receptors. Competition receptor binding studies, using mouse brain membranes, showed that all four cannabinoids bound with high affinity to CB1 receptors with a rank order of affinity (Ki values) of 5F-ADB > 5F-ADB-M2 > THC > 5F-ADB-M7. Furthermore, functional experiments examining modulation of G-protein activity demonstrated that 5F-ADB and both Phase I metabolites acted as full agonists at CB1 receptors, relative to partial agonist effects produced by THC. Subsequently, in vivo studies were conducted utilizing the cannabinoid tetrad in mice to compare the effects of THC with those of 5F-ADB-M2. Both 5F-ADB-M2 and THC produced CB1-mediated dose-dependent hypothermia, analgesia, and locomotor suppression, within 30 minutes of injection; however, catalepsy was not elicited by the metabolite. Consistent with higher CB1 affinity determined from in vitro studies, 5F-ADB-M2 produced tetrad effects with higher potency compared to THC. Future studies are planned to examine in vivo effects of 5F-ADB-M7 compared to THC. If 5F-ADB metabolites exhibit in vivo activity similar to that predicted from the in vitro studies presented here, this suggests that the enhanced, often fatal, effects of 5F-ADB may be due to an accumulation of the parent and active, high affinity metabolites acting at CB1 receptors.

Toxicity of synthetic cannabinoids is increasing along with the regulatory measures taken for their control

Introduction Novel psychoactive substances (NPS) represent a rising public health threat due to the associated side effects and the lack of success on their control policies. NPS are freely sold, mostly on the internet, as legal and safe replacements of controlled drugs of abuse. Synthetic cannabinoids (SCs) represent one of the largest groups of NPS and are designed as mimetics of Δ9-tetrahydrocannabinol from cannabis [1]. After the identification of JWH-018, the first SC appearing on the market, many countries took measures to control the free circulation of these products [2]. Nevertheless, efforts to control them are rapidly contoured, since clandestine manufacturers are constantly changing their chemical structures leading to previously unknown SCs [3]. The aim of this study is to show how chemical changes on recent generations of SCs to evade the law lead to the production of more harmful compounds, with potential application in forensic context. With that purpose, the toxicity of three SCs, representatives of the first, second and third generations [4], was assessed. Materials and methods The SC JWH-018 was obtained as >98.5% pure powders from Lipomed AG Switzerland. SCs THJ-018 and EG-018 were bought through an internet website (www.chem.eu). THJ-018 and EG-018 were purified through HPLC/DAD and confirmed by GC/MS. Pure SCs stock solutions were prepared in 100% DMSO accordingly to the stipulated final concentrations and diluted into the culture medium prior addition to cells. The neuroblastoma human cell line SH-SY5Y was exposed, for 24 h, to several concentrations of each SC. Cell toxicity was evaluated through MTT assays. Results Figure 1 shows the MTT results for SH-SY5Y viability in the presence of JWH-018, THJ-018 and EG-018. SH-SY5Y cells viability does not decrease in the presence of JWH-018 at the range of concentrations used. However, when the same cell line is exposed to THJ-018 or EG-018 there is a decrease in cell viability with the increase in the concentration of these substances. Discussion and conclusions: The results from the present study points THJ-018 and EG-018, JWH-018 analogues of 2nd and 3rd generations, as more toxic to the neuroblastoma cells than JWH-018, the first SC found on the street market. These results suggest that emerging modified SCs, to avoid the law, are becoming more toxic and dangerous. Given the emergence of this situation, it is time to rethink current legislation to prevent rise on public health issues derived from consumption of molecules of unknown toxicological profile. Figure 1. Cytotoxic evaluation by MTT assay of JWH-018, THJ-018 and EG-018 in SH-SY5Y cells. Data are expressed as the mean ± SD (n = 3).

Saccharomyces cerevisiae as a model to study synthetic cannabinoids: the impact of using different carbon sources

