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PurposeAMB-FUBINACA is a synthetic cannabinoid receptor agonist (SCRA) which is primarily metabolised by hepatic enzymes producing AMB-FUBINACA carboxylic acid. The metabolising enzymes associated with this biotransformation remain unknown. This study aimed to determine if AMB-FUBINACA metabolism could be reduced in the presence of carboxylesterase (CES) inhibitors and recreational drugs commonly consumed with it. The affinity and activity of the AMB-FUBINACA acid metabolite at the cannabinoid type-1 receptor (CB1) was investigated to determine the activity of the metabolite.MethodsThe effect of CES1 and CES2 inhibitors, and delta-9-tetrahydrocannabinol (Δ9-THC) on AMB-FUBINACA metabolism were determined using both human liver microsomes (HLM) and recombinant carboxylesterases. Radioligand binding and cAMP assays comparing AMB-FUBINACA and AMB-FUBINACA acid were carried out in HEK293 cells expressing human CB1.ResultsAMB-FUBINACA was rapidly metabolised by HLM in the presence and absence of NADPH. Additionally, CES1 and CES2 inhibitors both significantly reduced AMB-FUBINACA metabolism. Furthermore, digitonin (100 µM) significantly inhibited CES1-mediated metabolism of AMB-FUBINACA by ~ 56%, while the effects elicited by Δ9-THC were not statistically significant. AMB-FUBINACA acid produced only 26% radioligand displacement consistent with low affinity binding. In cAMP assays, the potency of AMB-FUBINACA was ~ 3000-fold greater at CB1as compared to the acid metabolite.ConclusionsCES1A1 was identified as the main hepatic enzyme responsible for the metabolism of AMB-FUBINACA to its less potent carboxylic acid metabolite. This biotransformation was significantly inhibited by digitonin. Since other xenobiotics may also inhibit similar SCRA metabolic pathways, understanding these interactions may elucidate why some users experience high levels of harm following SCRA use.

Synthetic cannabinoid receptor agonists (SCRAs) remain one the most prevalent classes of new psychoactive substances (NPS) worldwide, and examples are generally poorly characterised at the time of first detection. We have synthesised a systematic library of amino acid-derived indole-, indazole-, and 7-azaindole-3-carboxamides related to recently detected drugs ADB-BUTINACA, APP-BUTINACA and ADB-P7AICA, and characterised these ligands for in vitro binding and agonist activity at cannabinoid receptor subtypes 1 and 2 (CB(1) and CB(2)), and in vivo cannabimimetic activity. All compounds showed high affinity for CB(1) (K(i) 0.299–538 nM) and most at CB(2) (K(i) = 0.912–2190 nM), and most functioned as high efficacy agonists of CB(1) and CB(2) in a fluorescence-based membrane potential assay and a βarr2 recruitment assay (NanoBiT®), with some compounds being partial agonists in the NanoBiT® assay. Key structure–activity relationships (SARs) were identified for CB(1)/CB(2) binding and CB(1)/CB(2) functional activities; (1) for a given core, affinities and potencies for tert-leucinamides (ADB-) > valinamides (AB-) ≫ phenylalaninamides (APP-); (2) for a given amino acid side-chain, affinities and potencies for indazoles > indoles ≫ 7-azaindoles. Radiobiotelemetric evaluation of ADB-BUTINACA, APP-BUTINACA and ADB-P7AICA in mice demonstrated that ADB-BUTINACA and ADB-P7AICA were cannabimimetic at 0.1 mg kg(−1) and 10 mg kg(−1) doses, respectively, as measured by pronounced decreases in core body temperature. APP-BUTINACA failed to elicit any hypothermic response up to the maximally tested 10 mg kg(−1) dose, yielding an in vivo potency ranking of ADB-BUTINACA > ADB-P7AICA > APP-BUTINACA.

Over 200 synthetic cannabinoid receptor agonists (SCRAs) have been identified as new psychoactive substances. Effective monitoring and characterization of SCRAs are hindered by the rapid pace of structural evolution. Ahead of possible appearance on the illicit drug market, new SCRAs were synthesized to complete a systematic library of cumyl-indole- (

The present work is the last of a three-part study investigating a panel of 30 systematically designed synthetic cannabinoid receptor agonists (SCRAs) including features such as the 4-pentenyl tail and varying head groups including amides and esters of l-valine (MMB, AB), l-tert-leucine (ADB), and l-phenylalanine (APP), as well as adamantyl (A) and cumyl moieties (CUMYL). Here, we evaluated these SCRAs for their capacity to activate the human cannabinoid receptor 1 (CB1) via indirect measurement of G protein recruitment. Furthermore, we comparatively evaluated the results obtained from three in vitro assays, based on the recruitment of beta-arrestin 2 (beta arr2 assay) or G alpha(i) protein (mini-G alpha(i) assay), or binding of [S-35]-GTP gamma S. The observed efficacies (E-max) varied depending on the conducted assay. Statistical analysis suggests that the population means of the relative intrinsic activity (RA(i)) significantly differ for the [S-35]-GTP gamma S assay and the other two assays, but the population means of the beta arr2 and mini-G alpha(i) assays were not statistically different. Our data suggest that differences observed between the beta arr2 and mini-G alpha(i) assays are the best predictor for 'biased agonism' towards beta arr or G protein recruitment in our study. SCRAs carrying an ADB or MPP moiety as a head group tended to produce elevated E-max values in the beta arr2 assay, which might result in a tendency of these compounds to cause pronounced tolerance in users-a hypothesis that should be evaluated further by future studies. In general, a comparison of efficacies derived from different assays is difficult and should only be conducted very cautiously.

Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest and most structurally diverse classes of new psychoactive substances (NPS). Despite this, pharmacological data are often lacking following the identification of a new SCRA in drug markets. In this first of a three-part series, we describe the synthesis, analytical characterization, and binding affinity of a proactively generated, systematic library of 30 indole, indazole, and 7-azaindole SCRAs related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA featuring a 4-pentenyl (4en-P), butyl (B/BUT), or 4-cyanobutyl (4CN-B/BUT) tail and a methyl l-valinate (MMB), methyl l-tert-leucinate (MDMB), methyl l-phenylalaninate (MPP), l-valinamide (AB), l-tert-leucinamide (ADB), l-phenylalaninamide (APP), adamantyl (A), or cumyl head group. Competitive radioligand binding assays demonstrated that the indazole core conferred the highest CB1 binding affinity (Ki = 0.17-39 nM), followed by indole- (Ki = 0.95-160 nM) and then 7-azaindole-derived SCRAs (Ki = 5.4-271 nM). Variation of the head group had the greatest effect on binding, with tert-leucine amides and methyl esters (Ki = 0.17-14 nM) generally showing the greatest affinities, followed by valine derivatives (Ki = 0.72-180 nM), and then phenylalanine derivatives (Ki = 2.5-271 nM). Adamantyl head groups (Ki = 8.8-59 nM) were suboptimal for binding, whereas the cumyl analogues consistently conferred high affinity (Ki = 0.62-36 nM). Finally, both butyl (Ki = 3.1-163 nM) and 4-cyanobutyl (Ki = 5.5-44 nM) tail groups were less favorable for CB1 binding than their corresponding 4-pentenyl counterparts (Ki = 0.72-25 nM).

Synthetic cannabinoid receptor agonists (SCRAs) are the second largest class of new psychoactive substances (NPS) and are associated with serious adverse effects and even death. Despite this, little pharmacological data are available for many of the most recent SCRAs. This study consists of three different parts, aiming to systematically evaluate a panel of 30 SCRAs using binding and different in vitro human cannabinoid 1 receptor (CB1 ) activation assays. The present Part II investigated the SCRA analogs for their CB1 activation via a β-arrestin recruitment assay. The panel was systematically designed to include key structural sub-features of recent SCRAs. Thus, the 4-pentenyl tail of MMB-4en-PICA and MDMB-4en-PINACA was retained while incorporating varying head groups from other prevalent SCRAs, including amides and esters of L-valine, L-tert-leucine, and L-phenylalanine, and adamantyl and cumyl moieties. All 30 SCRAs activated CB1 , with indazoles generally showing the greatest potency (EC50 = 1.88-281 nM), followed by indoles (EC50 = 11.5-2293 nM), and the corresponding 7-azaindoles (EC50 = 62.4-9251 nM). Several subunit-linked structure-activity relationships were identified: (i) tert-leucine-functionalized SCRAs were more potent than the corresponding valine derivatives; (ii) no major difference in potency or efficacy was observed between tert-leucine/valine-derived amides and the corresponding methyl esters; however, phenylalanine analogs were affected by this change; and (iii) minor structural changes to the 4-pentenyl substituent had little influence on activity. These findings elucidate structural features that modulate the CB1 activation potential of currently prevalent SCRAs and a systematic panel of analogs, some of which may appear in NPS markets in future.

Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances (NPS) with structurally diverse compounds emerging each year. Due to the rapid pace at which these drugs enter the market, there is often little or nil information regarding the pharmacology of these substances despite widespread human use. In this study, 12 recently emerged SCRAs (reported between 2018 and 2020) were synthesized, analytically characterized, and pharmacologically evaluated using a live cell-based nanoluciferase complementation reporter assay that monitors in vitro cannabinoid receptor type 1 (CB1) activation via its interaction with beta-arrestin 2 (beta arr2). All synthesized SCRAs acted as agonists of CB1, although differences in potency (EC50 = 2.33-5475 nM) and efficacy (E-max = 37-378%) were noted, and several structure-activity relationships were identified. SCRAs featuring indazole cores (EC50 = 2.33-159 nM) were generally of equal or greater potency than indole analogues (EC so = 32.9-330 nM) or 7-azaindole derivatives (EC50 = 64.0-5475 nM). Interestingly, with the exception of APP-BINACA (E max = 75.7%) and SF-A-P7AICA (E-max = 37.4%), all SCRAs showed greater efficacy than the historical SCRA JWH-018 to which responses were normalized (E-max = 142-378%). The most potent CBI agonists in the study were ADB-BINACA (EC50 = 6.36 nM), 4F-MDMB-BINACA (EC50 = 7.39 nM), and MDMB-4en-PINACA (EC50 = 2.33 nM). Notably, all of these SCRAs featured an indazole core as well as a "bulky" tert-butyl moiety in the pendant amino acid side chain. This study confirms that recently detected SCRAs 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-ABP7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA were all able to activate the CB1 receptor in vitro, albeit to different extents, and are potentially psychoactive in vivo. These results indicate that further evaluation of these widely used NPS is warranted to better understand the risks associated with human consumption of these drugs.

Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS). They commonly comprise

The sigma 1 receptor (S1R) is widely expressed in the CNS and is mainly located on the endoplasmic reticulum. The S1R is involved in the regulation of many neurotransmission systems and, indirectly, in neurodegenerative diseases. The S1R may therefore represent an interesting neuronal biomarker in neurodegenerative diseases such as Parkinson's (PD) or Alzheimer's diseases (AD). Here we present the characterisation of the S1R-specific 18F-labelled tracer 18F-IAM6067 in two animal models and in human brain tissue. Methods: Wistar rats were used for PET-CT imaging (60 min dynamic acquisition) and metabolite analysis (1, 2, 5, 10, 20, 60 min post-injection). To verify in vivo selectivity, haloperidol, BD1047 (S1R ligand), CM398 (S2R ligand) and SB206553 (5HT2B/C antagonist) were administrated for pre-saturation studies. Excitotoxic lesions induced by intra-striatal injection of AMPA were also imaged by 18F-IAM6067 PET-CT to test the sensitivity of the methods in a well-established model of neuronal loss. Tracer brain uptake was also verified by autoradiography in rats and in a mouse model of PD (intrastriatal 6-hydroxydopamine (6-OHDA) unilateral lesion). Finally, human cortical binding was investigated by autoradiography in three groups of subjects (control subjects with Braak ≤2, and AD patients, Braak >2 & ≤4 and Braak >4 stages). Results: We demonstrate that despite rapid peripheral metabolism of 18F-IAM6067, radiolabelled metabolites were hardly detected in brain samples. Brain uptake of 18F-IAM6067 showed differences in S1R anatomical distribution, namely from high to low uptake: pons-raphe, thalamus medio-dorsal, substantia nigra, hypothalamus, cerebellum, cortical areas and striatum. Pre-saturation studies showed 79-90% blockade of the binding in all areas of the brain indicated above except with the 5HT2B/C antagonist SB206553 and S2R ligand CM398 which induced no significant blockade, indicating good specificity of 18F-IAM6067 for S1Rs. No difference between ipsi- and contralateral sides of the brain in the mouse model of PD was detected. AMPA lesion induced a significant 69% decrease in 18F-IAM6067 uptake in the globus pallidus matching the neuronal loss as measured by NeuN, but only a trend to decrease (-16%) in the caudate putamen despite a significant 91% decrease in neuronal count. Moreover, no difference in the human cortical binding was shown between AD groups and controls. Conclusion: This work shows that 18F-IAM6067 is a specific and selective S1R radiotracer. The absence or small changes in S1R detected here in animal models and human tissue warrants further investigations and suggests that S1R might not be the anticipated ideal biomarker for neuronal loss in neurodegenerative diseases such as AD and PD.

Cannabis sativa produces a complex mixture of many bioactive molecules including terpenophenolic compounds known as phytocannabinoids. Phytocannabinoids come in neutral forms (e.g., Δ9-tetrahydrocannabinol, THC; cannabidiol, CBD; etc.) or as acid precursors, which are dominant in the plant (e.g., Δ9-tetrahydrocannabinolic acid, THCA; cannabidiolic acid, CBDA; etc.). There is increasing interest in unlocking the therapeutic applications of the phytocannabinoid acids; however, the present understanding of the basic pharmacology of phytocannabinoid acids is limited. Herein the brain and plasma pharmacokinetic profiles of CBDA, THCA, cannabichromenic acid (CBCA), cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA), and cannabigerovarinic acid (CBGVA) were examined following intraperitoneal administration in mice. Next it was examined whether CBDA was anticonvulsant in a mouse model of Dravet syndrome (Scn1aRX/+ mice). All the phytocannabinoid acids investigated were rapidly absorbed with plasma tmax values of between 15 and 45 min and had relatively short half-lives (

Synthetic cannabinoid receptor agonists (SCRAs) remain a prolific class of new psychoactive substances (NPS) and continue to expand rapidly. Despite the recent identification of hydroxybenzotriazole (HOBt) containing SCRAs in synthetic cannabis samples, there is currently no information regarding the pharmacological profile of these NPS with respect to human CB1 and CB2 receptors. In the current study, a series consisting of seven HOBt indole-, indazole-, and 7-azaindole-carboxylates bearing a range of N-alkyl substituents were synthesized and pharmacologically evaluated. Competitive binding assays at CB1 and CB2 demonstrated that all analogues except a 2-methyl-substituted derivative had low affinity for CB1 (Ki = 3.80-43.7 μM) and CB2 (Ki = 2.75-18.2 μM). A fluorometric functional assay revealed that 2-methylindole- and indole-derived HOBt carboxylates were potent and efficacious agonists of CB1 (EC50 = 12.0 and 63.7 nM; Emax = 118 and 120%) and CB2 (EC50 = 10.9 and 321 nM; Emax = 91 and 126%). All other analogues incorporating indazole and 7-azaindole cores and bearing a range of N1-substituents showed relatively low potency for CB1 and CB2. Additionally, a reporter assay monitoring β-arrestin 2 (βarr2) recruitment to the receptor revealed that the 2-methylindole example was the most potent and efficacious at CB1 (EC50 = 131 nM; Emax = 724%) and the most potent at CB2 (EC50 = 38.2 nM; Emax = 51%). As with the membrane potential assay, the indazole and other indole HOBt carboxylates were considerably less potent at both receptors, and analogues comprising a 7-azaindole core showed little activity. Taken together, these data suggest that NNL-3 demonstrates little CB1 receptor activity and is unlikely to be psychoactive in humans. NNL-3 is likely an unintended SCRA manufacturing byproduct. However, the synthesis of NNL-3 analogues proved simple and general, and some of these showed potent cannabimetic profiles in vitro, indicating that HOBt esters of this type may represent an emerging class of SCRA NPS.

