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Synthetic Cannabinoids-Further Evidence Supporting the Relationship Between Cannabinoids and Psychosis
Abstract
Consumption of synthetic mind-altering compounds, also known as “new psychoactive substances”, is increasing globally at an alarming rate. Synthetic cannabinoids are among the most commonly used new psychoactive substances. They are usually purchased as marijuana-like drugs, marketed as herbal blends and perceived as risk-free by inexperienced users. Yet, contrary to Tetrahydrocannabinol (THC), synthetic cannabinoids may lead to severe health consequences, including anxiety, tachycardia, hallucinations, violent behavior and psychosis. This review focuses on the latest (2010–2015) evidence of psychotic symptoms induced by ingestion of products containing synthetic cannabinoids. Reports suggesting that synthetic cannabinoids may either exacerbate previously stable psychotic symptoms (in vulnerable individuals) or trigger new-onset psychosis (in subjects with no previous history of psychosis) are reviewed. Pharmacology and toxicology of these compounds are discussed, with particular reference to their psychoactive effects.
... Synthetic cannabinoids (SCs), which are the most numerous and diverse group of NPS, cause more frequent and severe side effects than cannabis, while being more difficult to detect by regular tests [28]. Most SCs users are adolescents and the lifetime prevalence of SCs use is 0.2-4% in the general population [28][29][30]. SCs are full CB1 receptor agonists, with much higher affinity than cannabis. They produce an effect similar to THC but stronger [29]. ...
... SCs are full CB1 receptor agonists, with much higher affinity than cannabis. They produce an effect similar to THC but stronger [29]. ...
... Case reports suggest that patients with premorbid psychiatric entities are more likely to develop SC-induced psychosis than the general population [29]. SCs cause paranoid delusions, dissociative thinking, hallucinations, suicidal thoughts, flattened affect, psychomotor inhibition, alogy, memory impairment, deficits in verbal learning, making decisions, attention, and executive functions [30]. ...
Purpose of Review
Novel integrative reviews that give detail information regarding various psychoactive substances (PS) with ability of inducing psychosis in adults are lacking. This review aims to scope the latest knowledge about substance-induced psychosis (SIP) through the comprehensive review of the most common misused PS inducing psychosis.
Recent Findings
Epidemiological data on the prevalence of SIP are insufficiently harmonized, so clear conclusions for most PS can not be drawn. Etiological mechanisms include three pathophysiological mechanisms: the modulation of GABA transmission, NMDA antagonism, and effects on the monoaminergic system. Beside positive symptoms, PS may induce negative and cognitive symptoms. There are no uniform therapeutic guidelines for specific SIP, but some antipsychotics appear to be more effective than others. It is likely that the conversion rate of SIP to schizophrenia may be higher in the future because novel PS with a higher psychotic potential are increasingly being consumed.
Summary
This review presents epidemiological data, etiological mechanisms, details of clinical pictures, and treatment options for psychoses induced by specific PS.
... Beyond the most relevant physical effects following acute SCB consumption that include diaphoresis, psychomotor agitation, palpitations, tachycardia, tachyarrhythmia, convulsion and hyperflexia (Chung et al., 2021;Zawilska & Wojcieszak, 2014), psychotic symptoms have also been reported, including perceptual alterations, illusions, paranoia, catatonia, depersonalization, hallucination, dissociation, anxiety and psychosis (Deng et al., 2018;Fattore, 2016;Orsolini et al., 2019). Interestingly, SCBs can precipitate psychosis in vulnerable individuals, by increasing the risk of developing mental disorders such as schizophrenia (van Amsterdam et al., 2015). ...
... Interestingly, SCBs can precipitate psychosis in vulnerable individuals, by increasing the risk of developing mental disorders such as schizophrenia (van Amsterdam et al., 2015). Notably SCBs, including JWH-018, are also able to induce psychotic symptoms in subjects with no previous history of psychosis (Deng et al., 2018;Fattore, 2016;Orsolini et al., 2019). ...
... While the acute effects of SCBs have been extensively reported (for details, see Fattore, 2016), much less is known about the consequences of repeated exposure to this synthetic cannabinoid. Recently, an elegant study from Pintori et al. (2021) employed a low dose of JWH-018 and showed behavioural and biochemical effects 7 days after drug discontinuation suggesting that repeated JWH-018 exposure induces long-lasting neuroplastic effects in the rodent brain. ...
Background and purpose:
Psychotic disorders have been reported in long-term users of synthetic cannabinoids. This study aims at investigating the long-lasting effects of repeated JWH-018 exposure.
Experimental approach:
Male CD-1 mice were injected with vehicle, JWH-018 (6 mg/kg), NESS-0327 (1mg/kg) and co-administration of NESS-0327 and JWH-018, every day for 7 days. After 15 or 16 days of washout, we investigated the effects of JWH-018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB1 receptors and the levels of the endocannabinoid anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their main synthetic and degrading enzymes in the striatum and hippocampus.
Key results:
The repeated treatment with JWH-018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. Moreover, JWH-018 disrupted hippocampal LTP and decreased BDNF expression. In addition, JWH-018 reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. The repeated exposure to JWH-018, also, reduced hippocampal CB1 receptor density and induced a long-term alteration in AEA and 2-AG levels and their degrading enzymes, FAAH and MAGL, in the striatum.
Conclusion:
Our findings suggest that repeated administration of a high dose of JWH-018 leads to the manifestation of psychotic-like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system.
... Compared with natural cannabis, the intoxication duration of SCs is shorter and they induce a quicker peak effect ( Winstock & Barratt, 2013 ). SCs are also associated with various types of adverse effects, some of which are not associated with natural cannabis use such as seizures, and long-term severe psychotic symptoms ( Fattore, 2016 ;Fattore & Fratta, 2011 ;Winstock & Barratt, 2013 ). ...
... Again, these compounds have greater affinity to endocannabinoid receptors than THC. In order to induce a greater psychoactive effect, these drugs contain additional psychoactive ingredients beside SCs, including preservatives, fatty acids, amides, esters, benzodiazepines, and opioids ( Fattore, 2016 ). Moreover, there is substantial diversity in the psychoactive constituents of different types of SC products even within same package. ...
... There is growing evidence that either acute or chronic consumption of SC drugs is associated with severe psychiatric and neurological conditions ( Gunderson et al., 2012 ;Müller et al., 2010 ;Papanti et al., 2013 ;Wells & Ott, 2011 ). Recent studies have suggested that SC may either exacerbate previously psychotic symptoms (in vulnerable individuals) or trigger new-onset psychosis (in individuals with no previous history of psychiatric conditions) ( Fattore, 2016 ). Recent studies in Europe have suggested that 15% of SC users who report to emergency departments present psychotic symptoms. ...
... There is a growing use of novel psychoactive substances (NPSs) which contain various psychoactive agents (1,2). Some of these NPSs contain Synthetic Cannabinoid (SC) compounds which are marketed as a natural herbal mixture under different brands names (3)(4)(5). These drugs are composed of multiple types of extremely potent synthetic cannabinoid-agonists as well as additional psychoactive constituents, of which some are unknown (5,6). ...
... Some of these NPSs contain Synthetic Cannabinoid (SC) compounds which are marketed as a natural herbal mixture under different brands names (3)(4)(5). These drugs are composed of multiple types of extremely potent synthetic cannabinoid-agonists as well as additional psychoactive constituents, of which some are unknown (5,6). The intoxicating effects of SC drugs are similar to the effects of cannabis, commonly with; SC drugs induce reactions such as relaxation, euphoria, perceptual disturbances, and alterations in cognitive abilities (7)(8)(9). ...
... Similar to herbal cannabis, SCs induce their effect through the activation of cannabinoid receptors (CB 1 and CB 2 ) within the Central Nerves System (CNS) (15). In contrast to the psychoactive and non-psychoactive compounds in herbal cannabis such as D-9tetrahydro-cannabinol (THC) and Cannabidiol (CBD) (3)(4)(5), SC drugs contain a mixture of psychoactive ingredients, which are more potent and efficacious at the CB 1 and CB 2 receptors (16)(17)(18). Therefore, although SC drugs are designed to mimic the effect of cannabis, their effects even in low doses are more severe, persistent and unpredictable (8,19,20). ...
Background
We have recently shown that chronic use of Synthetic Cannabinoids (SCs) has been associated with mood disorders and impairments in executive functions. There is also evidence indicating that chronic SC users have higher rates of comorbidity with depression and psychotic symptoms. Here, we investigate performance on executive function and emotional processing tasks in regular SC users and a measure of schizotypal traits.Method
Thirty chronic SC users, 32 recreational cannabis users, and 32 non-using control participants, without history of mental disorder, or current substance abuse diagnosis (mean age 26 ± 4.27 years; 85 males, 9 females), were tested in addiction treatment centers in Israel. Computerized neurocognitive function tests; the N-back task, Go/No-Go task, Wisconsin Sorting Card-like Task (WSCT), and emotional face recognition task and questionnaires of depression, anxiety and schizotypal traits and symptoms were used.ResultsSC users have performed worse than recreational cannabis users and non-cannabis users on the N-back working-memory task (lower accuracy) and the WSCT cognitive flexibility task. SC users showed greater schizotypal traits and symptoms compared with recreational cannabis users and non-user control participants. A positive association was found in cannabinoid-user groups between schizotypal traits and symptoms and cognitive and emotional processing measures. Finally, SC users have scored higher on depression and state-trait anxiety measures than recreational cannabis users or healthy control participants.Conclusions
Repeated use of SCs is associated with impairment in executive functions and emotional processing. These alterations are associated with depression and schizotypal traits and symptoms. This adds to existing evidence on the long-term consequences of SC drugs and their risks for mental health.
... A range of side-effects of SCRA intoxication are described, many overlapping with those seen after highdose cannabis intoxication (Fattore 2016). The present results suggest that SCRAs are more likely to induce negative side-effects (rapid heartbeat, nausea, hallucinations, chest pain, sweatiness, dizziness, and panic) than cannabis, although survey design limitations should be acknowledged. ...
... Some effects may be difficult to attribute due to variability in the psychoactive ingredients used in SCRA products. Age, gender and concurrent use of other substances may also impact the number and severity of self-reported effects (Fattore 2016;Barratt et al. 2013). ...
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.
... New psychoactive substances (NPS) are substances synthesized by making minor structural changes to the chemical formula of controlled natural or synthetic analogs [2]. According to the European Monitoring Center for Drugs and Drug Addiction (EMCDDA, 2017) [3], a significant part of the seized uncontrolled NPS refers to synthetic cannabinoids (SC) that received slang term "spice" [3,4]. Since September 2014, there have been periodically recorded cases of mass poisoning of persons whose urine tests revealed MDMB (N)-Bz-F tridimethylbutanoic acid of JWH group [5,6] in the Russian Federation. ...
... New psychoactive substances (NPS) are substances synthesized by making minor structural changes to the chemical formula of controlled natural or synthetic analogs [2]. According to the European Monitoring Center for Drugs and Drug Addiction (EMCDDA, 2017) [3], a significant part of the seized uncontrolled NPS refers to synthetic cannabinoids (SC) that received slang term "spice" [3,4]. Since September 2014, there have been periodically recorded cases of mass poisoning of persons whose urine tests revealed MDMB (N)-Bz-F tridimethylbutanoic acid of JWH group [5,6] in the Russian Federation. ...
In the last 10 years, virtually all countries have faced a change in the structure of drug use due to a decrease in the number of opiate along with an increase in the number of users of the so-called “new” psy-choactive substances Upon data collection from 126 patients, a dynamic clinical study of 356 psychotic states due to the use of synthetic cannabinoids was undertaken. Consecutive stages of development of psychosis along with its delirious, oneiroic, and amentive-like clinical variants were identified. The likelihood of development of psychosis and its clinical variants is determined by a complex of clinical, biological, psychopathological, and socio-psychological factors.A complex of clinical, biological and socio-psychological factors was shown to determine the pathokinetic patterns of development of psychosis due to the use of synthetic cannabinoids. It was established that as the clinical picture of psychosis worsens, the psychopathological symptoms of a deeper level develop (hallucinations - delusions - mental automatisms - motor disorders) with a simultaneous gradual depletion of a psychopathologi-cal picture of psychosis due to a narrowing range of existing productive symptoms.
... Case studies and epidemiological data affirm the link between the use of cannabis and psychosis (Every-Palmer 2010; Papanti et al. 2013;Peglow et al. 2012;Fattore 2016). In individuals with a preexisting psychotic disorder, cannabis can aggravate psychotic symptoms or induce a relapse, while it can evoke transient psychotomimetic symptoms in people with no prior history of the disorder (Volkow et al. 2016;Radhakrishnan et al. 2014). ...
... Synthetic cannabinoids produce stronger and more frequent psychotic effects because they are potent and full CB1 agonists (Fattore 2016). THC, on the other hand, is a partial agonist. ...
Background
Synthetic cannabinoids (SCs) are the largest class of novel psychoactive substances (NPS) and are associated with an increased risk of overdosing and adverse events such as psychosis. JWH-018 is one of the earliest SCs and still widely available in large parts of the world. Controlled studies to assess the safety and behavioural profiles of SCs are extremely scarce.
Aim
The current study was designed to assess the psychotomimetic effects of a moderate dose of JWH-018.
Methods
Twenty-four healthy participants (10 males, 14 females) entered a placebo-controlled, double blind, within-subjects trial and inhaled vapour of placebo or 75μg/kg bodyweight JWH-018. To ascertain a minimum level of intoxication, a booster dose of JWH-018 was administered on an as-needed basis. The average dose of JWH-018 administered was 5.52 mg. Subjective high, dissociative states (CADSS), psychedelic symptoms (Bowdle), mood (POMS) and cannabis reinforcement (SCRQ) were assessed within a 4.5-h time window after drug administration.