Introduction Synthetic cannabinoids (SC) are potent agonists of cannabinoid receptors, that mime the psychoactive effect of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive component of cannabis [1]. JWH-018 was the first novel psychoactive SC found in the recreational drug marketplace in 2008. A few years later, JWH-018 started to be controlled by authorities, so alternative molecules started to emerge. THJ-018 was designed to replace JWH-018, having a similar structural skeleton and also a naphthalene and pentyl chain connected via a middle core substructure. Eventually, THJ-018 was scheduled and alternatives emerged, such as EG-018 [2]. This practice makes almost impossible to characterise SC toxicological profiles on an acceptable time scale, mostly due to the time-consuming experiments that must be held in animal models or human cells by standard methods. The yeast Saccharomyces cerevisiae shares highly conserved molecular and cellular mechanisms with human cells and has been used before for synthetic cathinones [3]. The present work has studied the best carbon source (glucose or galactose) to measure the impact of synthetic cannabinoids on S. cerevisiae growth, aiming to develop a method able to profile synthetic cannabinoids toxicity in a short time scale. The difference between carbon sources is that in Crabtree-positive yeast strains, glucose induce a strong inhibition of mitochondrial oxidative phosphorylation [4]. Materials and methods The effect of EG-018 was evaluated by its impact on S. cerevisiae BY4741 (WT) growth on minimal medium with 2% Glucose or 1% Galactose as sole carbon sources, in the presence and absence of the SC, followed at OD600nm. Growth rates at each condition was fitted to a logistic equation. Results Figure 1 shows OD600max obtained from the non-linear regression to the logistic equation in the presence of different concentrations of EG-018. While in galactose there is no effect, in 2% Glucose the results points to a growth decrease with EG-018. Discussion and conclusions: Comparing the two carbon sources, yeast growth on glucose is more susceptible to EG-018. Recent studies points that JWH-018, a similar SC, exerts an effect on glycolytic and pentose phosphate pathway at high concentrations of glucose (personal communication). As yeast growth in galactose proceeds simultaneously via respiration and fermentation due to the “Crabtree effect” [4] an impact of EG-018 on glycolysis might be less effective. These results, suggest that glucose is the best carbon source to develop a yeast based toxicity sensor for SC. Figure 1. OD600max results in S. cerevisiae BY4741 in the presence of 0, 25 and 50 µM of EG-018 in glucose and galactose.

Pattern of Acute Synthetic Cannabinoids Toxicity in Patients Presented to the Poison Control Center of Ain Shams University Hospitals

Background: Toxicity by synthetic cannabinoids (SCs) is increasing steadily with limited data concerning their use. Serious adverse effects after acute exposure to SCs include myocardial ischemia, stroke, seizures, coma, and acute kidney injury. Aim: Characterization of the epidemiological pattern of acute toxicity by SCs in patients presented to Poison Control Center of Ain Shams University hospitals (PCC-ASUH), Cairo, Egypt; from January 2018 to June 2019, and severity assessment using poisoning severity score (PSS). Methods: A cross-sectional study included adult patients presented to emergency department of PCC-ASUH from January 2018 to June 2019, with history of acute exposure to SCs. Results: About 541 patients attended the PCC-ASUH with history of acute SCs toxicity and only 448 patients were enrolled to our study. Males outnumbered females (96.43 versus 3.57%, respectively). Strox predominated (72.54%) followed by voodoo (27.45%). Recorded PSS was minor in 42.63% of patients, moderate in 18.97% and severe in 5.36%. Two patients (0.45%) died. Metabolic abnormalities predominated (60%), followed by gastrointestinal manifestations (46.2%). Conclusion: Incidence of SCs toxicity has recently increased. Several variables could worsen PSS in acute SCs poisoning like age, sex, type of SCs, co-ingestion, medical comorbidities, and respiratory acidosis. Recommendations: Early combination of PSS and arterial blood gas analysis could help in identifying patients at risk for acute SCs toxicity.

Evaluation of CB1 antagonists as antidotes for synthetic cannabinoid toxicity in male and female mice