Background Purified cannabidiol (CBD), a non-psychoactive phytocannabinoid, has gained regulatory approval to treat intractable childhood epilepsies. Despite this, artisanal and commercial CBD-dominant hemp-based products continue to be used by epilepsy patients. Notably, the CBD doses used in these latter products are much lower than that found to be effective in reducing seizures in clinical trials with purified CBD. This might be because these CBD-dominant hemp products contain other bioactive compounds, including phytocannabinoids and terpenes, which may exert unique effects on epilepsy-relevant drug targets. Voltage-gated sodium (NaV) channels are vital for initiation of neuronal action potential propagation and genetic mutations in these channels result in epilepsy phenotypes. Recent studies suggest that NaV channels are inhibited by purified CBD. However, the effect of cannabis-based products on the function of NaV channels is unknown. Methods Using automated-planar patch-clamp technology, we profile a hemp-derived nutraceutical product (NP) against human NaV1.1–NaV1.8 expressed in mammalian cells to examine effects on the biophysical properties of channel conductance, steady-state fast inactivation and recovery from fast inactivation. Results NP modifies peak current amplitude of the NaV1.1–NaV1.7 subtypes and has variable effects on the biophysical properties for all channel subtypes tested. NP potently inhibits NaV channels revealing half-maximal inhibitory concentration (IC50) values of between 1.6 and 4.2 μg NP/mL. Purified CBD inhibits NaV1.1, NaV1.2, NaV1.6 and NaV1.7 to reveal IC50 values in the micromolar range. The CBD content of the product equates to IC50 values (93–245 nM), which are at least an order of magnitude lower than purified CBD. Unlike NP, hemp seed oil vehicle alone did not inhibit NaV channels, suggesting that the inhibitory effects of NP are independent of hemp seed oil. Conclusions This CBD-dominant NP potently inhibits NaV channels. Future study of the individual elements of NP, including phytocannabinoids and terpenes, may reveal a potent individual component or that its components interact to modulate NaV channels.

Cannabis ( Cannabis sativa) is the most widely used illicit drug in the world, with an estimated 192 million users globally. The main psychoactive component of cannabis is (-)- trans-Δ9-tetrahydrocannabinol (Δ9-THC), a compound with a diverse range of pharmacological actions. The unique and distinctive intoxication caused by Δ9-THC primarily reflects partial agonist action at central cannabinoid type 1 (CB1) receptors. Δ9-THC is an approved therapeutic treatment for a range of conditions, including chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis, and is being investigated in indications such as anorexia nervosa, agitation in dementia, and Tourette's syndrome. It is available as a regulated pharmaceutical in products such as Marinol, Sativex, and Namisol as well as in an ever-increasing range of unregistered medicinal and recreational cannabis products. While cannabis is an ancient medicament, contemporary use is embroiled in legal, scientific, and social controversy, much of which relates to the potential hazards and benefits of Δ9-THC itself. Robust contemporary debate surrounds the therapeutic value of Δ9-THC in different diseases, its capacity to produce psychosis and cognitive impairment, and the addictive and "gateway" potential of the drug. This review will provide a profile of the chemistry, pharmacology, and therapeutic uses of Δ9-THC as well as the historical and societal import of this unique, distinctive, and ubiquitous psychoactive substance.

Neuropathic pain is caused by a lesion or dysfunction in the nervous system, and it may arise from illness, be drug-induced or caused by toxin exposure. Since the discovery of two G-protein-coupled cannabinoid receptors (CB1 and CB2) nearly three decades ago, there has been a rapid expansion in our understanding of cannabinoid pharmacology. This is currently one of the most active fields of neuropharmacology, and interest has emerged in developing cannabinoids and other small molecule modulators of CB1 and CB2 as therapeutics for neuropathic pain. This short review article provides an overview of the chemotypes currently under investigation for the development of novel neuropathic pain treatments targeting CB1 receptors.

Cannabichromene (CBC) and cannabichromenic acid (CBCA) are cannabis constituents currently under evaluation for their therapeutic potential, but their pharmacological properties have not been thoroughly investigated. The most studied ATP-binding cassette (ABC) transporters, ABC subfamily G member 2 (ABCG2) and ABC subfamily B member 1 (ABCB1) limit absorption of substrate drugs in the gut and brain. Moreover, inhibitors of these proteins can lead to clinically significant drug-drug interactions (DDIs). The current study sought to examine whether CBC and CBCA affect ABCB1 and ABCG2 to advance their basic pharmacological characterisation. The plant cannabinoids CBC and CBCA were screened in vitro in a bidirectional transport assay to determine whether they were substrates and/or inhibitors of ABCB1 and ABCG2. Transwell assays with polarized epithelial Madin-Darby Canine Kidney II (MDCK) cells expressing ABCB1 or ABCG2 were used. Samples were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS). CBCA was found to be an ABCB1 substrate, but not an ABCG2 substrate. CBC was not a substrate of either transporter. Neither CBCA nor CBC inhibited ABCB1 transport of prazosin or ABCG2 transport of digoxin. In silico molecular docking suggested CBCA binds ABCB1 in the access tunnel and the central binding pocket. CBC, an agent with anticonvulsant, anti-inflammatory and anti-depressant properties, is not a substrate or inhibitor of ABCB1 or ABCG2, which is favourable to its therapeutic development. CBCA is an ABCB1 substrate in vitro which might contribute to its poor absorption. These findings provide important basic pharmacological data to assist the therapeutic development of these cannabis constituents.