Results
JWH-018 caused psychedelic effects, such as altered internal and external perception, and dissociative effects, such as amnesia, derealisation and depersonalisation and induced feelings of confusion.
Conclusion
Overall, these findings suggest that a moderate dose of JWH-018 induces pronounced psychotomimetic symptoms in healthy participants with no history of mental illness, which confirms that SCs pose a serious risk for public health.
... Synthetic cannabinoids (SCs) and cathinones are among the most commonly used NPSs ( Assi et al., 2017, Fattore, 2016, with young men, who also use other substances, as typical users ( Graddy et al., 2018 ). SCs, for example, emerged as drugs of abuse in the late 2000s. ...
... SCs, for example, emerged as drugs of abuse in the late 2000s. Currently, more than 150 SCs are known, with new analogs appearing rapidly, marketed as herbal blends, and often perceived as risk-free by inexperienced users ( Armenian et al., 2018, Davidson et al., 2017, Fattore, 2016. Given SCs' structural complexity, there are ample chemical modification options that explain their market's scale and speed and make legal control and analytical detection extremely difficult ( Armenian et al., 2018, Potts et al., 2020. ...
... In addition, it has been demonstrated that SCs use is correlated with an increased risk of psychiatric disorders [34]. Psychosis, in particular, has been described as the most serious toxic effect of long term use of SCs that is not reported with natural cannabinoid use; this may be due to the protective effect of cannabidiol, which is a component of the natural compounds, but is not found in psychoactive SCs products [35]. Activation of CB1R and CB2R in the presynaptic membrane stimulates pertussis toxin-sensitive G proteins (G i/o ), which inhibits adenylyl cyclase and leads to a decrease in protein kinase A activity. ...
Synthetic cannabinoids (SCs) are chemically classified as psychoactive substances that target the endocannabinoid system in many body organs. SCs can initiate pathophysiological changes in many tissues which can be severe enough to damage the normal functionality of our body systems. The majority of SCs-related side effects are mediated by activating Cannabinoid Receptor 1 (CB1R) and Cannabinoid Receptor 2 (CB2R). The activation of these receptors can enkindle many downstream signalling pathways, including oxidative stress, inflammation, and apoptosis that ultimately can produce deleterious changes in many organs. Besides activating the cannabinoid receptors, SCs can act on non-cannabinoid targets, such as the orphan G protein receptors GPR55 and GPR18, the Peroxisome Proliferator-activated Receptors (PPARs), and the Transient receptor potential vanilloid 1 (TRPV1), which are broadly expressed in the brain and the heart and their activation mediates many pharmacological effects of SCs. In this review, we shed light on the multisystem complications found in SCs abusers, particularly discussing their neurologic, cardiovascular, renal, and hepatic effects, as well as highlighting the mechanisms that intermediate SCs-related pharmacological and toxicological consequences to provide comprehensive understanding of their short and long-term systemic effects.
Graphical Abstract
... For our review, we focused on studies involving patients with the following characteristics: 1) diagnosed with schizophrenic spectrum disorders or diagnosed with cannabis or SCs induced non-affective psychotic disorder; 2) current or past use of cannabinoids or SCs or other cannabis components; 3) presence of suicidal ideation/ attempt or death by suicide (we will use the expression 'suicide risk' to refer to these three scenarios); 4) only reports written in English. Specifically, we included all articles that reported on the effects of cannabis and synthetic cannabinoids (Fattore et al. 2016). In particular, considering that cannabis is a plant that contains multiple psychoactive components (Cohen et al. 2019), we chose to consider also the studies that reported the effects of the two main components: THC and CBD. ...
Proof of correlation between psychotic spectrum disorders and suicide are found in literature, as well as between cannabis use disorder (CUD) and suicide and between CUD and schizophrenia. The study population of the selected papers consists of subjects diagnosed with schizophrenia spectrum or cannabis or SCs induced psychosis. Our objective is to assess how suicide risk (defined as suicidal ideation/attempt or death by suicide) in this population may vary with exposure to cannabis or one of its main active compounds. We searched PubMed, Scopus and Psycinfo database from January 2010 to February 2022. Study designs of the included articles are distributed as follows: 6 cross-sectional studies, 3 cohort studies, 1 case-control studies, 1 randomized double-blind study, 1 case report. Selected cohort studies seem to agree in identifying an increased suicide risk in patients with schizophrenia spectrum disorders when exposed to cannabis use. The case-control study and selected cross-sectionals provide contradictory data. However, qualitative analysis seem to point toward a positive correlation between cannabis use and increased suicidal risk in patients with schizophrenia spectrum disorders. In conclusion, emerging data on the correlation between cannabis use and suicide risk in patients with schizophrenia or other schizophrenic spectrum disorders are insufficient to draw firm conclusions. Nonetheless these studies seem to suggest a positive correlation of cannabis use with increased suicide risk, particularly regarding first episode psychosis (FEP) and male gender. Clinicians should be aware of the possibility of a higher risk of suicidal behavior associated specifically with cannabis use for men and patients during FEP.
... However, severe sensory gating deficits were also observed 120 min after the injection of 1 mg/kg of MAM-2201 (Fig. 5). Thus, these findings confirm that abuse of these SC substances might result in severe information processing and sensory impairments as demonstrated by the numerous intoxication cases reported in the literature over the last years (Yeruva et al. 2019;Fattore 2016;Hermanns-Clausen et al. 2013;Every-Palmer 2010, 2011. ...
Rationale
1-[(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl) methanone (MAM-2201) is a potent synthetic cannabinoid receptor agonist illegally marketed in “spice” products and as “synthacaine” for its psychoactive effects. It is a naphthoyl-indole derivative which differs from its analogue 1-[(5-Fluoropentyl)-1H-indol-3-yl](1-naphthylenyl) methanone (AM-2201) by the presence of a methyl substituent on carbon 4 (C-4) of the naphthoyl moiety. Multiple cases of intoxication and impaired driving have been linked to AM-2201 and MAM-2201 consumption.
Objectives
This study aims to investigate the in vitro (murine and human cannabinoid receptors) and in vivo (CD-1 male mice) pharmacodynamic activity of MAM-2201 and compare its effects with those induced by its desmethylated analogue, AM-2201.
Results
In vitro competition binding studies confirmed that MAM-2201 and AM-2201 possess nanomolar affinity for both CD-1 murine and human CB1 and CB2 receptors, with preference for the CB1 receptor. In agreement with the in vitro binding data, in vivo studies showed that MAM-2201 induces visual, acoustic, and tactile impairments that were fully prevented by pretreatment with CB1 receptor antagonist/partial agonist AM-251, indicating a CB1 receptor mediated mechanism of action. Administration of MAM-2201 also altered locomotor activity and PPI responses of mice, pointing out its detrimental effect on motor and sensory gating functions and confirming its potential use liability. MAM-2201 and AM-2201 also caused deficits in short- and long-term working memory.
Conclusion
These findings point to the potential public health burden that these synthetic cannabinoids may pose, with particular emphasis on impaired driving and workplace performance.
... Further examination with the multivariable logistic regression resulted in finding a significant relationship only in NPS subgroup. Such results correlate with the data provided by other authors in terms of an increased likelihood of developing psychoses among people using various illicit substances from NPS group 18,21,39,40 . According to Martinotti et al., the use of potent and highly rewarding NPS is frequently associated with SREP 21 . ...
Adolescents are known to be particularly vulnerable, compared to children and adults, to initiation of substance use and progression to problematic use. This study aimed to examine the prevalence and type of illicit drug use in a population of adolescents and young adults who were hospitalized in a psychiatric hospital. The purpose of the study was also to find the link between age, sex, type of admission and particular mental disorders and using psychoactive substances at least once in a lifetime. A 12-month retrospective cross-sectional analysis of medical records compiled for adolescent and youth psychiatric patients who had been admitted to the Regional Psychiatric Hospital in Olsztyn, Poland, between October 1, 2018, and September 30, 2019, was conducted. After analyzing the available medical records, 506 cases were included and analyzed. Data for the study were collected in an Excel spreadsheet from discharge reports, including data from psychiatric examinations, especially anamnesis. Subsequently, statistical calculations were performed. Lifetime prevalence of any illicit substance use (34.0%) was common. The most frequently used drug was Cannabis (29.2%), the next New Psychoactive Substance—NPS (14.2%) and Amphetamine (13.0%). The higher number of people declaring to take illicit substances was proportional to the increasing age. Except for the group 10–15 years, the subject group was dominated by males. The highest, statistically significant percentage of patients who declared taking illicit substances in general, was found in people with diagnoses F20–F29 (schizophrenia, schizotypal and delusional disorders) (55%), additionally, we found a statistically significant association between NPS use and these diagnoses. Only in the group of patients diagnosed with eating disorders no one declared taking psychoactive substances. However, the correlation between taking illicit drugs and the subgroups with diagnosed psychiatric diseases should be treated with caution because of the small sample size in some cases. Our findings have shown the significant prevalence of the phenomenon in this population. These data highlight the need to explore this population at high risk carefully.
... However, SC-related adverse effects often develop, mostly due to (a) biotransformation into toxic metabolites, (b) by-products of pyrolysis of smoked herbal blends, and/or (c) drug-drug interactions (e.g., shared metabolic pathways with frequently used medications). Notably, the contribution of SCs per se to the onset of adverse effects remains undetermined (74). Similarly to their psychoactive effects, adverse symptoms may also appear minutes or hours after consumption, and last from minutes to several hours (11,75). ...
Synthetic cannabinoids (SCs) are a chemically diverse group of new psychoactive substances (NPSs) that target the endocannabinoid system, triggering a plethora of actions (e.g., elevated mood sensation, relaxation, appetite stimulation) that resemble, but are more intense than, those induced by cannabis. Although some of these effects have been explored for therapeutic applications, anticipated stronger psychoactive effects than cannabis and reduced risk perception have increased the recreational use of SCs, which have dominated the NPS market in the United States and Europe over the past decade. However, rising SC-related intoxications and deaths represent a major public health concern and embody a major challenge for policy makers.
Here, we review the pharmacology and toxicology of SCs. A thorough characterization of SCs’ pharmacodynamics and toxicodynamics is important to better understand the main mechanisms underlying acute and chronic effects of SCs, interpret the clinical/pathological findings related to SC use, and improve SC risk awareness.
Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... There are various theories implicating neurotransmitters in the experience of psychosis. The endogenous cannabinoid system has shown to play a role in schizophrenia as cannabis sativa, a psychoactive 4. INTERNATIONAL CONGRESS ON LIFE, SOCIAL, AND HEALTH SCIENCES IN A CHANGING WORLD FEBRUARY 12-13, 2022 Congress Full-Text Book 133 https://www.changingworldcongress.com/ compound, induces psychotic symptoms (Fattore, 2016). The existence of cannabinoid compounds results in perceptual inaccuracies such as in visual processing that are responsible for positive symptoms of psychosis (Koethe, 2006). ...
The Pandemic leads to different changes in the daily life such as eating, smoking behavior. The study mainly focused to comparatively analyze the change of eating and smoking behavior during lockdown among the people of Gujranwala, Mumbai and New York and also highlight what significant changes come in life due to pandemic. The study is cross national study and quantitative in nature. The survey method was used for data collection. The data was collected through Google survey from. The population of this study was people who belong to Gujranwala, Mumbai and New York and sample
sized of 450 people were selected by using convenience sampling technique. The study results showed that participants of these three cities recorded changes in their eating and smoking behavior during pandemic. Most of the respondent’s weight were observed increased. They started eating extra food against their normal routine. The study results also noted that people have also changed their smoking
behavior. They increased the frequency of smoking per day in confinement. The study also found that people spent more time with their family after the pandemic, because government of these three countries imposed a lockdown. The study concluded that Covid-19 effect on smoking and eating behavior negatively.
... Other adults who use marijuana regularly are those addicted to substances and those diagnosed with SUD or CUD (Azagba et al., 2019;NIDA, 2020;Scocard et al., 2017). Participants' clients were substantially represented among CUD patients whose drug use behaviors were elevated past recreational use, with many experiencing polydrug use addictions (Diao & Huestis, 2017;Fattore, 2016;Henrichson & Delaney, 2016). Participants 4, 7, and 9 had patients who had experienced overdosing on a combination of drugs where marijuana played a part. ...
... On top of that, potency of THC in herbal Cannabis doubled in the 10 years up to 2005 in Europe and USA [33,34], Cannabis extract may have up to 75% THC content nowadays [35], and synthetic cannabinoids which bind to the cannabinoid CB1 receptor with higher affinity than THC (i.e. potentially more harmful) have been gaining on popularity [36]. Neuroimaging studies have reported modification in different brain structures related to adolescent Cannabis use, such as altered hippocampal surface shape [37], and reduced white [38] and gray matter volume [39]. ...
The recent shift in socio-political debates and growing liberalization of Cannabis use across the globe has raised concern regarding its impact on vulnerable populations such as adolescents. Concurrent with declining perception of Cannabis harms, more adolescents are using it daily in several countries and consuming marijuana strains with high content of psychotropic delta (9)-tetrahydrocannabinol (THC). These dual, related trends seem to facilitate the development of compromised social and cognitive performance at adulthood, which are described in preclinical and human studies. Cannabis exerts its effects via altering signalling within the endocannabinoid system (ECS), which modulates the stress circuitry during the neurodevelopment. In this context early interventions appear to circumvent the emergence of adult neurodevelopmental deficits. Accordingly, Cannabis sativa second-most abundant compound, cannabidiol (CBD), emerges as a potential treatment for neuropsychiatric disorders. We first focus on human and preclinical studies on the long-term effects induced by adolescent THC exposure as “critical window” of enhanced neurophysiological vulnerability, which could be involved in the pathophysiology of schizophrenia and related primary psychotic disorders. Then, we focus on adolescence as “window of opportunity” for early pharmacological treatment, as novel risk reduction strategy for neurodevelopmental disorders. Thus, we review current preclinical and clinical evidence regarding the efficacy of CBD in terms of positive, negative and cognitive symptoms treatment, safety profile, and molecular targets.