While a plethora of recreational marijuana and cannabis derived products have been legalized across the United States, recent trends also indicate an increase in the number of emergency calls relating to the overdose or accidental exposure to Δ9‐tetrahydrocannabinol (THC) and/or synthetic psychoactive cannabinoids. There are currently no FDA approved medications for treating acute cannabinoid toxicity. To address this public health issue, here we provide key data towards the discovery and development of an effective antidote for treating acute toxicity symptoms that may be associated with cannabis overdose, and by ingestion of certain cannabimimetics such as the potent CB1 receptor agonist JWH‐018. Previously, we established proof‐of‐concept and presented preliminary data showing that the novel CB1 antagonist AM11503 (10 mg/kg, i.v.) effectively reversed the hypothermic effects of an acute dose of JWH‐018 (6 mg/kg, i.p.), effects that were similar to the known CB1 antagonist rimonabant (10 mg/kg, i.v.). Herein, we extend this line of research in male and female CD‐1 mice by: a) examining whether AM11503 induces rimonabant‐like effects on observable behavior; b) assessing the ability of AM11503 to prevent JWH‐018‐mediated tremors and convulsions; and c) comparing the ability of AM11503 and rimonabant to precipitate somatic signs of withdrawal in JWH‐018‐dependent mice. Results show that rimonabant (3.2–32 mg/kg, i.v.) produced a dose‐related increase in scratching and grooming in both male and female mice compared to controls, whereas AM11503 (3.2–32 mg/kg, i.v.) did not alter stereotypic behavior. In interaction studies, administration of 10 mg/kg (i.v.) AM11503 fully blocked tremors and convulsions induced by “suprapharmacological” doses of JWH‐018 (18 mg/kg, i.p.). Finally, rimonabant (10 mg/kg, i.v.) induced significant somatic signs of withdrawal, i.e., head twitches and paw tremors, in male and female mice that were repeatedly exposed to JWH‐018 (3 mg/kg, i.p. once per day for 6 days) compared to vehicle‐treated subjects. In contrast, AM11503 (10 mg/kg, i.v.) did not induce somatic signs of withdrawal in JWH‐018‐dependent mice and effects were similar to vehicle‐treated mice. In conjunction, the inability of AM11503 to produce rimonabant‐like stereotypic behaviors and precipitate somatic signs of withdrawal yet prevent CB1 agonist‐induced acute toxicity allows for the identification and development of safer CB1 antagonist‐based therapies for nullifying synthetic cannabinoid toxicity.Support or Funding InformationFunding Information: Work supported by NIDA/NIH grants R21DA045882 and R41DA044048

Uses, Effects and Toxicity of Synthetic Cannabinoids from the Perspective of People with Lived Experiences

ABSTRACT Synthetic cannabinoids (SCs) are a class of synthetic chemicals with cannabis-like properties, and little is known about their pharmacological and toxicological effects. The objective of this study was to explore the effects of SCs and the underlying motivations of use among participants with lived experiences. Content analysis of experiences of people using SCs was carried out based on online discussions. A total of 1660 posts from 50 threads between 2004 and 2016 were examined. Relevant information was recorded on characteristics of users as well as on characteristics of SCs, the modality of their use, and the SC-related experienced effects and toxicity. Users exchanged online significant information on SCs consumption. While a growing amount of attention has been given to the chemical and pharmacological profile of SCs, very little is known about the subjective components of such use. It remains important to study the lived experiences of people who used novel psychoactive substances (NPSs) to implement prevention and treatment, and to guide future research in the field.

Neuropsychiatric Sequelae in Adolescents With Acute Synthetic Cannabinoid Toxicity

Amongst users of synthetic cannabinoids, adolescents make up the largest group that present to the Emergency Department. Compared to tetrahydrocannabinol (cannabinoids), synthetic cannabinoids (SC) have more adverse cardiotoxic and neurotoxic effects, especially in pediatric populations. Patients seek medical attention after SC abuse 30 times more than cannabis. The acute neuropsychiatric toxicities that adolescents experience after SC abuse are poorly understood. The goal of this study was to better characterize the neuropsychiatric toxicities of SC use compared to cannabis.

Neuropsychiatric Sequelae in Adolescents With Acute Synthetic Cannabinoid Toxicity.

Adolescents represent the largest age group that presents to emergency departments (ED) for synthetic cannabinoid (SC) toxicity; however, the neurotoxic effects of acute SC exposures in this group are understudied. Our aim was to characterize the neuropsychiatric presentation of adolescents with SC-related exposure in the ED compared with those with traditional cannabis exposure. A multicenter registry of clinical information prospectively collected by medical toxicologists (Toxicology Investigators Consortium Case Registry) was reviewed for adolescents presenting to the ED after SC or cannabis exposure from 2010 through 2018. Associations were measured between drug exposures and neuropsychiatric symptoms and/or signs. Exposures were classified into 4 groups: SC-only exposure, SC-polydrug exposures, cannabis-only exposure, and cannabis-polydrug exposures. Adolescents presenting to the ED with SC-only exposure (n = 107) had higher odds of coma and/or central nervous system depression (odds ratio [OR] 3.42; 95% confidence interval [CI] 1.51-7.75) and seizures (OR 3.89; 95% CI 1.39-10.94) than those with cannabis-only exposure (n = 86). SC-only drug exposure was associated with lower odds of agitation than cannabis-only exposure (OR 0.18; 95% CI 0.10-0.34). In contrast, the group with SC-polydrug exposures (n = 38) had higher odds of agitation (OR 3.11; 95% CI 1.56-7.44) and seizures (OR 4.8; 95% CI 1.80-12.74) than the cannabis-polydrug exposures group (n = 117). In this multisite cohort of US adolescents assessed in the ED, SC exposure was associated with higher odds of neuropsychiatric morbidity than cannabis exposure providing a distinct neurospychiatric profile of acute SC toxicity in adolescents.