The term 'synthetic cannabis' has been widely used in public discourse to refer to a group of cannabinoid receptor agonists. In this paper we detail the characteristics of these drugs, and present the case that the term is a misnomer. We describe the pharmacodynamics of these drugs, their epidemiology, mechanisms of action, physiological effects and how these differ substantially from delta-9-tetrahydrocannabinol (THC). We argue that not only is the term a misnomer, but it is one with negative clinical and public health implications. Rather, the substances referred to as 'synthetic cannabis' in public discourse should instead be referred to consistently as synthetic cannabinoid receptor agonists (SCRAs), a drug class distinct from plant-derived cannabinoids. SCRAs have greater potency and efficacy, and psychostimulant-like properties. While such terminology may be used in the scientific community, it is not widely used amongst the media, general public, people who use these drugs or may potentially do so. A new terminology has the potential to reduce the confusion and harms that result from the misnomer 'synthetic cannabis'. The constant evolution of this distinct drug class necessitates a range of distinct policy responses relating to terminology, harm reduction, epidemiology, treatment, and legal status.

Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest and most structurally diverse classes of new psychoactive substances (NPS). Despite this, pharmacological data are often lacking following the identification of a new SCRA in drug markets. In this first of a three-part series, we describe the synthesis, analytical characterization, and binding affinity of a proactively generated, systematic library of 30 indole, indazole, and 7-azaindole SCRAs related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA featuring a 4-pentenyl (4en-P), butyl (B/BUT), or 4-cyanobutyl (4CN-B/BUT) tail and a methyl l-valinate (MMB), methyl l-tert-leucinate (MDMB), methyl l-phenylalaninate (MPP), l-valinamide (AB), l-tert-leucinamide (ADB), l-phenylalaninamide (APP), adamantyl (A), or cumyl head group. Competitive radioligand binding assays demonstrated that the indazole core conferred the highest CB

Cannabis-based products are increasingly being used to treat refractory childhood epilepsies such as Dravet syndrome. Cannabis contains at least 140 terpenophenolic compounds known as phytocannabinoids. These include the known anticonvulsant compound cannabidiol (CBD) and several molecules showing emergent anticonvulsant properties in animal models. Cannabichromene (CBC) is a phytocannabinoid frequently detected in artisanal cannabis oils used in the community by childhood epilepsy patients. Here we examined the brain and plasma pharmacokinetic profiles of CBC, cannabichromenic acid (CBCA), cannabichromevarin (CBCV), and cannabichromevarinic acid (CBCVA) following intraperitoneal administration in mice. The anticonvulsant potential of each was then tested against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome. All phytocannabinoids within the CBC series were readily absorbed and showed substantial brain penetration (brain-plasma ratios ranging from 0.2 to 5.8). Anticonvulsant efficacy was evident with CBC, CBCA, and CBCVA, each significantly increasing the temperature threshold at which Scn1a+/- mice had a generalized tonic-clonic seizure. We synthesized a fluorinated derivative of CBC (5-fluoro-CBC), which showed improved brain penetration relative to the parent CBC molecule but not any greater anticonvulsant effect. Since CBC and derivatives are anticonvulsant in a model of intractable pediatric epilepsy, they may constitute part of the mechanism through which artisanal cannabis oils are anticonvulsant in patients.

Cannabidiol is claimed to bind to a large number of protein targets based on in vitro assays. This suggests opportunities for a wide range of therapeutic applications. On the other hand, the existence of phytochemical 'nuisance compounds' suggests some measure of caution - these compounds are capable of altering membrane biophysical properties and changing protein function without directly contacting a binding site. Like cannabidiol, cholesterol alters membrane properties, but it also binds directly to membrane proteins through abundant cholesterol recognition sites. We present the evidence that cannabidiol and cholesterol may bind to the same site on some proteins. As a starting point for further research, we also used blind docking to show that cannabidiol binds to a cholesterol binding site on the CB1 receptor. Elucidation of the mechanism(s) of action of cannabidiol will assist the prioritisation of in vitro hits across targets, improve the success rate of medicinal chemistry campaigns, and ultimately benefit patient populations by focusing resources on programs with the most translational potential.

Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances (NPS) with structurally diverse compounds emerging each year. Due to the rapid pace at which these drugs enter the market, there is often little or nil information regarding the pharmacology of these substances despite widespread human use. In this study, 12 recently emerged SCRAs (reported between 2018 and 2020) were synthesized, analytically characterized, and pharmacologically evaluated using a live cell-based nanoluciferase complementation reporter assay that monitors

Synthetic cannabinoid receptor agonists (SCRAs) represent the most rapidly expanding class of new psychoactive substances (NPSs). Despite the prevalence and potency of recent chiral indole-3-carboxamide SCRAs, few pharmacological data are available regarding the enantiomeric bias of these NPSs toward human CB1 and CB2 receptors. A series of homochiral indole-3-carboxamides derived from (S)- and (R)-α-methylbenzylamine and featuring variation of the 1-alkyl substituent were prepared, pharmacologically evaluated, and compared to related achiral congeners derived from cumyl- and benzylamine. Competitive binding assays demonstrated that all analogues derived from either enantiomer of α-methylbenzylamine (14-17) showed affinities for CB1 (Ki = 47.9-813 nM) and CB2 (Ki = 47.9-347 nM) that were intermediate to that of the corresponding benzylic (10-13, CB1 Ki = 550 nM to >10 μM; CB2 Ki = 61.7 nM to >10 μM) and cumyl derivatives (6-9, CB1 Ki = 12.6-21.4 nM; CB2 Ki = 2.95-24.5 nM). In a fluorometric membrane potential assay, all α-methylbenzyl analogues (excluding 17) were potent, efficacious agonists of CB1 (EC50 = 32-464 nM; Emax = 89-104%) and low efficacy agonists of CB2 (EC50 = 54-500 nM; Emax = 52-77%), with comparable or greater potency than the benzyl analogues and much lower potency than the cumyl derivatives, consistent with binding trends. The relatively greater affinity and potency of (S)-14-17 compared to (R)-14-17 analogues at CB1 highlighted an enantiomeric bias for this series of SCRAs. Molecular dynamics simulations provided a conformational basis for the observed differences in agonist potency at CB1 pending benzylic substitution.

Synthetic cannabinoid receptor agonists (SCRAs) are new psychoactive substances associated with acute intoxication and even death. However, the molecular mechanisms through which SCRAs may exert their toxic effects remain unclear—including the potential differential activation of G protein subtypes by cannabinoid receptor type 1 (CB1), a major target of SCRA. We measured CB1‐mediated activation of Gαs and Gαi/o proteins by SCRAs by examining stimulation (pertussis toxin, PTX treated) as well as inhibition (non‐PTX treated) of forskolin (FSK)‐induced cyclic adenosine monophosphate (cAMP) accumulation in human embryonic kidney (HEK) cells stably expressing CB1. Real‐time measurements of stimulation and inhibition of cAMP levels were made using a BRET biosensor. We found that the maximum concentration of SCRAs tested (10 µmol L−1), increased cAMP levels 12%‐45% above that produced by FSK alone, while the phytocannabinoid THC did not significantly alter cAMP levels in PTX‐treated HEK‐CB1 cells. All SCRAs had greater potency to inhibit FSK‐induced cAMP levels than to stimulate cAMP levels. The rank order of potencies for SCRA stimulation of cAMP (Gαs) was PB‐22 > 5F‐MDMB‐PICA > JWH‐018 ≈ AB‐FUBINACA > XLR‐11. By contrast, the potency of SCRAs for inhibition of cAMP (Gαi/o) was 5F‐MDMB‐PICA > AB‐FUBINACA > PB‐22 > JWH‐018 > XLR‐11. The different rank order of potency and EMax of the SCRAs to stimulate Gαs‐like signaling compared to Gαi/o signaling suggests differences in G protein preference between SCRAs. Understanding the apparent differences among these drugs may contribute to unravelling their complex effects in humans.

Synthetic cannabinoid receptor agonists (SCRAs) are a dynamic class of new psychoactive substances (NPS), with novel chemotypes emerging each year. Following the putative detection of 5F-CUMYL-P7AICA in Australia in 2016, the scaffold-hopping SCRAs 5F-CUMYL-PICA, 5F-CUMYL-PINACA, and 5F-CUMYL-P7AICA were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-quadrupole time-of-flight-MS (LC-QTOF-MS). Since little is known of the pharmacology of 7-azaindole SCRAs like 5F-CUMYL-P7AICA, the binding affinities and functional activities of all compounds at cannabinoid type 1 and type 2 receptors (CB1 and CB2 , respectively) were assessed using tritiated radioligand competition experiments and fluorescence-based plate reader membrane potential assays. Despite CB1 binding affinities differing by over two orders of magnitude (Ki = 2.95-174 nM), all compounds were potent and efficacious CB1 agonists (EC50 = 0.43-4.7 nM), with consistent rank order for binding and functional activity (5F-CUMYL-PINACA >5F-CUMYL-PICA >5F-CUMYL-P7AICA). Additionally, 5F-CUMYL-P7AICA was found to exert potent cannabimimetic effects in mice, inducing hypothermia (6°C, 3 mg/kg) through a CB1 -dependent mechanism.