... Finally, future longitudinal studies must attend to the diverse methods used to consume cannabis (such as oils, extracts, vaporizers, etc. [127]), as anecdotal evidence alleges that certain forms of cannabinoids, such as synthetic cannabinoids (e.g. full cannabinoid-CB 1 receptor agonists), may confer additional psychotomimetic properties [128]. ...
Introduction
Mounting evidence has begun establishing a link between cannabis use and adverse psychotic outcomes in patients affected by psychosis. However, we have yet to determine if this relationship is maintained when controlling for important confounding variables. As such, the following systematic review aims to investigate if the association between cannabis use and psychotic outcomes (relapse or change in positive symptoms) is preserved when accounting for important confounding variables, and whether discontinued use mitigates any potential negative impacts.
Area covered
The authors conducted an exhaustive search of the MEDLINE database and Google Scholar to identify articles pertaining to our systematic review. Thirty-three articles were retained for meeting the eligibility criteria.
Expert opinion
Overall, the evidence confirms an overarching pattern of negative psychotic outcomes of cannabis intake in populations with psychosis, even when accounting for crucial confounding determinants. The authors recommend that psychosis patients be informed with evidence-based health information regarding the effects of cannabis use, as well as the potential benefits of cessation of use, on clinical outcomes. They also recommend that clinicians systematically evaluate cannabis intake patterns in psychosis patients and offer intervention services geared toward reducing problematic cannabis consumption. Researchers should record confounding factors (such as medication compliance) in a more systematic manner in future longitudinal investigations, while paying careful attention to the potency as well as the dose-response effects of the ingested cannabis. Finally, deciders will need to help investigate the potential impact of cannabis regulations on psychosis populations.
... Together with the CBR antagonists/inverse agonist diaryl-pyrazole derivatives, such as rimonabant [47], SCs significantly contributed to the pharmacological mapping of the ECS. Since SCs greatly mimic the effects of cannabis, aminoalkylindoles, cyclohexylphenols, and naphtholylindoles especially, are the most common SCs found in the K2/Spice products, which are the most widely abused class of drugs nowadays [11,48,49]. Indole, indazole carboxamides structured SCs (e.g., AB-PICA and AB-PINACA, respectively) were joined to this class very recently [46]. ...
Substance use/abuse is one of the main causes of depressive symptoms. Cannabis and synthetic cannabinoids in particular gained significant popularity in the past years. There is an increasing amount of clinical data associating such compounds with the inflammatory component of depression, indicated by the up-regulation of pro-inflammatory cytokines. Pro-inflammatory cytokines are also well-known to regulate the enzymes of the kynurenine pathway (KP), which is responsible for metabolizing tryptophan, a precursor in serotonin synthesis. Enhanced pro-inflammatory cytokine levels may over-activate the KP, leading to tryptophan depletion and reduced serotonin levels, which can subsequently precipitate depressive symptoms. Therefore, such mechanism might represent a possible link between the endocannabinoid system (ECS) and the KP in depression, via the inflammatory and dysregulated serotonergic component of the disorder. This review will summarize the data regarding those natural and synthetic cannabinoids that increase pro-inflammatory cytokines. Furthermore, the data on such cytokines associated with KP activation will be further reviewed accordingly. The interaction of the ECS and the KP has been postulated and demonstrated in some studies previously. This review will further contribute to this yet less explored connection and propose the KP to be the missing link between cannabinoid-induced inflammation and depressive symptoms.
... Few clinical and preclinical studies have investigated the impact of cannabis consumption on PPI and reported mixed results (Quednow, Kuhn, Hoenig, Maier, & Wagner, 2004;Tournier & Ginovart, 2014). Our findings are in line with the notion that SC may possess psychotomimetic potential (Deng, Verrico, Kosten, & Nielsen, 2018;Fattore, 2016). Finally, in an attempt to get a better picture of behavioural anomalies relevant to hedonic/aversive state, we evaluated potential modifications of taste reactions to an intraoral sweet chocolate solution. ...
Background and purpose:
Spice/K2 herbal mixtures, containing synthetic cannabinoids such as JWH-018, have been marketed as marijuana surrogates since 2004. We demonstrated that JWH-018 has cannabinoid CB1 receptor-dependent reinforcing properties and acutely increases dopamine transmission selectively in the NAc shell. Here we tested the hypothesis that repeated administration of JWH-018 (i) modulates behaviour, (ii) affects dopamine transmission and its responsiveness to motivational stimuli, and (iii) is associated with a neuroinflammatory phenotype.
Experimental approach:
Rats were administered with JWH-018 once a day for 14 consecutive days, then we performed behavioural, electrophysiological, and neurochemical evaluation at multiple time points after drug discontinuation.
Key results:
Our data demonstrated that repeated JWH-018 exposure (i) induces anxious and aversive behaviours, transitory attentional deficits and withdrawal signs, (ii) decreases spontaneous activity and number of dopamine neurons in the VTA and (iii) reduces the stimulation of dopamine transmission in the NAc shell while potentiating that in the NAc core in response to acute JWH-018 challenge. Moreover, (iv) we observed a decreased dopamine sensitivity in the NAc shell and core, but not in the mPFC, to the first chocolate exposure; conversely, after the second exposure, dialysate dopamine fully increased in the NAc shell and core but not in the mPFC. Finally, selected dopamine brain areas showed (v) astrogliosis (mPFC, NAc shell and core, VTA), microgliosis (NAc shell and core), and downregulation of CB1Rs (mPFC, NAc shell and core).
Conclusion and implications:
These results suggest that repeated JWH-018 exposure may reflect a useful model to clarify the detrimental effects of recurring use of Spice/K2 drugs.
... Both values were significantly higher in the SC group than in the cannabis group. Consistent with our findings, an increase in suicides was reported following SC use (23). A 23-year-old man with no psychiatric disorder history was reported to have committed suicide by stabbing himself after using a high concentration of AM-2201(1-[5-fluoropentyl]-3-[1-naphthyl]indole) (24) and another case of suicide by jumping from height after using an unknown SC derivative (25). ...
... Reports of hallucinations following exposure to cannabis in adults are mixed [54][55][56]. Whilst perceptual alterations in healthy individuals during the acute effects of THC are often described [57] hallucinogen-like effects are quite rare, with recent research reporting hallucinations in response to the use of synthetic cannabinoids [58], which are typically a full CB1 receptor agonists with greater potency than THC (a partial CB1 receptor agonist) in plant-based cannabis. In the current study, hallucinations were not shown to be associated specifically with high potency cannabis, suggesting that the presence of hallucinations was not solely due to high doses of THC on dopaminergic neurotransmission. ...
Adolescents have access to a wide range of cannabis products with patterns of use becoming increasingly diverse. This study aimed to identify subgroups of adolescents in the general population who use similar types of cannabis and their association with psychotic experiences. Data on cannabis use were obtained from 467 adolescents aged between 16-17 years. Latent class analysis (LCA) identified groups of adolescents based on the type of cannabis used in the past 12 months. Univariate analysis explored differences in socio-demographics, substance use and mental health symptoms between groups. Multivariate analysis examined associations between class membership and psychotic experiences controlling for frequency and amount of cannabis. Finally, we explored the association between motives for cannabis and class membership using multi-nominal logistic regression. LCA identified 3 classes of adolescents: i) herbal only (47.9%); ii) skunk only (20.8%) and 3) mixed use (31.3%). Relative to non-users, skunk only use was associated with a 2-fold increase in paranoia (OR= 2.45, 95% CI = 1.29-4.63), along with, sleep disturbance and anxiety. Monthly cannabis use and consuming 2 or more joints on one occasion was associated with a 2-fold increase in hallucinations (OR =2.2; 95% CI =1.0-4.8 and OR =1.9; 95% CI = 1.2-3.2), but did not reach the Bonferroni corrected p-value. Expansion and conformity motives differentiated the mixed cannabis class from the herbal only class. The findings suggest that different subgroups of cannabis users exist in adolescence as defined by the type of cannabis consumed and are differentially related to psychotic experiences and motives for use.
... Synthetic opioids cause initial eu-phoria, states of ecstasy, later disorders of consciousness, disorientation, mental confusion, psychosis, and in the most severe cases, respiratory arrest and death. Due to their high potency, they often cause severe intoxications and over-dose [9,10,11]. Adequate diagnosis in patients, who are seen in emergency units and centers, is often very difficult [12,13]. Patients usually come to the state of altered consciousness or are not ready to give detailed information, followers are usually not present. ...
Introduction: The United Nation Office of Drugs and Crime (UNODC) defines "new psychoactive substances" (NPS) as substances for abuse that are not under the control of the 1961 Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but may constitute the definition of a group of different substances, which have been developing very rapidly since 2000 and are difficult to identify due to frequent changes in pharmacological and toxicological properties.The health risk assessment of consumers has been insufficiently researched.The use of NPS is reaching epidemic proportions worldwide and poses an increasing danger to the individual and public health. There are several basic groups of NPS, according to their chemical composition and pharmacological properties. All NPS cannot be safely differentiated according to these groups, and their effects, potency and risk profile are not similar to the substances from which they are derived. The highest percentage of abused NPS is from the group of synthetic cathinones and synthetic cannabinoids. Clinicaly, NPS abuse is categorized as acute intoxications, which is more common, because NPS is most often used on certain occasions (outings, musical events) or as an addiction. Acute intoxications with different types of NPS are severe, with numerous mental and physical symptoms, often life-threatening and with fatal outcomes. Adequate diagnosis is uncertain, diagnostic laboratory tests for drugs are generally not applicable to NPS. Symptomatic internal medicine and psychiatric therapy are used in the treatment because there are no specific antidotes, except for the group of synthetic opioids, (naltrexone). Patients with more serious complications are taken care of in intensive care units. Addiction to certain types of NPS is diagnosed and treated according to the principles of treatment of addiction to already known drugs. Methods: The paper presents an overview of available foreign and domestic literature and experiences of various authors on the topic of NPS from the previous 10 years, as well as the latest reports of regulatory bodies in the USA and Europe, in charge of monitoring epidemiological data on NPS. Topic: The main goal of the paper is to draw the attention of the professional public to the problem of the epidemic wave of new psychoactive substances in the world, as well as significant amounts of knowledge and experience and developing new strategies for registration, monitoring, diagnosis and treatment of abuses and dependence on these substances. Conclusion: These facts impose the need to raise the vigilance of the health and legal system according to the presence of NPS on the market and the prevalence of use in the population, their health risks, as well as connecting with European organizations for monitoring NPS and developing new strategies for their control and prevention.
... Synthetic cannabinoids emerged in the mid-2000s and were first formally identified and reported to the EMCDDA in 2008, initially being used as alternatives to herbal cannabis, particularly to avoid detection in those settings with forensic drug testing regimes such as prisons, sports programmes and the military. 68 They have since proliferated worldwide in many different structures, forms and potencies, and currently represent the largest and most structurally diverse class of NPS. 69,70 The UNODC have reported approximately 280 synthetic cannabinoids had been identified by the end of 2019. ...
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.
... Type 1 receptors are mostly on the presynaptic terminals of GABAergic and glutamatergic neurons and maintain homeostasis, preventing excessive or, conversely, insuffi cient activity via release of neurotransmitters by presynaptic regulation. Animal experiments have shown that activation of CB 1 receptors increases dopamine release from the nucleus accumbens [13]. Modulation of CB 1 receptors in turn leads to activation of the serotoninergic system via actions on 5-HT 2A or 5-HT 4 receptors [14]. ...
Objectives. To create a complex model of the individual risk of developing dependence on synthetic cannabinoids taking account of the combined influences of genetic predisposition and attention deficit hypera-ctivity disorder (ADHD). Materials and methods. A total of 146 male adolescents consuming synthetic cannabinoids and 136 healthy subjects (controls) were observed. Genetic studies assessed cases with the combination of these dependencies with ADHD. DNA was collected and six polymorphic loci of genes of the dopaminergic and serotoninergic systems were determined; results were analyzed using a series of special statistical methods. Results and conclusions. These data demonstrate the important role of the dopaminergic and serotoninergic systems in the pathogenesis of dependence on psychoactive substances and the significance of changes in the nucleotide sequences of the DRD2, SLC6A3, and HTR2A genes in the development of dependence on synthetic cannabinoids in males with ADHD.
... For example, it is unclear whether psychosis reported was preexisting or new-onset. Precipitation of psychosis has been associated with SCRA use in vulnerable individuals [14,[45][46][47], although first-episode psychosis also develops in individuals without a history of mental disorders [48][49][50]. Psychosis-like conditions may occur more frequently due to the high potency and efficacy of SCRA relative to cannabis [51], or from the absence of other potentially modifying phytocannabinoids such as cannabidiol [52][53][54][55]. The mechanism by which SCRA contribute to psychosis is not clear [56]. ...
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.
... Our patient liked k2 which is a man-made functional analog of cannabis that binds to cannabinoid receptors type 1 (cbr1) with much higher affinity and potency than delta-9-tetrahydrocannabinol. They also lack protective effects of cannabidiol including anxiolytic and antipsychotic effects [5,6]. ...