Synthetic cannabinoids: A review of the clinical implications of a new drug of choice.

Synthetic marijuana use is an emerging public health problem in the United States, and can cause agitation, severe psychosis, bizarre hallucinations, and possibly death. This article describes these products, which are unregulated and can vary widely in composition, and how clinicians can recognize patients with synthetic cannabinoid toxicity and treat them appropriately to minimize morbidity and mortality.

Qualitative Analysis and Detection of the Pyrolytic Products of JWH-018 and 11 Additional Synthetic Cannabinoids in the Presence of Common Herbal Smoking Substrates.

Synthetic cannabinoids have become a ubiquitous challenge in forensic toxicology and seized drug analysis. Thermal degradation products have yet to be identified and evaluated for toxicity in comparison to parent and metabolic compounds. An investigation into these pyrolytic products, as the major route of ingestion is inhalation, may produce additional insight to understand the toxicity of synthetic cannabinoids. The pyrolysis of JWH-018 and 11 additional synthetic cannabinoids and six herbal plant substrates were conducted using an in-house constructed smoking simulator. After pyrolysis of herbal material alone, the plant substrate was spiked with the drug compounds to 2-5% w/w concentrations. Samples were collected, filtered, evaporated under nitrogen gas, reconstituted in methanol, and analyzed via gas chromatograph-mass spectrometer. Pyrolysis of the plant material alone produced 10 consistently observed compounds between the six plant species. The pyrolysis of the synthetic cannabinoids produced a total of 52 pyrolytic compounds, where 32 were unique to a particular parent compound and the remaining 20 were common products between multiple cannabinoids. The thermal degradation followed three major pathways that are outlined to assist in producing a predictive model for new synthetic cannabinoids that may arise in case samples. The observed pyrolytic products are also viable options for analysis in post mortem samples and the evaluation of toxicity.

Supraventricular tachycardia and acute confusion following ingestion of e-cigarette fluid containing AB-FUBINACA and ADB-FUBINACA: a case report with quantitative analysis of serum drug concentrations

Background: AB-FUBINACA and ADB-FUBINACA are structurally similar synthetic cannabinoids with potent CB1 receptor agonistic effects. Very little is known about their pharmacology and toxicology.Objective: To report a case of supraventricular tachycardia and acute confusion after ingestion of e-cigarette fluid containing AB-FUBINACA and ADB-FUBINACA, with quantitative analysis of the serum drug concentrations.Case report: A healthy 24-year-old man ingested two drops of e-cigarette fluid which were later found to contain AB-FUBINACA and ADB-FUBINACA. Within 30 min of ingestion, he became somnolent, confused, and agitated, with palpitation and vomiting. On arrival to the emergency department, a short run of supraventricular tachycardia was noted, which resolved spontaneously. Bedside urine immunoassay failed to detect recreational drugs. Laboratory blood tests showed mild hypokalemia. Exposure to AB-FUBINACA and ADB-FUBINACA was confirmed analytically, with serum concentrations of 5.6 ng/mL and 15.6 ng/mL, respectively, in the blood sample collected on presentation. The patient recovered uneventfully with supportive treatment and was discharged 22 h after admission.Discussion: AB-FUBINACA and ADB-FUBINACA are orally bioavailable with rapid onset of toxicity after ingestion. In this case, supraventricular tachycardia was likely the result of exposure to AB-FUBINACA and ADB-FUBINACA. The serum concentrations of AB-FUBINACA and ADB-FUBINACA were higher than those previously reported in fatal cases.Conclusion: In the context of acute poisoning, the presence of unexplained tachyarrhythmias, confusion, and a negative recreational drug screen should prompt clinicians to consider synthetic cannabinoid toxicity as a differential diagnosis.

Characteristics and Treatment of Patients with Clinical Illness Due to Synthetic Cannabinoid Inhalation Reported by Medical Toxicologists: A ToxIC Database Study.