Synthetic cannabinoid receptor agonists (SCRAs) represent the most rapidly proliferating class of "designer drugs" or "new psychoactive substances". SCRAs offer unregulated alternatives to cannabis that evade routine drug tests, but their use is increasingly associated with severe toxicity and death worldwide. Little is currently known about SCRA molecular pharmacology, or the mechanisms underpinning their toxicity, although the effects are believed to be primarily mediated by the type 1 cannabinoid receptor (CB1). In this study, we aimed to characterise the signalling profiles of a structurally diverse panel of novel SCRAs at CB1. We compare SCRAs to traditional reference cannabinoids CP55,940, WIN55,212-2, and THC. The activity of the SCRAs was assessed in key receptor signalling and regulatory pathways, including cAMP production, translocation of β-arrestin 1 and 2, and receptor internalisation. The activity profiles of the ligands were also evaluated using operational analysis to identify ligand bias. Results revealed that SCRAs activities were relatively balanced in the pathways evaluated (compared to WIN55,212-2), although 5F-CUMYL-P7AICA and XLR-11 possessed partial efficacy in cAMP stimulation and β-arrestin translocation. Notably, the SCRAs showed distinct potency and efficacy profiles compared to THC. In particular, while the majority of SCRAs demonstrated robust β-arrestin translocation, cAMP stimulation, and internalisation, THC failed to elicit high efficacy responses in any of these assays. Further study is required to delineate if these pathways could contribute to SCRA toxicity in humans.

BACKGROUND AND PURPOSE: The morbidity and mortality associated with recreational use of synthetic cannabinoid receptor agonists (SCRAs) may reflect strong activation of CB(1) receptors and is a major health concern. The properties of SCRA at CB(1) receptors are not well defined. Here we have developed an assay to determine acute CB(1) receptor efficacy using receptor depletion with the irreversible CB(1) receptor antagonist AM6544, with application of the Black and Leff operational model to calculate efficacy. EXPERIMENTAL APPROACH: Receptor depletion in mouse AtT‐20 pituitary adenoma cells stably expressing human CB(1) receptors was achieved by pretreatment of cells with AM6544 (10 μM, 60 min). The CB(1) receptor‐mediated hyperpolarisation of AtT‐20 cells was measured using fluorescence‐based membrane potential dye. From data fit to the operational model, the efficacy (τ) and affinity (K (A)) parameters were obtained for each drug. KEY RESULTS: AM6544 did not affect the potency or maximal effect of native somatostatin receptor‐induced hyperpolarization. The τ value of ∆(9)‐THC was 80‐fold less than the reference CB receptor agonist CP55940 and 260‐fold less than the highest efficacy SCRA, 5F‐MDMB‐PICA. The operational efficacy of SCRAs ranged from 233 (5F‐MDMB‐PICA) to 28 (AB‐PINACA), with CP55940 in the middle of the efficacy rank order. There was no correlation between the τ and K (A) values. CONCLUSIONS AND IMPLICATIONS: All SCRAs tested showed substantially higher efficacy at CB(1) receptors than ∆(9)‐THC, which may contribute to the adverse effects seen with these drugs but not ∆(9)‐THC.

Synthetic cannabinoid receptor agonists (SCRAs) are new psychoactive substances associated with acute intoxication and even death. However, the molecular mechanisms through which SCRAs may exert their toxic effects remain unclear - including the potential differential activation of G protein subtypes by CB1, a major target of SCRA. We measured CB1-mediated activation of Gαs and Gαi/o proteins by SCRAs by examining stimulation (PTX-treated) as well as inhibition (non-PTX treated) of forskolin-induced cAMP accumulation in HEK cells stably expressing CB1. Real-time measurements of stimulation and inhibition of cAMP levels were made using a BRET biosensor. We found that the maximum concentration of SCRAs tested (10 μM), increased cAMP levels 12 to 45% above that produced by forskolin alone, while the phytocannabinoid THC did not significantly alter cAMP levels in PTX-treated HEK-CB1 cells. All SCRAs had greater potency to inhibit of forskolin-induced cAMP levels than to stimulate cAMP levels. The rank order of potencies for SCRA stimulation of cAMP (Gαs) was PB-22 > 5F-MDMB-PICA > JWH-018 > AB-FUBINACA > XLR-11. By contrast, the potency of SCRAs for inhibition of cAMP (Gαi/o) was 5F-MDMB-PICA > AB-FUBINACA > PB-22 > JWH-018 > XLR-11. The different rank order of potency of the SCRAs to stimulate Gαs-like signalling compared to Gαi/o signalling suggests differences in G protein preference between SCRAs. Understanding the apparent differences among these drugs may contribute to unravelling their complex effects in humans.

Rationale A novel benzimidazole compound ZLN005 was previously identified as a transcriptional activator of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in certain metabolic tissues. Upregulation of PGC-1α by ZLN005 has been shown to have beneficial effect in a diabetic mouse model and in a coronary artery disease model in vitro. ZLN005 could also have therapeutic potential in neurodegenerative diseases involving down-regulation of PGC-1α. Given the phenotypic efficacy of ZLN005 in several animal models of human disease, its metabolic profile was investigated to guide the development of novel therapeutics using ZLN005 as the lead compound. Methods ZLN005 was incubated with both rat and human liver microsomes and S9 fractions to identify in vitro metabolites. Urine from rats dosed with ZLN005 was used to identify in vivo metabolites. Extracted metabolites were analyzed by LC-MS/MS using a hybrid linear ion trap triple quadrupole mass spectrometer under full scan, enhanced product ion scan, neutral loss scan and precursor scan modes. Metabolites in plasma and brain of ZLN005-treated rats were also profiled using multiple reaction monitoring. Results Identified in vitro transformations of ZLN005 include mono- and dihydroxylation, further oxidation to carboxylic acids, and mono-O-glucuronide and sulfate conjugation to hydroxy ZLN005 as well as glutathione conjugation. Identified in vivo metabolites are mainly glucuronide and sulfate conjugates of dihydroxyl, carboxyl, and hydroxy acid of the parent compound. The parent compound as well as several major phase I metabolites were found in rat plasma and brain. Conclusions Using both in vitro and in vivo methods, we elucidated the metabolic pathway of ZLN005. Phase I metabolites with hydroxylation and carboxylation, as well as phase II metabolites with glucuronide, sulfate and glutathione conjugation, were identified.