Schizophrenia has a multidomain symptom cluster, including positive, negative, and cognitive symptoms. Synthetic cannabinoids (SC) commonly perpetuate the positive symptoms of schizophrenia. We present a case of predominant negative symptoms following the use of SC even though our patient had a consistent history of experiencing positive symptoms in the past. The hypoactive dopaminergic system in the prefrontal cortex can induce negative symptoms in schizophrenia. However, the modulating properties of SC on cannabinoid receptors can feed into the negative symptom progression. The psychoactive properties of SC need further research to understand its clinical characteristics.
... The long-term or residual effects of SCRAs are almost unknown, but aggression, self-harm and self-mutilation, including self-inflicted burns, have been reported [40,43]. Case reports suggest that SCRAs are able to trigger long-term psychotic symptoms, not only among psychiatric patients, but also in subjects without a previous history of psychosis [44]. Chronic SCRAs users display poorer performance on working memory, Brain Sci. ...
Sex and gender deeply affect the subjective effects and pharmaco-toxicological responses to drugs. Men are more likely than women to use almost all types of illicit drugs and to present to emergency departments for serious or fatal intoxications. However, women are just as likely as men to develop substance use disorders, and may be more susceptible to craving and relapse. Clinical and preclinical studies have shown important differences between males and females after administration of "classic" drugs of abuse (e.g., Δ9-tetrahydrocannabinol (THC), morphine, cocaine). This scenario has become enormously complicated in the last decade with the overbearing appearance of the new psychoactive substances (NPS) that have emerged as alternatives to regulated drugs. To date, more than 900 NPS have been identified, and can be catalogued in different pharmacological categories including synthetic cannabinoids, synthetic stimulants (cathinones and amphetamine-like), hallucinogenic phenethylamines, synthetic opioids (fentanyls and non-fentanyls), new benzodiazepines and dissociative anesthetics (i.e., methoxetamine and phencyclidine-derivatives). This work collects the little knowledge reached so far on the effects of NPS in male and female animal and human subjects, highlighting how much sex and gender differences in the effects of NPS has yet to be studied and understood.
... While 9-THC has shown moderate affinity for the CB1 receptor (Pertwee, 2008), synthetic cannabinoids have higher affinity, also showing full agonist action (Cohen and Weinstein, 2018). Consistent with this, risk of severe acute (Papanti et al., 2013;Castaneto et al., 2014) and long-lasting psychotic reactions for such compounds is much higher compared to 9-THC (Fattore, 2016;Murray et al., 2017). This is relevant, as synthetic cannabinoid recreational use has increased considerably over the last decade (Law et al., 2015). ...
Research evidence suggests a dose–response relationship for the association between cannabis use and risk of psychosis. Such relationship seems to reflect an increased risk of psychosis not only as a function of frequent cannabis use, but also of high-potency cannabis use in terms of concentration of Δ-9-tetrahydrocannabinol (Δ9-THC), its main psychoactive component. This finding would be in line with the evidence that Δ9-THC administration induces transient psychosis-like symptoms in otherwise healthy individuals. Conversely, low-potency varieties would be less harmful because of their lower amount of Δ9-THC and potential compresence of another cannabinoid, cannabidiol (CBD), which seems to mitigate Δ9-THC detrimental effects. A growing body of studies begins to suggest that CBD may have not only protective effects against the psychotomimetic effects of Δ9-THC but even therapeutic properties on its own, opening new prospects for the treatment of psychosis. Despite being more limited, evidence of the effects of cannabis on cognition seems to come to similar conclusions, with increasing Δ9-THC exposure being responsible for the cognitive impairments attributed to recreational cannabis use while CBD preventing such effects and, when administered alone, enhancing cognition. Molecular evidence indicates that Δ9-THC and CBD may interact with cannabinoid receptors with almost opposite mechanisms, with Δ9-THC being a partial agonist and CBD an inverse agonist/antagonist. With the help of imaging techniques, pharmacological studies in vivo have been able to show opposite effects of Δ9-THC and CBD also on brain function. Altogether, they may account for the intoxicating and therapeutic effects of cannabis on psychosis and cognition.
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
The endogenous cannabinoid system regulates diverse aspects of physiological functions via specific cannabinoid receptors (CB) expressed in the brain and periphery. CB1 receptors mediate various neurological processes, whereas CB2 receptors mainly regulate immune responses and are involved in development of drug addiction and neuroinflammation. The cannabinoids are a heterogeneous group of endo-, phyto-, and synthetic cannabinoids. Cannabis and its products have been used for millennia, and these remain the most frequently used substances around the world. Δ9-Tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of cannabis, produces psychotic-like symptoms. Acute and chronic cannabis use may impair learning and memory, attention, and psychomotor functions; however, studies on the life-lasting effects of cannabis on brain structure are ambiguous. During the last decade, a worrying trend has been observed regarding the increasing popularity of more potent, addictive, and harmful synthetic cannabinoids (SCs). Unlike Δ9-THC, SCs use may lead to severe adverse effects including seizures, agitation, aggression, violence, anxiety, and panic attacks. Acute intoxication may be life-threatening or lead to persistent impairments in emotional and cognitive processing as a result of irreversible brain damage. This chapter describes the current state of knowledge regarding various aspects of the neurotoxicity of exogenous cannabinoids, including the harmful effects of their use during pregnancy.
Across communities worldwide, various new psychoactive substances (NPS) continue to emerge, which worsens the challenges to global mental health, drug rules, and public health risks, as well as combating their usage. Specifically, the vast number of NPS currently available, coupled with the rate at which new ones emerge worldwide increasingly challenges both forensic and clinical testing strategies. The well-established NPS detection techniques include immunoassays, colorimetric tests, mass spectrometric techniques, chromatographic techniques, and hyphenated types. Nonetheless, mitigating drug abuse and NPS usage is achievable through extensive community-based initiatives, with increased focus on harm reduction. Clinically validated and reliable testing of NPS from human samples, along community-driven solution, such as harm reduction, will be of great importance, especially in combating their prevalence and the use of other illicit synthetic substances. There is a need for continued literature synthesis to reiterate the importance of NPS, given the continuous emergence of illicit substances in the recent years. All these are discussed in this overview, as we performed another look into NPS, from differentiating the major groups, identifying with laboratory testing challenges, to community-based initiatives.
The endogenous cannabinoid system regulates diverse aspects of physiological
functions via specific cannabinoid receptors (CB) expressed in the brain and
periphery. CB1 receptors mediate various neurological processes, whereas CBreceptors mainly regulate immune responses and are involved in development of
drug addiction and neuroinflammation. The cannabinoids are a heterogeneous
group of endo-, phyto-, and synthetic cannabinoids. Cannabis and its products
have been used for millennia, and these remain the most frequently used substances around the world. Δ9-Tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of cannabis, produces psychotic-like symptoms. Acute and chronic cannabis use may impair learning and memory, attention, and psychomotor functions; however, studies on the life-lasting effects of cannabis on brain structure are ambiguous. During the last decade, a worrying trend has been
observed regarding the increasing popularity of more potent, addictive, and
harmful synthetic cannabinoids (SCs). Unlike Δ9-THC, SCs use may lead to
severe adverse effects including seizures, agitation, aggression, violence, anxiety,
and panic attacks. Acute intoxication may be life-threatening or lead to persistent
impairments in emotional and cognitive processing as a result of irreversible brain
damage. This chapter describes the current state of knowledge regarding various
aspects of the neurotoxicity of exogenous cannabinoids, including the harmful
effects of their use during pregnancy.
Cannabis sativa is among the most abused drugs worldwide. THC, its main psychoactive component, represents a risk factor of several mental pathologies, such as cannabis use disorder, addiction, and psychosis. Being a biphasic drug, high doses of THC cause hypoactivity and aversion, whereas low doses of THC cause hyperactivity and reward. THC acts on the type-1 cannabinoid receptor (CB1), one of the most abundant G-protein coupled-receptors (GPCRs) in the brain, whose signaling is biased, meaning that different transducers can carry specific pathway following different conditions. Biased signaling was proven to be extremely relevant in drug discovery and understanding CB1 signaling in pathologic conditions is essential for cannabinoid-based drug development. It is known that different doses of THC bring along different behavioral, cellular, and molecular outcomes. However, the link between those phenomena has never been investigated.Thus, for a therapeutic purpose PREG-like CB1-SSi compounds have been synthetized that share the same PREG therapeutic potential, but cannot be metabolized in downstream steroids. The CB1-SSi studied in the current work is the CB1-SSi lead compound, AEF0117.The first aim of the current work was to understand the intracellular signaling pathways following low, medium, and high doses of THC, leading to three distinct known behavioral outputs in mice, hyperlocomotion, asociability, and hypolocomotion, respectively.The second aim of the thesis was to understand the mechanism of action of AEF0117, and its capability to block the behavioral and molecular effects of THC at low, medium, and high doses.The doctoral dissertation is divided into five main parts. The introduction serves to preface the concepts of the endocannabinoid system, as well as cannabis abuse in humans and the counterpart behavioral outcomes of THC in mice, including hyperlocomotion, asociability, and hypolocomotion. The state of the art of CB1 signaling involving the biased CB1 system is described with particular emphasis on CB1 Signaling Specific Inhibitors (CB1-SSi), in particular the endogenous pregnenolone (PREG), and its synthetic analogue, the lead CB1-SSi compound, AEF0117.The article Zanese*, Tomaselli* et al., 2020 (published in J. Neurosci. Methods) oversees the validation of the high throughput analytical technique (AlphaLISA) of choice in this study for detection of protein phosphorylation in brain tissue lysates.The article Tomaselli et al. (to be submitted), is devoted to the studies of the low dose of THC that causes hyperlocomotion, with the discovering of its related intracellular CB1 signaling pathway, along with the signaling transducer involved in the CB1-rich brain areas relevant for locomotor activity (NAc, Str, CB). The main data revealed that THC via CB1 recruits the β-Arrestin1-PI3K-Akt-GSK3β signaling pathway that lead to hyperlocomotion. Furthermore, both PREG and AEF0117 were able to block the THC-induced hyperlocomotion and altered signaling in mice.The third part of the data represent studies on the effects of THC at medium and high doses that induce asocial behavior and hypolocomotion, respectively. Each dose of THC induced specific alterations in the CB1intracellular signaling pathways in the most CB1-rich brain areas, and the treatment with AEF0117 rescued both behaviors.The general discussion then addresses conclusions and perspectives, highlighting the role of specific CB1 pathways in THC-induced addiction and psychosis, and proposes a mechanism of action for CB1-SSi compounds, including AEF0117.
Substanzkonsumstörungen und Psychosen stehen häufig in einem kausalen Zusammenhang. Dieser kann uni- oder bidirektional sein – oder beide Störungen beruhen auf gemeinsamen ätiopathogenetischen Faktoren. Substanzen wie Cannabinoide, Stimulanzien oder Halluzinogene scheinen wichtige Ko-Faktoren für die Entwicklung einer (sekundären) Psychose darzustellen. Der Beitrag gibt einen Überblick über die Substanzgruppen, Diagnostik und Therapie.
Background
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.
Methods
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.
Results
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.
Synthetic cannabinoids (SC) are the most common type of new psychoactive substances used predominantly as a replacement for cannabis. There is a wealth of literature on the negative effects experienced by users of SC. However, there is a paucity of research on the experience of addiction to SC from the users' perspectives. The present study qualitatively explored the experience of addiction to SC. Online blog entries detailing the experience of SC addiction were analyzed using thematic analysis. Users reported being stuck in a cycle of addiction which was composed of addiction hallmarks. They also experienced a range of significant physical, mental health and psychosocial problems. Suicidal ideation was also reported, with potential for its occurrence during withdrawal, due to shame of being addicted, and as the only way to stop the addiction cycle. Additionally, both psychotic and cognitive symptoms were reported to persist following cessation, enhancing current understanding of long-term SC effects. Therefore, users require both clinical and psychosocial support for these issues, most notably suicidal ideation.
Due to differences in potency, efficacy, and affinity for CB1 receptors, similarities and differences in psychoactive effect profiles of natural cannabis and synthetic cannabinoids (SCs) cannot reliably be derived from equipotent dose comparisons. Instead, the current study proposes to compare the intrinsic psychoactive effects of natural cannabis (THC) and an SC, JWH-018, at psychotropic dose equivalence. Participants from two placebo-controlled studies were matched for their levels of subjective high to compare neurocognitive and psychotomimetic effects of THC and JWH-018. At equal subjective intoxication levels, both drugs impaired psychomotor, divided attention, and impulse control, with no significant difference between the two drugs. Both drugs also caused significant psychotomimetic effects, but dissociative effects were considerably more pronounced for JWH-018 than THC. We conclude that psychotropic dose equivalence provides a uniform approach for comparing the neurocognitive and psychotomimetic profiles of CB1 agonists, which can also be applied to other drug classes.
The objective of the present study was the development and validation of the method for determining AMB-FUBINACA and its metabolite - AMB-FUBINACA O-desmethyl acid – in blood samples, followed by verification of the method in toxicological judicial and forensic medicine practice employing the example of post-aggression suicide. Most likely in consequence of development of adverse effects resulting in psychotic symptoms, a male being under the influence of the synthetic cannabinoid AMB-FUBINACA and the new synthetic opioid U-47700, mortally wounded his female partner and subsequently committed suicide. Identification and determination of the afore-mentioned xenobiotics in blood samples collected from the male and female victims were performed employing high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The analytes were isolated from blood samples using the solid phase extraction (SPE) method. The blood samples collected from the male and female demonstrated respectively 110 and 196 ng/mL of AMB-FUBINACA O-desmethyl acid metabolite, 1935 and 357 ng/mL of U-47700, 250 and 200 ng/mL of N-desmethyl-U-47700, as well as 410 and 200 ng/mL of N,N-didesmethyl-U-47700. The concentration values of new psychoactive substances (NPS’s) in blood samples originating from the male and female were within the ranges encountered in cases of poisoning, including these resulting in death. Nevertheless, the evident signs of exsanguination proof that the woman was alive when she sustained lethal injuries. The presented cases illustrate the difficult to be anticipated effect exerted on the users by NPS’s.