Synthetic cannabinoid (SC) abuse has resulted in numerous outbreaks of severe clinical illness across the United States over the past decade. The primary objective of this study was to determine the clinical characteristics of patients abusing SC requiring bedside consultation by medical toxicologists. This was a multicenter analysis from a prospectively collected cohort of patients presenting to medical care after synthetic cannabinoid exposure, utilizing the ToxIC Registry. Management of cases by medical toxicologists in this cohort occurred in emergency departments, inpatient medical floors, and intensive care units. Cases were identified from January 5, 2010 - July 31, 2015. We characterized the clinical presentations, treatments, outcomes, and sociologic factors associated with SC use in these patients. Medical toxicologists participating in the ToxIC Registry cared for 39,925 cases between 2010 and 2015. Three hundred fifty three of these cases were determined to be SC toxicity. The median age of patients was 25 (IQR: 18, 36) and the majority were males (84%). The most common symptoms were agitation, delirium and toxic psychosis, n=146 (41%). Forty-four (12.5%) had heart rates above 140 beats per minute. Bradycardia was the second most commonly reported severe vital sign abnormality with 20 (5.7%) having heart rates of less than 50 beats per minute. Fifteen (4.2%) patients had hypotension. Fifty-nine (17%) had seizures. The most common pharmacologic treatment provided was benzodiazepines (n=131, 37%) followed by antipsychotics (n=36, 10%).Disposition was available for 276; of these 167 (61%) were managed in the emergency department, 42 (15%) were admitted to the hospital floor, and 67 (24%) were admitted to the ICU. Synthetic cannabinoids are associated with severe central nervous system and cardiovascular effects.

Acute and residual effects in adolescent rats resulting from exposure to the novel synthetic cannabinoids AB-PINACA and AB-FUBINACA.

Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with ∆9-tetrahydrocannabinol (THC) and control treatments. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB-FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 × 1 mg/kg and 6 × 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1α and IL-12 were reduced by AB-FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation.

Signs and symptoms associated with synthetic cannabinoid toxicity: systematic review.

Use of synthetic cannabinoids is associated with significant physical and psychological harms. This research quantified reported toxicities from published reports and assessed the influence of size of the reported study population on rates of symptom reporting. Systematic review of published case reports and case series of toxicity associated with use of synthetic cannabinoids. Symptoms associated with synthetic cannabinoid toxicity were reported for 3695 individuals, predominantly young males. Symptoms included physiological (e.g. tachycardia, hypertension, nausea/vomiting), emotional (e.g. agitation, irritability, paranoia), behavioural (e.g. drowsiness, aggression) and perceptual (e.g. hallucinations) domains. Most common symptoms were tachycardia (30.2% of cases), agitation (13.5%), drowsiness (12.3%), nausea/vomiting (8.2%) and hallucinations (7.6%). Death or serious medical complications were uncommon (e.g. death 0.2%, stroke 0.1%, myocardial infarction 0.09%). Case reports/smaller case series (n<10) reported statistically significantly higher rates for 29/34 symptoms than larger case series (n≥10), which could represent selection bias. Symptoms of synthetic cannabinoid toxicity are variable and cover a number of physical and psychological domains. Symptom reporting varies by study population size. Due to the variable presenting symptoms of synthetic cannabinoid toxicity, clinicians in emergency services should consider synthetic cannabinoid toxicity when evaluating young adult male patients presenting with unexplained agitation or cardiovascular symptoms.

Adverse Effects of Synthetic Cannabinoids: Management of Acute Toxicity and Withdrawal.

Although several chemical structural classes of synthetic cannabinoids (SCs) were recently classified as Schedule I substances, rates of use and cases of serious toxic effects remain high. While case reports and media bring attention to severe SC toxicity, daily SC use resulting in dependence and withdrawal is a significant concern that is often overlooked when discussing the risks of these drugs. There is a rich literature on evidence-based approaches to treating substance use disorders associated with most abused drugs, yet little has been published regarding how to best treat symptoms related to SC dependence given its recency as an emerging clinically significant issue. This review provides a background of the pharmacology of SCs, recent findings of adverse effects associated with both acute intoxication and withdrawal as a consequence of daily use, and treatment approaches that have been implemented to address these issues, with an emphasis on pharmacotherapies for managing detoxification. In order to determine prevalence of use in cannabis smokers, a population at high risk for SC use, we obtained data on demographics of SC users, frequency of use, and adverse effects over a 3.5-year period (2012-2015) in the New York City metropolitan area, a region with a recent history of high SC use. While controlled studies on the physiological and behavioral effects of SCs are lacking, it is clear that risks associated with using these drugs pertain not only to the unpredictable and severe nature of acute intoxication but also to the effects of long-term, chronic use. Recent reports in the literature parallel findings from our survey, indicating that there is a subset of people who use SCs daily. Although withdrawal has not been systematically characterized and effective treatments have yet to be elucidated, some symptom relief has been reported with benzodiazepines and the atypical antipsychotic, quetiapine. Given the continued use and abuse of SCs, empirical studies characterizing (1) SCs acute effects, (2) withdrawal upon cessation of use, and (3) effective treatment strategies for SC use disorder are urgently needed.