Purpose
This paper aims to understand the current scale of substance misuse in psychiatric intensive care units (PICUs), identify how substance misuse affects members of staff, patients and the running of wards and explore with staff what resources would be most useful to more effectively manage substance misuse and dual diagnosis on PICUs.
Design/methodology/approach
The paper used a mixed-methods approach, using a quantitative survey to determine the extent of substance use in PICUs and a co-design workshop to understand the impact of substance misuse on PICU wards, staff and patients.
Findings
The estimated rate of substance misuse in PICUs over a 12-month period is 67%, with cannabis the most frequently used substance. Despite the range of problems experienced on PICUs because of substance misuse, the availability of training and resources for staff was mixed.
Research limitations/implications
The findings may not be fully generalisable as research participants were members of a national quality improvement programme, and therefore, may not be representative of all PICUs. Data was collected from clinicians only; if patients were included, they might have provided another perspective on substance misuse on PICUs.
Practical implications
This paper emphasises the importance of substance misuse training for PICU staff to adequately respond to patients who misuse substances, improve the ward environment, staff well-being and patient outcomes.
Originality/value
This paper provides an updated estimation of rates of substance misuse in PICUs over a 12-month period and make suggestions for a training programme that can better support staff to address substance misuse on PICUs.
Objectives:
Recently, there has been an obvious increase in the synthetic cannabinoid abuse that can cause severe toxicity and major physical and psychological consequences. Here we have assessed the impacts of synthetic cannabinoids intake on induction of seizures and on electroencephalographic activity, allowing for exploration of one of the physical hazards that might associate synthetic cannabinoids use helping for better management.
Methods:
Forty male patients using synthetic cannabinoids and 40 nonusing males were registered in this work. All individuals were determined via a detailed history of substance use and diagnosed according to International Classification of Diseases version 11 as synthetic cannabinoid use disorders, detailed history of seizures from close relatives who witnessed seizure occurrence and its correlation with the last dose of synthetic cannabinoid use and then investigated by long-term electroencephalograph.
Results:
Seizures were considerably more common in the synthetic cannabinoid using group than in the nonusing group, with the main presenting event in the form of the generalized tonic-clonic seizure. Seizures occurred within 15 minutes of intake in 81.8% of patients. Long-term electroencephalography showed electroencephalographic changes in 45% of cases using synthetic cannabinoids that were statistically more significant than in the nonusing group (2.5%), with the most prominent electroencephalographic change in the form of left frontal focus in 22.5% of cases.
Conclusion:
Synthetic cannabinoid usage has been linked to seizure induction and has been shown to alter electroencephalographic activity.
Introduction:
Synthetic cannabinoids are abused substances with strong psychoactive effects. Little is known about the effects on neurotransmission and the toxicity of the second-generation cannabinoid 5F-APINAC. The objective was to assess the influence of short- and long-term exposures of 5F-APINAC on metabolites associated with neurotransmission on zebrafish.
Methods:
Short-term ("acute", 4 h) and long-term ("chronic", 96 h) exposures to 5F-APINAC were performed at 0.001, 0.01, 0.1, 1.0 and 10 μM. Intervention groups were compared with a vehicle control. Each group n = 20 zebrafish eggs/larvae. Metabolites related to neurotransmission were determined.
Results:
In chronic exposure, larvae exposed to 10 μM 5F-APINAC presented morphological and developmental alterations. GABA had the lowest concentrations at higher exposure in acute (p < 0.01) and chronic (p < 0.001) experiments. Glutamine showed a descending trend in the acute experiment, but an ascending trend in the chronic exposure (p < 0.05). In chronic exposure, tryptophan presented an overall descending trend, but with a neat increase at 10 μM 5F-APINAC (p < 0.001). Tryptamine in acute exposure presented lower (p < 0.05) concentrations at higher doses. Dopamine and acetylcholine presented highest (p < 0.05) concentrations in the acute and chronic exposures, but with a drop at the highest doses in the chronic experiments. In chronic exposure, xanthurenic acid decreased, except for the highest dose. Picolinic acid was increased at the highest doses in the chronic experiment (p < 0.001).
Conclusions:
Short- and long-term exposures induced metabolomic alterations associated with the gamma-aminobutyric acid/glutamic acid, dopaminergic/adrenergic, cholinergic neurotransmitter systems, and the kynurenine pathway. Chronic exposure at 10 μM 5F-APINAC was associated with embryotoxicity confirmed by teratogenesis.
Az indiai kender (Cannabis sativa) fő hatóanyaga a THC, illet ve a szintetikus kannabinoidok az agy CB1 típusú endocannabinoid receptorain fejtik ki hatásukat. A marihuána és a szintetikus kannabinoidok tartós használata függőséghez vezethet, ennek ellenére a fiatalok körében fogyasztásuk egyre népszerűbb, 2018-ban a felnőtt népesség 7,4%-a próbálta ki a kannabiszt, és 1,9% a szintetikus kannabinoidokat. Főleg a szintetikus kannabinoid fogyasztás terjed, 2018 végére a cannabis utáni negyedik helyről második helyre került a felmérések szerint (EMCCDA, 2018). A szintetikus kannabinoid termékekhez sokszor amfetamint, benzodiazepineket, ópiátokat is kevernek, emiatt hatásuk kiszámíthatatlan. A kannabisz és a kannabinoidok veszélyeit sokan alábecsülik, pedig a genetikai adottságaik miatt skizofréniára hajlamos, illet ve a szociális vagy pszichikai problémáik elől szerhasználatba menekülő fiatalok különösen veszélyeztetettek, a körükben végzett prevenció kiemelkedő jelentőségű lenne.
Background Substitution can be defined as the consciously motivated choice to use one drug, either licit or illicit, instead of another, due to perceptions of cost, availability, safety, legality, substance characteristics, and substance attributions. Substitution represents a potential risk to drug users, mainly when substitutes are of higher potency and toxicity. This study offers a basic conceptualization of illicit substitution behavior and describes substitution patterns among users of two highly prevalent drugs of abuse—heroin and cannabis. Methods Here, 592 high-risk drug users undergoing pharmacological and psycho-social treatment were interviewed. Patients were asked questions about current drug use, lifetime substitution, and substitution patterns. Descriptive statistics, chi-square tests of independence, and multinomial logistic regressions were used to identify and test correlates of substitution patterns for heroin and cannabis. Results Of the 592 drug users interviewed, 448 subjects (75.7%) reported having substituted their preferred drug for another illicit substance. Interviews yielded a total of 275 substitution events reported by users of cannabis, and 351 substitution events reported by users of heroin. The most frequently reported substitution substances for responders who preferred heroin were illicit non-prescribed “street” methadone (35.9%), followed by oral and transdermal prescription opioids (17.7%). For responders who preferred cannabis, substitution for synthetic cannabinoid receptor agonists (33.5%) followed by alcohol (16.0%) were the most commonly reported. Age at onset–of–use (p
Palliative care is a specialized medical care that focuses on quality of life for patients with serious illnesses. In the realm of palliative care and symptom management, there is growing interest in the role for cannabis-based medicine. There is some evidence to support the use of cannabinoids for the palliation of some symptoms and quality of life issues. Most notably, research supports the efficacy of cannabinoids for the treatment of chemotherapy-induced nausea and vomiting, though the evidence for phytocannabinoids is lacking. Moreover, cannabis use in the treatment of neuropathic pain is supported by several small high-quality studies. There is great interest in cannabis-based medicine to aid in the management of other symptoms such as anorexia, cachexia, insomnia, fatigue, anxiety, and delirium, among others that are prevalent in palliative care patients. Though there are limited studies for these various applications of cannabis, the data is not conclusive, and patients’ treatment goals must be carefully considered prior to the administration of medical cannabis. Further research is needed to better understand the possible benefits of medical cannabis as well as the safety, side effects, and drug interactions.
Over 300,000 individuals enter treatment for cannabis-use disorders (CUDs) in the United States annually. Cannabis withdrawal is associated with poor CUD-treatment outcomes, but no prior studies have examined sex differences in withdrawal among treatment-seeking cannabis users. Treatment-seeking cannabis users (45 women and 91 men) completed a Marijuana Withdrawal Checklist (Budney, Novy, & Hughes, 1999, Budney, Moore, Vandrey, & Hughes, 2003) at treatment intake to retrospectively characterize withdrawal symptoms experienced during their most recent quit attempt. Scores from the 14-item Composite Withdrawal Discomfort Scale (WDS), a subset of the Marijuana Withdrawal Checklist that corresponds to valid cannabis withdrawal symptoms described in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; APA, 2013) were calculated. Demographic and substance-use characteristics, overall WDS scores, and scores on individual WDS symptoms were compared between women and men. Women had higher overall WDS scores than men, and women had higher scores than men on 6 individual symptoms in 2 domains, mood symptoms (i.e., irritability, restlessness, increased anger, violent outbursts), and gastrointestinal symptoms (i.e., nausea, stomach pain). Follow-up analyses isolating the incidence and severity of WDS symptoms demonstrated that women generally reported a higher number of individual withdrawal symptoms than men, and that they reported experiencing some symptoms as more severe. This is the first report to demonstrate that women seeking treatment for CUDs may experience more withdrawal then men during quit attempts. Prospective studies of sex differences in cannabis withdrawal are warranted. (PsycINFO Database Record
There is no specific antidote for intoxication with synthetic cannabinoids. In this case series, we considered the efficiency of intravenous lipid emulsion therapy in four cases, who presented to emergency department with synthetic cannabinoid (bonzai) intoxication. The first patient had a GCS of 3 and a left bundle branch block on electrocardiography. The electrocardiography revealed sinus rhythm with normal QRS width after the treatment. The second patient had bradycardia, hypotension, and a GCS of 14. After intravenous lipid emulsion therapy, the bradycardia resolved, and the patient’s GCS improved to 15. The third patient presented with a GCS of 8, and had hypotension and bradycardia. After the treatment, not only did the bradycardia resolve, but also the GCS improved to 15. The fourth patient, whose electrocardiography revealed accelerated junctional rhythm, had a GCS of 13. The patient’s rhythm was sinus after the treatment. Cardiovascular recovery was seen in all four cases, and neurological recovery was also seen in three of them. Based on the fact that intravenous lipid emulsion is beneficial in patients intoxicated with lipophilic drugs, unstable patients presenting to the emergency department with acute synthetic cannabinoid intoxication may be candidates for intravenous lipid emulsion treatment.
Over the last 5 years there has been an influx of novel designer drugs (mostly illegal) which are intended to mimic the effects of cannabis (synthetic cannabinoids). Many of these compounds are created by research groups attempting to find an analog of cannabis that can be used therapeutically to treat pain and other conditions.PB-22 (1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid) is a relatively new synthetic cannabinoid which has cannabis like activity and possibly other as yet unknown effects. There is no published data on the pharmacodynamics, pharmacokinetics or toxicology of PB-22. However, a recent publication has reported 4 deaths associated with use of 5F-PB-22 which is a derivative of PB-22 [1]. Although synthetic cannabinoids have been reported in association with sudden death, the precise pathophysiological mechanisms by which death occurs remain obscure.We have identified three cases in Victoria over a recent 4 month period all of which have PB-22 as the main tox ...
Synthetic cannabinoids are touted as legal alternatives to cannabis, at least when first released, and routine urine cannabinoid screening methods do not detect these novel psychoactive substances. Synthetic cannabinoids are widely available, are a major public health and safety problem, and a difficult challenge for drug testing laboratories. We evaluated performance of the NMS JWH-018 direct ELISA kit to sensitively, selectively, and rapidly screen urinary synthetic cannabinoids.
The NMS ELISA kit targeting the JWH-018 N-(5-hydroxypentyl) metabolite was utilized to screen 2492 urine samples with 5 and 10µg/L cutoffs. A fully validated LC-MS/MS method for 29 synthetic cannabinoids markers confirmed all presumptive positive and negative results. Performance challenges at ±25 and ±50% of cutoffs determined intra- and inter-plate imprecision around proposed cutoffs.
The immunoassay was linear from 1-500µg/L with intra- and inter-plate imprecision of ≤8.2% and <14.0%, respectively. No interferences were present from 93 common drugs of abuse, metabolites, co-administered drugs, over-the-counter medications or structurally similar compounds, and 19 of 73 individual, synthetic cannabinoids (26%) exhibited moderate to high cross-reactivity to JWH-018 N-(5-hydroxypentyl) metabolite. Sensitivity, specificity, and efficiency results were 83.7%, 99.4% and 97.6% and 71.6%, 99.7% and 96.4%, with the 5 and 10µg/L urine cutoffs, respectively.
This high throughput immunoassay exhibited good diagnostic efficiency and documented that the NMS JWH-018 direct ELISA is a viable method for screening synthetic cannabinoids in urine targeting the JWH-018 N-(5-hydroxypentyl) and related analytes. Optimal performance was achieved with a matrix-matched 5µg/L urine cutoff.
Novel psychoactive substances include synthetic cannabinoids, cathinone derivatives, psychedelic phenethylamines, novel stimulants, synthetic opioids, tryptamine derivatives, phencyclidine-like dissociatives, piperazines,GABA-A/B receptor agonists, a range of prescribedmedications, psychoactive plants/herbs, and a large series of performance and image enhancing drugs. Users are typically attracted by these substances due to their intense psychoactive effects and likely lack of detection in routine drug screenings. This paper aims at providing psychiatrists with updated knowledge of the clinical pharmacology and psychopathological consequences of the use of these substances. Indeed, these drugs act on a range of neurotransmitter pathways/receptors whose imbalance has been associated with psychopathological conditions, including dopamine, cannabinoid CB1, GABA-A/B, 5-HT2A, glutamate, and k opioid receptors. An overall approach in terms of clinical management is briefly discussed.
Key words: Novel psychoactive substances, legal highs, smart drugs, research chemicals, substance abuse, dual diagnosis, psychedelic phenethylamines, synthetic cannabimimetics, phencyclidine-like drugs, cathinones, tryptamines
Cannabis use is associated with an increased risk of psychosis in vulnerable individuals. Cannabis containing high levels of the partial cannabinoid receptor subtype 1 (CB1) agonist tetrahydrocannabinol (THC) is associated with the induction of psychosis in susceptible subjects and with the development of schizophrenia, whereas the use of cannabis variants with relatively high levels of cannabidiol (CBD) is associated with fewer psychotic experiences. Synthetic cannabinoid receptor agonists (SCRAs) are full agonists and often more potent than THC. Moreover, in contrast to natural cannabis, SCRAs preparations contain no CBD so that these drugs may have a higher psychosis-inducing potential than cannabis. This paper reviews the general toxicity profile and the adverse effects of SCRAs with special emphasis on their psychosis-inducing risk. The review shows that, compared with the use of natural cannabis, the use of SCRAs may cause more frequent and more severe unwanted negative effects, especially in younger, inexperienced users. Psychosis and psychosis-like conditions seem to occur relatively often following the use of SCRAs, presumably due to their high potency and the absence of CBD in the preparations. Studies on the relative risk of SCRAs compared with natural cannabis to induce or evoke psychosis are urgently needed.
© The Author(s) 2015.
Introduction and AimsSynthetic cannabinoid dependence and withdrawal are not well described in the literature. We aimed to report on the characteristics and treatment course of clients attending a detoxification service for support with synthetic cannabinoid withdrawal in Auckland, New Zealand.Design and MethodsA retrospective audit of electronic and paper files for clients presenting for treatment in association with problematic synthetic cannabinoid use between May 2013 and May 2014 was conducted. Demographic information, reported synthetic cannabinoid use, other substance use, reported adverse effects, withdrawal symptoms and treatment information were recorded using a piloted template. Descriptive statistics were used to summarise the characteristics of the audit sample.ResultsIn the 12 month period, 47 people presented to detoxification services reporting problems withdrawing from synthetic cannabinoids. Twenty clients were admitted for medical management within an inpatient setting. Coexisting substance dependence apart from nicotine dependence was low. The most common withdrawal symptoms were agitation, irritability, anxiety and mood swings. Withdrawal symptoms were managed with diazepam and quetiapine.Discussion and Conclusions
The harm associated with use of synthetic cannabinoids has had a direct impact on the utilisation of specialist alcohol and drug services in Auckland, New Zealand. Many clients with synthetic cannabinoid withdrawal symptoms required intensive support including medication and admission to an inpatient detoxification unit. Clients withdrawing from synthetic cannabinoids were the third largest group of clients admitted to inpatient detoxification services in Auckland, New Zealand, between May 2013 and May 2014. [Macfarlane V, Christie G. Synthetic cannabinoid withdrawal: A new demand on detoxification services. Drug Alcohol Rev 2015]
Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases.
© 2014 Pharmacotherapy Publications, Inc.
The abuse of synthetic psychoactive substances known as "designer drugs," or "new psychoactive substances" (NPS), is increasing at an alarming rate. NPS are purchased as alternatives to traditional illicit drugs of abuse and are manufactured to circumvent laws regulating the sale and use of controlled substances. Synthetic cathinones (i.e., "bath salts") and synthetic cannabinoids (i.e., "spice") are two types of NPS that have received substantial media attention. Although low recreational doses of bath salts or spice compounds can produce desirable effects, high doses or chronic exposure often leads to dangerous medical consequences, including psychosis, violent behaviors, tachycardia, hyperthermia, and even death. Despite the popularity of NPS, there is a paucity of scientific data about these drugs. Here we provide a brief up-to-date review describing the mechanisms of action and neurobiological effects of synthetic cathinones and cannabinoids.
Synthetic cannabinoid use has become widespread, leading to increased burdens on health care providers. Symptoms range from agitation and psychosis to seizures and acute kidney injury. We report a case where a patient was assessed and treated twice within 12 h for seizures following synthetic cannabinoid intoxication. Blood sample determinations showed low concentrations of analogues not previously reported, some of which are legal. Clinicians should be aware that synthetic cannabinoids may cause an array of severe health consequences. Given the ever evolving structure of available analogues, clinicians must also be prepared for other unexpected adverse effects.
An increasing number of synthetic cannabinoids have become available on the black market in recent years, and health professionals have seen a corresponding increase in use of these compounds among patients with psychiatric disorders. Unfortunately, there is almost no research available in the literature on this topic, and what little exists is based on case reports of individuals without psychiatric disorders. Synthetic cannabinoids are functionally similar to, but structurally different from, delta-9-tetrahydrocannabinol, the active principle in cannabis, and are problematic for many reasons. The psychotropic action of synthetic cannabinoids in patients with schizophrenia is unpredictable, with very diverse clinical presentations. These drugs can be much more potent than delta-9-tetrahydrocannabinol, they are readily available and difficult to detect. The gold standard for identification of synthetic cannabinoids is gas chromatography with mass spectrometry, but even this is difficult because new formulations of these designer drugs are constantly emerging. In this manuscript, we provide an overview and discussion of synthetic cannabinoids and present four cases of patients with synthetic cannabinoid intoxication who were hospitalized in our intensive psychiatric unit at the time of intoxication. All patients had a history of schizophrenia and had been hospitalized several times previously. While hospitalized, they smoked an unknown substance brought in by a visitor, which was then confirmed using gas chromatography with mass spectrometry to be the synthetic cannabinoid AM-2201. Our patients experienced predominantly psychiatric adverse clinical effects. We observed the appearance of new psychotic phenomena, without exacerbation of their previously known psychotic symptoms, as well as the occurrence or marked worsening of mood and anxiety symptoms. Despite several similar reactions, and even though they ingested the same exact substance, the clinical picture differed markedly between individual patients. We assume that the acute effects of synthetic cannabinoids in patients with schizophrenia would be different from those in persons without psychotic disorders. The reasons for this difference could be the actual symptomatology of the presenting disorder, the impact of psychopharmacotherapy, individual patient differences and probably many, as yet unknown, factors. The long-term consequences of synthetic cannabinoid use on preexisting psychotic disorders are unclear.
Purpose - 'Spice’ products are synthetic cannabimetics (SC; also called 'synthetic cannabinoids')-based designer drugs used as a legal alternative to cannabis for their very strong THC-like effects. We aimed here at providing an analysis of more recent clinical and pharmacology/toxicology findings relating to SC and describe how they could impact on health, with a particular focus on mental health.
Design/methodology/approach - A systematic search and descriptive analysis of the available evidence on psychopathological issues related to misuse was here performed, whilst taking into account the Pubmed/Medline databases, a range of conference proceedings and national/international agencies’ reports.
Findings - While THC is a partial agonist, SC are full agonists on the CB-rs and the administration of multiple SC can produce additive and/or synergistic agonistic interaction effects on the endocannabinoid system. These levels of strong CB-rs’ activation may be high enough to produce severe physiological and psychological disturbances. The available evidence suggests an existing relationship between SC use and psychosis (‘Spiceophrenia’). The acute SC intoxication is usually characterized by tachycardia/hypertension; visual/auditory hallucinations; mydriasis; agitation/anxiety; tachypnoea; nausea/vomiting; and seizures.
Research limitations/implications - The absence of clinical trials and longitudinal studies, together with the heterogeneity of SC compounds does not facilitate a precise assessment of the health risks related to their use, with long-term effects being of particular concern.
Originality/value - Appropriate, non judgemental, prevention campaigns with a special focus on the differences between SC and cannabis may need to be organized on a large scale. At the same time, clinicians need to be regularly updated about NPS, including SC, to promptly recognize signs/symptoms of intoxication.
Context and objectives:
Synthetic cannabinoids are illegal drugs of abuse known to cause adverse neurologic and sympathomimetic effects. They are an emerging health risk: 11% of high school seniors reported smoking them during the previous 12 months. We describe the epidemiology of a toxicologic syndrome of acute kidney injury associated with synthetic cannabinoids, review the toxicologic and public health investigation of the cluster, and describe clinical implications of the cluster investigation.
Materials and methods:
Case series of nine patients affected by the toxicologic syndrome in Oregon and southwestern Washington during May-October 2012. Cases were defined as acute kidney injury (creatinine > 1.3 mg/dL) among persons aged 13-40 years without known renal disease who reported smoking synthetic cannabinoids. Toxicology laboratories used liquid chromatography and time-of-flight mass spectrometry to test clinical and product specimens for synthetic cannabinoids, their metabolites, and known nephrotoxins. Public health alerts informed clinicians, law enforcement, and the community about the cluster and the need to be alert for toxidromes associated with emerging drugs of abuse.
Results:
Patients were males aged 15-27 years (median, 18 years), with intense nausea and flank or abdominal pain, and included two sets of siblings. Peak creatinine levels were 2.6-17.7 mg/dL (median, 6.6 mg/dL). All patients were hospitalized; one required dialysis; none died. No alternate causes of acute kidney injury or nephrotoxins were identified. Patients reported easily purchasing synthetic cannabinoids at convenience, tobacco, and adult bookstores. One clinical and 2 product samples contained evidence of a novel synthetic cannabinoid, XLR-11 ([1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone).
Discussion and conclusion:
Whether caused by direct toxicity, genetic predisposition, or an as-yet unidentified nephrotoxin, this association between synthetic cannabinoid exposure and acute kidney injury reinforces the need for vigilance to detect new toxicologic syndromes associated with emerging drugs of abuse. Liquid chromatography and time-of-flight mass spectrometry are useful tools in determining the active ingredients in these evolving products and evaluating them for toxic contaminants.
Sudden cardiac death (SCD) accounts for up to 450,000 deaths every year in the United States (Zipes et al. (2006)). Most cases of sudden cardiac death occur in subjects with no prior history of heart disease (Myerburg et al. (1998)). The incidence of sudden death in a general population has been shown to increase contemporaneously with substance abuse (Phillips et al. (1999)). The causative association of sudden death with cocaine, methadone, and volatile agents is well established (Adgey et al. (1995) and Isner et al. (1986)). We describe a case of out-of-hospital cardiac arrest temporally related to abuse of the synthetic cannabinoid street drug known as K2. To our knowledge, there are no previously documented cases of sudden cardiac death associated with synthetic cannabinoids although they have been linked to myocardial infarction in teenagers despite normal coronary angiography (Mir et al. (2011)).
Context:
Synthetic cannabinoids have been manufactured, sold, and consumed for recreational purposes since at least 2004; their use has been associated with adverse psychiatric, cardiovascular, renal, pulmonary, and neurologic effects. We report simultaneous canine and human clinical cases associated with exposure to a novel synthetic cannabinoid, PB-22 (QUPIC).
Case report:
A 22-year-old man brought his dog to a veterinary clinic after it had a seizure. During the course of the canine's evaluation, the human patient was witnessed to have a generalized tonic-clonic seizure. He was intubated for agitation and combativeness after his arrival to the emergency department (ED). He was extubated the next day without discernable sequelae. The canine patient received intravenous hydration and was also discharged to home after a period of close observation. The man later endorsed smoking three containers of a substance called "Crazy Monkey" daily for several weeks, but would not disclose how his dog had been exposed. The convulsant effects of "Crazy Monkey" were confirmed in this patient when, three months later, he was sedated, paralyzed, intubated, and admitted to another local hospital for seizures in the context of smoking the same product.
Discussion:
Laboratory analysis of samples obtained from the human and canine patients. A sample of the product (labeled "Crazy Monkey") revealed the presence of PB-22 (QUPIC), a novel synthetic cannabinoid. Additionally, serum and urine samples from the human patient contained metabolites of a second compound, UR-144.
Conclusion:
We present a laboratory-confirmed case report of human and canine neurotoxicity associated with a novel synthetic cannabinoid, PB-22 (QUIPIC).
Context. Synthetic cannabinoids have been manufactured, sold, and consumed for recreational purposes since at least 2004; their use has been associated with adverse psychiatric, cardiovascular, renal, pulmonary, and neurologic effects. We report simultaneous canine and human clinical cases associated with exposure to a novel synthetic cannabinoid, PB-22 (QUPIC). Case report. A 22-year-old man brought his dog to a veterinary clinic after it had a seizure. During the course of the canine's evaluation, the human patient was witnessed to have a generalized tonic-clonic seizure. He was intubated for agitation and combativeness after his arrival to the emergency department (ED). He was extubated the next day without discernable sequelae. The canine patient received intravenous hydration and was also discharged to home after a period of close observation. The man later endorsed smoking three containers of a substance called "Crazy Monkey" daily for several weeks, but would not disclose how his dog had been exposed. The convulsant effects of "Crazy Monkey" were confirmed in this patient when, three months later, he was sedated, paralyzed, intubated, and admitted to another local hospital for seizures in the context of smoking the same product. Discussion. Laboratory analysis of samples obtained from the human and canine patients. A sample of the product (labeled "Crazy Monkey") revealed the presence of PB-22 (QUPIC), a novel synthetic cannabinoid. Additionally, serum and urine samples from the human patient contained metabolites of a second compound, UR-144. Conclusion. We present a laboratory-confirmed case report of human and canine neurotoxicity associated with a novel synthetic cannabinoid, PB-22 (QUIPIC).
The link between cannabis use and psychosis comprises three distinct relationships: acute psychosis associated with cannabis intoxication; acute psychosis that lasts beyond the period of acute intoxication; and persistent psychosis not time-locked to exposure. Experimental studies reveal that cannabis, delta-9-tetrahydrocannabinol (THC) and synthetic cannabinoids reliably produce transient positive, negative, and cognitive symptoms in healthy volunteers. Case studies indicate that cannabinoids can induce acute psychosis that lasts beyond the period of acute intoxication but resolves within a month. Exposure to cannabis in adolescence is associated with a risk for later psychotic disorder in adulthood; this association is consistent, temporally related, shows a dose response, and is biologically plausible. However, cannabis is neither necessary nor sufficient to cause a persistent psychotic disorder. More likely, it is a component cause that interacts with other factors to result in psychosis. The link between cannabis and psychosis is moderated by age at onset of cannabis use, childhood abuse, and genetic vulnerability. While more research is needed to better characterize the relationship between cannabinoid use and the onset and persistence of psychosis, clinicians should be mindful of the potential risk of psychosis, especially in vulnerable populations, including adolescents and those with a psychosis diathesis.
Background:
Service user perspectives are essential for the evaluation and development of mental health services. Service users expressing less satisfaction with services subsequently have poorer treatment outcomes.
Aims:
To measure satisfaction with services following psychiatric admission, and to explore its relationship with a number of clinical and service factors.
Methods:
A multi-centre observational study was conducted across three mental health services in Ireland. Service users were interviewed and provided with self-report questionnaires. The Client Satisfaction Questionnaire (CSQ-8) was used to measure treatment satisfaction.
Results:
The overall level of satisfaction with services was good (CSQ-8 mean score 24.5). Service users who were admitted involuntarily, who experienced physical coercion and lower levels of procedural justice were less satisfied. A better therapeutic relationship, improved insight and better functioning were associated with higher levels of treatment satisfaction.
Conclusion:
Mental health services should implement strategies to ameliorate the effects of factors associated with lower levels of treatment satisfaction.
Background:
This is the 31st Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of January 1, 2013, 57 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 8.08 [7.10, 11.63] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.
Methodology:
We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center (PC) cases with medical outcomes of death were evaluated by a team of 38 medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death.
Results:
In 2013, 3,060,122 closed encounters were logged by NPDS: 2,188,013 human exposures, 59,496 animal exposures, 806,347 information calls, 6,116 human-confirmed nonexposures, and 150 animal-confirmed nonexposures. Total encounters showed a 9.3% decline from 2012, while health care facility human exposure calls were essentially flat, decreasing by 0.1%.All information calls decreased 21.4% and health care facility (HCF) information calls decreased 8.5%, medication identification requests (drug ID) decreased 26.8%, and human exposures reported to US PCs decreased 3.8%. Human exposures with less serious outcomes have decreased 3.7% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.7% per year since 2000. The top five substance classes most frequently involved in all human exposures were analgesics (11.5%), cosmetics/personal care products (7.7%), household cleaning substances (7.6%), sedatives/hypnotics/antipsychotics (5.9%), and antidepressants (4.2%). Sedative/hypnotics/antipsychotics exposures as a class increased most rapidly (2,559 calls/year) over the last 13 years for cases showing more serious outcomes. The top five most common exposures in children of 5 years or less were cosmetics/personal care products (13.8%), household cleaning substances (10.4%), analgesics (9.8%), foreign bodies/toys/miscellaneous (6.9%), and topical preparations (6.1%). Drug identification requests comprised 50.7% of all information calls. NPDS documented 2,477 human exposures resulting in death with 2,113 human fatalities judged related (RCF of 1, undoubtedly responsible; 2, probably responsible; or 3, contributory).
Conclusions:
These data support the continued value of PC expertise and need for specialized medical toxicology information to manage the more severe exposures, despite a decrease in calls involving less severe exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the United States. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for public health surveillance for all types of exposures, public health event identification, resilience response and situational awareness tracking. NPDS is a model system for the nation and global public health.
Unlabelled:
Cannabis use is associated with an earlier age of onset of psychosis (AOP). However, the reasons for this remain debated.
Methods:
We applied a Cox proportional hazards model to 410 first-episode psychosis patients to investigate the association between gender, patterns of cannabis use, and AOP.
Results:
Patients with a history of cannabis use presented with their first episode of psychosis at a younger age (mean years = 28.2, SD = 8.0; median years = 27.1) than those who never used cannabis (mean years = 31.4, SD = 9.9; median years = 30.0; hazard ratio [HR] = 1.42; 95% CI: 1.16-1.74; P < .001). This association remained significant after controlling for gender (HR = 1.39; 95% CI: 1.11-1.68; P < .001). Those who had started cannabis at age 15 or younger had an earlier onset of psychosis (mean years = 27.0, SD = 6.2; median years = 26.9) than those who had started after 15 years (mean years = 29.1, SD = 8.5; median years = 27.8; HR = 1.40; 95% CI: 1.06-1.84; P = .050). Importantly, subjects who had been using high-potency cannabis (skunk-type) every day had the earliest onset (mean years = 25.2, SD = 6.3; median years = 24.6) compared to never users among all the groups tested (HR = 1.99; 95% CI: 1.50- 2.65; P < .0001); these daily users of high-potency cannabis had an onset an average of 6 years earlier than that of non-cannabis users.
Conclusions:
Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users.
Abstract In 2008, the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) detected unregulated, psychoactive synthetic cannabinoids (SCBs) in purportedly all-natural herbal incense products (often known as K2 or Spice) that were being covertly abused as marijuana substitutes. These drugs, which include JWH-018, JWH-073 and CP-47,497, bind and activate the cannabinoid receptors CB1R and CB2R with remarkable potency and efficacy. Serious adverse effects that often require medical attention, including severe cardiovascular, gastrointestinal and psychiatric sequelae, are highly prevalent with SCB abuse. Consequently, progressively restrictive legislation in the US and Europe has banned the distribution, sale and use of prevalent SCBs, initiating cycles in which herbal incense manufacturers replace banned SCBs with newer unregulated SCBs. The contents of the numerous, diverse herbal incense products was unknown when SCB abuse first emerged. Furthermore, the pharmacology of the active components was largely uncharacterized, and confirmation of SCB use was hindered by a lack of known biomarkers. These knowledge gaps prompted scientists across multiple disciplines to rapidly (1) monitor, identify and quantify with chromatography/mass spectrometry the ever-changing contents of herbal incense products, (2) determine the metabolic pathways and major urinary metabolites of several commonly abused SCBs and (3) identify active metabolites that possibly contribute to the severe adverse effect profile of SCBs. This review comprehensively describes the emergence of SCB abuse and provides a historical account of the major case reports, legal decisions and scientific discoveries of the "K2/Spice Phenomenon". Hypotheses concerning potential mechanisms SCB adverse effects are proposed in this review.
Neurologists and emergency department physicians are frequently involved in the comprehensive evaluation of a first generalized seizure. An important aspect of this evaluation is a detailed history which can identify a provoked seizure secondary to drug toxicity and hence avoid unnecessary treatment with antiepileptic drugs. "Spice" is an umbrella term for a variety of synthetic cannabinoid products whose inhalation has been associated with an increasing number of toxic side effects resulting in emergency department visits. These side effects (including psychosis, tachyarrhythmia, and seizures) are not typically seen with marijuana (Cannabis sativa) use. We report 2 patients with no prior history of neurological disease that experienced their first generalized tonic-clonic seizure after smoking Spice. The mechanism behind the possible proconvulsant effect of synthetic cannabinoids is not known, but it may be due to their effects at the cannabinoid receptor CB1. Although the US Drug Enforcement Administration placed 5 synthetic cannabinoids into schedule 1 for a 12-month period beginning March 2011, new Spice products containing different synthetic cannabinoids continue to emerge. Because synthetic cannabinoids are not detectable on commercial drug screens it is important that neurologists and emergency department physicians consider Spice inhalation in their differential diagnosis of a first generalized seizure.
In recent years, several synthetic cannabinoid compounds have become popular recreational drugs of abuse because of their psychoactive properties. This paper presents toxicological findings of synthetic cannabinoids in whole blood from some cases of severe intoxication including quantitative data from recreational users and a fatal intoxication. Samples were analyzed by liquid chromatography-tandem mass spectrometry in a scheduled multiple reaction mode after a basic liquid extraction. Twenty-nine synthetic cannabinoids were included in the method. In our data set of ∼3000 cases, 28% were found positive for one or more synthetic cannabinoid(s). The most common finding was AM-2201. Most of the analytes had median concentrations of <0.5 ng/g in agreement with other published data. The emerging drugs MAM-2201 (n = 151) and UR-144 (n = 181) had mean (median) concentrations of 1.04 (0.37) and 1.26 (0.34), respectively. The toxicity of the synthetic cannabinoids seems to be worse than that of natural cannabis, probably owing to the higher potency and perhaps also to the presence of several different cannabinoids in the smoked incense and the difficulties of proper dosing. The acute toxic effects may under certain circumstances contribute to death.
Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally.
The availability, acute subjective effects-including self-reports posted on Erowid-laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed.
Spice is sold under the guise of potpourri or incense. Unlike delta-9-tetrahydrocannabinol, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned.
There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug detection tests for synthetic cannabinoids need to become clinically available.
The Deputy Administrator of the Drug Enforcement Administration (DEA) is issuing this final order to temporarily schedule four synthetic cannabinoids into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act (CSA). The substances are: Quinolin-8-yl 1-pentyl-1H-indole-3-carboxylate (PB-22; QUPIC); quinolin-8-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5-fluoro-PB-22; 5F-PB-22); N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA); and N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (ADB-PINACA). This action is based on a finding by the Deputy Administrator that the placement of these synthetic cannabinoids and their optical, positional, and geometric isomers, salts and salts of isomers into schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, import, export, engage in research, conduct instructional activities, and possess), or propose to handle these synthetic cannabinoids.
Recent advances in knowledge about cannabinoid receptor function have renewed interest in the association between cannabis and psychosis. Converging lines of evidence suggest that cannabinoids can produce a full range of transient schizophrenia-like positive, negative and cognitive symptoms. Cannabinoids also produce some psychophysiological deficits that are known to be present in schizophrenia. Also clear is that in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Increasing evidence suggests that early and heavy cannabis exposure may increase the risk of developing a psychotic disorder such as schizophrenia. The relationship between cannabis exposure and schizophrenia fulfills some, but not all, of the usual criteria for causality. However, most people who use cannabis do not develop schizophrenia, and many people diagnosed with schizophrenia have never used cannabis. Therefore, it is likely that cannabis exposure is a "component cause" that interacts with other factors to contribute to the development of schizophrenia or other psychotic disorders, but is neither necessary nor sufficient to do so alone. As direct causes of schizophrenia have not been identified, the implications for public health policy are such that the role of component causes such as cannabinoid exposure should remain a focus of further study. Finally, further work is necessary in order to identify the factors that underlie individual vulnerability to cannabinoid-related psychosis and to elucidate the biological mechanisms underlying this risk.
The recent recreational use of synthetic cannabinoid ligands, collectively referred to as 'Spice', has raised concerns about their safety and possible differences in their biological effect(s) from marijuana/Δ-tetrahydrocannabinol (THC). AM2201, a highly efficacious, potent cannabinoid receptor 1 (CB1R) agonist, is a recently detected compound in 'Spice' preparations. Furthermore, structural analogs of AM2201 are now being found in 'Spice'. The present studies were conducted to investigate their Δ-THC-like effects using drug (Δ-THC) discrimination in rats. Results show that the tested compounds were potent cannabinergics that generalized to the response to Δ-THC, with AM2201 being most potent, exhibiting a 14-fold potency difference over Δ-THC. The other analogs were between 2.5-fold and 4-fold more potent than THC. Surmountable antagonism of AM2201 with the selective CB1R antagonist/inverse agonist rimonabant also established that the discrimination is CB1R dependent. Time-course data reveal that AM2201 likely peaks rapidly with an in-vivo functional half-life of only 60 min. The present data confirm and extend previous observations regarding Δ-THC-like effects of 'Spice' components.
The urge to gain information on a new drug marketed online as 'Psyclone' has emerged after the death of a 38-year-old man in Bolton (UK). The fatality appeared to be a consequence of smoking this psychoactive product.
From October to December 2013, qualitative searches of the Web have been carried out in English and Italian, using the keywords 'Psyclone', 'Psyclone legal high', 'Psyclone incense' and 'Psyclone research chemical' on the Google search engine and on the database provided by the Global Public Health Intelligence Network.
Our research highlighted the existence of two psychoactive products labelled as Psyclone but with different contents and packaging: a herbal blend containing two synthetic cannabinoids (AKB-48 and 5f-PB-22) and a research chemical containing 50% ethylphenidate, 30% caffeine and 20% lidocaine. Desired and side effects of both compounds are explored in the paper.
Being sold as a legal product, Psyclone may appeal to recreational users, who remain unaware of its real content. This is a serious public health threat, which may lead to acute intoxications and fatalities. Further studies in the field, including Internet monitoring, are therefore required. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
Diversion of synthetic cannabinoids for abuse began in the early 2000s. Despite legislation banning compounds currently on the drug market, illicit manufacturers continue to release new compounds for recreational use. This study examined new synthetic cannabinoids AB-CHMINACA, AB-PINACA, and FUBIMINA, with the hypothesis that these compounds, like those before them, would be highly susceptible to abuse. Cannabinoids were examined in vitro for binding and activation of CB1 receptors, and in vivo for pharmacological effects in mice and in Δ(9)-THC discrimination. AB-CHMINACA, AB-PINACA and FUBIMINA bound to and activated CB1 and CB2 receptors, and produced locomotor suppression, antinociception, hypothermia, and catalepsy. Further, these compounds, along with JWH-018, CP47,497, and WIN55,212-2, substituted for Δ(9)-THC in Δ(9)-THC discrimination. Rank order of potency correlated with CB1 receptor binding affinity, and all three compounds were full agonists in [(35)S]GTPγS binding, as compared to the partial agonist Δ(9)-THC. Indeed, AB-CHMINACA and AB-PINACA exhibited higher efficacy than most known full agonists of the CB1 receptor. Preliminary analysis of urinary metabolites of the compounds revealed the expected hydroxylation. AB-PINACA and AB-CHMINACA are of potential interest as research tools due to their unique chemical structures and high CB1 receptor efficacies. Further studies on these chemicals is likely to include research on understanding cannabinoid receptors and other components of the endocannabinoid system that underlie the abuse of synthetic cannabinoids.
The American Society for Pharmacology and Experimental Therapeutics.
Since 2009, synthetic cannabinoid (SC) use has emerged as a growing public health threat in the United States (US). Several outbreaks of unexpected, severe toxicity linked to SC use have been reported since 2012. Reports of varied and significant morbidity after SC use are expected to increase because newer compounds enter the marketplace more frequently as manufacturers attempt to circumvent regulatory efforts.
We report a cluster of 7 patients who experienced a spectrum of anxiety, delirium, psychosis, and aggressive behaviors after smoking the same SC-containing product at a party. An 8th patient with the same exposure source presented with delayed onset seizures. Biologic samples were analyzed for novel, newly identified SCs belonging to the FUBINACA family of compounds. A previously unknown SC, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (ADB-PINACA) was identified in biologic samples from 7 of the individuals. ADB-PINACA was identified in the SC-containing product ("Crazy Clown") seized by law enforcement and identified as the product smoked by the 8 patients in the reported cluster. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The information compiled using this cluster of cases, and a similar reported outbreak of altered mental status in Colorado, implicating the same SC (ADB-PINACA) and brands of SC-containing products, aided the US Drug Enforcement Administration in its temporary scheduling of ADB-PINACA and three other SCs. In this outbreak, close cooperation between public health and law enforcement allowed for a rapid intervention, which halted the outbreak by interrupting the common source and accelerated regulatory efforts to prevent further morbidity and mortality.
Copyright © 2015 Elsevier Inc. All rights reserved.
Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol (Δ9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50=0.01 mg/kg) and decreased response rate (ED50=0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940=JWH-018>Δ9-THC=WIN-55212-2=JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and Δ9-THC decreased rectal temperature by 2.2 and 2.8 °C, respectively; the doses decreasing temperature by 2 °C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and Δ9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoids on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects.
In January 2014, the US government temporarily designated 5F-PB-22, along with three other synthetic cannabinoids (AB-FUBINACA,
ADB-PINACA and PB-22), into Schedule I. Over the course of a 4-month time period (July–October 2013), our laboratory quantitatively
identified 5F-PB-22 in specimens obtained from four postmortem cases. We describe the four cases, to include pertinent autopsy
findings and decedent histories, together with quantitative results for 5F-PB-22 determined in postmortem blood and antemortem
serum. Samples were prepared via a liquid–liquid extraction at pH 10.2 into hexane : ethyl acetate. Instrumental analysis
was achieved with liquid chromatography coupled with electrospray ionization tandem mass spectrometry operating in multiple
reaction monitoring mode. Two ion transitions were monitored for the analyte of interest, and one ion transition was monitored
for the internal standard. The observed concentration range of 5F-PB-22 is 1.1–1.5 ng/mL for three postmortem blood specimens
and one antemortem serum specimen. Three of the decedents experienced abrupt, sudden death; however, one decedent expired
after a rapidly deteriorating hospital course.
Background:
Despite growing concern about the increased rates of synthetic cannabinoid (SC) use and their effects, only limited data are available that addresses these issues. This study assessed the extent of SC product use and reported effects among a cohort of adult marijuana and tobacco users.
Methods:
A brief telephone interview was conducted with individuals who had given permission to be contacted for future research while screening for a cannabis/nicotine dependence medication development study (NCT01204723).
Results:
Respondents (N = 42; 88% participation rate) were primarily young adults, male, racially diverse, and high school graduates. Nearly all currently smoked tobacco and cannabis, with 86% smoking cannabis on 5 or more days per week. Nearly all (91%) were familiar with SC products, half (50%) reported smoking SC products previously, and a substantial minority (24%) reported current use (i.e., past month). Despite a federal ban on 5 common SCs, which went into effect on March 1, 2011, a number of respondents reported continued SC product use. Common reasons reported for use included, but were not limited to, seeking a new "high" similar to that produced by marijuana and avoiding drug use detection via a positive urine screen. The primary side effects were trouble thinking clearly, headache, dry mouth, and anxiety. No significant differences were found between synthetic cannabinoid product users (ever or current) and nonusers by demographics or other characteristics.
Conclusions:
Among current marijuana and tobacco users, SC product consumption was common and persisted despite a federal ban. The primary reasons for the use of SC-containing products seem to be to evade drug detection and to experience a marijuana-like high.
Designer drugs are analogues or derivatives of illicit drugs with a modification of their chemical structure in order to circumvent current legislation for controlled substances. Designer drugs of abuse have increased dramatically in popularity all over the world for the past couple of years. Currently, the qualitative seized-drug analysis is mainly performed by gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) in which most of these emerging designer drug derivatives are extensively fragmented not presenting a molecular ion in their mass spectra. The absence of molecular ion and/or similar fragmentation pattern among these derivatives may cause the equivocal identification of unknown seized-substances. In this study, the qualitative identification of 34 designer drugs, mainly synthetic cannabinoids and synthetic cathinones, were performed by gas chromatography-triple quadrupole-tandem mass spectrometry with two different ionization techniques, including electron ionization (EI) and chemical ionization (CI) only focusing on qualitative seized-drug analysis, not from the toxicological point of view. The implementation of CI source facilitates the determination of molecular mass and the identification of seized designer drugs. Developed multiple reaction monitoring (MRM) mode may increase sensitivity and selectivity in the analysis of seized designer drugs. In addition, CI mass spectra and MRM mass spectra of these designer drug derivatives can be used as a potential supplemental database along with EI mass spectral database. Copyright © 2014 John Wiley & Sons, Ltd.
New types of synthetic cannabinoid designer drugs are constantly introduced to the illicit drug market to circumvent legislation. Recently, N- (1-Adamant yl)- 1- (5- fluoropentyl)- 1H- indazole- 3- carboxamide (5F-AKB-48), also known as 5F-APINACA, was identified as an adulterant in herbal products. This compound deviates from earlier JHW-type synthetic cannabinoids by having an indazole ring connected to an adamantyl group via a carboxamide linkage. Synthetic cannabinoids are completely metabolized, and identification of the metabolites is thus crucial when using urine as the sample matrix. Using an authentic urine sample and high-resolution accurate-mass Fourier transform Orbitrap mass spectrometry, we identified 16 phase-I metabolites of 5F-AKB-48. The modifications included mono-, di-, and trihydroxylation on the adamantyl ring alone or in combination with hydroxylation on the N-fluoropentylindazole moiety, dealkylation of the N-fluoropentyl side chain, and oxidative loss of fluorine as well as combinations thereof. The results were compared to human liver microsomal (HLM) incubations, which predominantly showed time-dependent formation of mono-, di-, and trihydroxylated metabolites having the hydroxyl groups on the adamantyl ring. The results presented here may be used to select metabolites specific of 5F-AKB-48 for use in clinical and forensic screening. Copyright © 2014 John Wiley & Sons, Ltd.
Synthetic cannabinoids have become a worldwide epidemic because they provide a sometimes legal, easily accessible, and presumably safe alternative to marijuana. Recently published reports have linked acute psychosis, myocardial infarctions, convulsions, self-harm, and even terrorist organizations to these designer substances. This case report outlines the first reported case of Black Diamond, a synthetic cannabis, leading to a self-inflicted burn to the bilateral upper extremities requiring a transradial amputation of the right arm and a toe transfer procedure of the left hand after loss of all digits. The patient presented to the emergency department with self-inflicted fourth-degree burns to the bilateral hands and forearms with second-degree burns of the face, for a total body surface area of 14.5%. The patient was found by firefighters with his hands aflame on his kitchen stove. With no previous medical or psychiatric history and collateral information to confirm the patient's mental status prior to use of Black Diamond, the patient's acute psychotic episode was attributed to Black Diamond. After multiple procedures and a lengthy recovery, the patient completed his post-graduate education and entered the professional world. As orthopedic surgeons, we should be involved in educating the public on the harm of these designer drugs, including self-mutilation. The popularity of synthetic drugs in the United States will continue to present a major challenge to all health care providers. Orthopedists are on the front lines of this epidemic because these drugs push patients into risky, traumatic behavior.
Stress-exposure produces excitoxicity and neuroinflammation, contributing to the cellular damage observed in stress-related neuropathologies. The endocannabinoid system is present in stress-responsive neural circuits and it is emerging as a homeostatic system. The aim of this study was to elucidate the possible regulatory role of cannabinoid-2 receptor in stress-induced excitotoxicity and neuroinflammation.
Different genetic and pharmacological approaches were used: 1) Wild type (WT), transgenic over-expressing CB2 receptor (CB2xP) and CB2 receptor knockout (CB2-KO) mice were exposed to immobilization/acoustic stress (2h/day for 4 days), and 2) the CB2 receptor agonist JWH-133 was administered daily (2 mg kg(-1) , i.p.) to WT and CB2 receptor-KO animals.
Stress-induced HPA axis activation was not modified by CB2 receptor manipulations. JWH-133 treatment or overexpression of CB2 resulted in an increase of control levels of glutamate uptake, which is then reduced by stress exposure back to control levels. JWH-133 prevented the stress-induced increase in the cytokines TNF-α and MCP-1, the nuclear factor kappa B, the enzymes inducible nitric oxide synthase 2 and cyclooxygenase-2 and the cellular oxidative/nitrosative damage (lipid peroxidation) in brain frontal cortex. CB2xP mice displayed anti-inflammatory/neuroprotective actions similar to those observed in JWH-133 pre-treated animals. Conversely, CB2-KO mice experiments indicated that the lack of CB2 receptor exacerbated stress-induced neuroinflammatory responses and validated the CB2 receptor-dependent effects of JWH-133.
These results suggest that pharmacological manipulation of CB2 receptor is a potential therapeutic strategy for the treatment of stress-related pathologies with a neuroinflammatory component, such as depression.
Young men in Colorado presented with altered mental status and seizures after ingestion of a synthetic cannabinoid known as black mamba. Medical toxicologists and public health and law enforcement officials identified 263 cases of exposure to this novel substance.To the Editor: Although early reports of exposure to synthetic cannabinoids described a benign course,(1) with little need for emergency care, on August 24, 2013, patients began to present to Denver emergency departments with severe symptoms after exposure to a novel synthetic cannabinoid known locally as black mamba. The Colorado Department of Public Health and Environment (CDPHE) was notified on September 3. Medical toxicologists and CDPHE epidemiologists developed a case definition and began prospective monitoring with assistance from the Centers for Disease Control and Prevention. Records from poison control centers, care providers in nonhospital settings, and law enforcement were reviewed. ...
A 59-year-old man was found dead in his house, where three sachets containing herbal blends were found on a table. The sachet contents were analyzed by gas chromatography–mass spectrometry and found to contain [1-(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl)methanone (MAM-2201). The deceased was subjected to forensic autopsy. There were neither external injuries nor endogenous diseases judged by macroscopic and microscopic observations. Liquid chromatography–electrospray ionization–tandem mass spectrometry was used to quantitate the concentrations of MAM-2201 in postmortem samples using deuterated MAM-2201 as internal standard. The MAM-2201 concentrations were: 12.4 ng/ml in whole blood; 18.1 ng/g in the liver; 11.2 ng/g in the kidney; 4.3 ng/g in the brain; and 1,535 ng/g in the adipose tissue. We concluded that the man’s death was caused by acute intoxication with MAM-2201. In addition, we propose that the adipose tissue is the specimen of choice to detect MAM-2201 in the unchanged form. To our knowledge, this is the first report of a fatal MAM-2201 poisoning case. In addition, this report is also the first to describe the distribution of the drug in postmortem human tissues and blood.
The use of synthetic cannabimimetics (SC; "spice" drugs) is increasing, especially among teenagers and young adults. In parallel with this, the number of studies describing intoxication episodes associated with psychotic symptoms in SC users is growing. We present both a systematic review of the related literature and a case report, which seems to highlight the existence of a possible association between SC use and psychosis.
Some 223 relevant studies were here identified and reviewed. Out of these, 120 full text articles were assessed for eligibility, and 41 were finally included in the systematic review.
According to the available data from the studies here identified, SC's average age of users was 22.97 years, and the male/female ratio was 3.16:1. SC compounds most often reported in studies using biological specimen analysis were JWH-018, JWH-073, JWH-122, CP-47,497, and JWH-250. Mounting evidence seemed to suggest that psychotic symptoms such as hallucinations and delusions may occur in acute/chronic SC users.
Although a clear causal link may not be here identified, the available evidence suggests that SC can trigger the onset of acute psychosis in vulnerable individuals and/or the exacerbation of psychotic episodes in those with a previous psychiatric history. Copyright © 2013 John Wiley & Sons, Ltd.