Synthetic cannabinoids (SCs) containing a 1-pentyl-1-H substituted indole or indazole are abused around the world and are associated with an array of serious side effects. These compounds undergo extensive phase 1 metabolism after ingestion with little understanding whether these metabolites are contributing to the cannabimimetic activity of the drugs. This work presents the synthesis and pharmacological characterization of the major metabolites of two high concern SCs; APICA and ADB-PINACA. In a fluorometric assay of membrane potential, all metabolites that did not contain a carboxylic acid functionality retained potent activity at both the CB1 (EC50 = 14–787 nM) and CB2 (EC50 = 5.5–291 nM) receptors regardless of heterocyclic core or 3-carboxamide substituent. Of note were the 5-hydroxypentyl and 4-pentanone metabolites which showed significant increases in CB2 functional selectivity. These results suggest that the metabolites of SCs potentially contribute to the overall pharmacological profile of these...

Indole or indazole-based synthetic cannabinoids (SCs) bearing substituents derived from valine or tert-leucine are frequently abused new psychoactive substances (NPS). The emergence of 5F-MDMB-PICA (methyl N-{[1-(5-fluoropentyl)-1H-indol-3-yl]carbonyl}-3-methylvalinate) on the German drug market is a further example of a substance synthesized in the context of scientific research being misused by clandestine laboratories by adding it to 'legal high' products. In this work, we present the detection of 5F-MDMB-PICA in several legal high products by gas chromatography-mass spectrometry (GC-MS) analysis. To detect characteristic metabolites suitable for a proof of 5F-MDMB-PICA consumption by urine analysis, pooled human liver microsome (pHLM) assays were performed and evaluated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS) techniques to generate reference spectra of the in vitro phase I metabolites. The in vivo phase I metabolism was investigated by the analysis of more than 20 authentic human urine specimens and compared to the data received from the pHLM assay. Biotransformation of the 5-fluoropentyl side chain and hydrolysis of the terminal methyl ester bond are main phase I biotransformation steps. Two of the identified main metabolites formed by methyl ester hydrolysis or mono-hydroxylation at the indole ring system were evaluated as suitable urinary biomarkers and discussed regarding the interpretation of analytical findings. Exemplary analysis of one urine sample for 5F-MDMB-PICA phase II metabolites showed that two of the main phase I metabolites are subject to extensive glucuronidation prior to renal excretion. Therefore, conjugate cleavage is reasonable for enhancing sensitivity. Commercially available immunochemical pre-tests for urine proved to be unsuitable for the detection of 5F-MDMB-PICA consumption. Copyright © 2017 John Wiley & Sons, Ltd.

BackgroundNew psychoactive substances constitute a growing and dynamic class of abused drugs in the United States. On July 12, 2016, a synthetic cannabinoid caused mass intoxication of 33 persons in one New York City neighborhood, in an event described in the popular press as a “zombie” outbreak because of the appearance of the intoxicated persons. MethodsWe obtained and tested serum, whole blood, and urine samples from 8 patients among the 18 who were transported to local hospitals; we also tested a sample of the herbal “incense” product “AK-47 24 Karat Gold,” which was implicated in the outbreak. Samples were analyzed by means of liquid chromatography–quadrupole time-of-flight mass spectrometry. ResultsThe synthetic cannabinoid methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (AMB-FUBINACA, also known as MMB-FUBINACA or FUB-AMB) was identified in AK-47 24 Karat Gold at a mean (±SD) concentration of 16.0±3.9 mg per gram. The de-esterified acid metabolite was found in the serum or...

Recreational consumption of synthetic cannabinoid receptor agonists (SCRAs) is a growing crisis in public health in many parts of the world. AMB-FUBINACA is a member of this class of drugs and is responsible for a large proportion of SCRA-related toxicity both in New Zealand and internationally. Strikingly, little is currently known about the mechanisms by which SCRAs exert toxic effects or whether their activity through the CB(1) cannabinoid receptor (the mediator of cannabinoid-related psychoactivity) is sufficient to explain clinical observations. The current study therefore set out to perform a basic molecular pharmacology characterization of AMB-FUBINACA (in comparison to traditional research cannabinoids CP55,940, WIN55,212–2, and Δ(9)-THC) in fundamental pathways of receptor activity, including cAMP inhibition, pERK activation, ability to drive CB(1) internalization, and ability to induce translocation of β-arrestins-1 and −2. Activity pathways were then compared by operational analysis to indicate whether AMB-FUBINACA may be a biased ligand. Results revealed that AMB-FUBINACA is highly efficacious and potent in all pathways assayed. However, surprisingly, bias analysis suggested that Δ(9)-THC, not AMB-FUBINACA, may be a biased ligand, with it being less active in both arrestin pathways than predicted by the activity of the other ligands tested. These data may help predict molecular characteristics of SCRAs. However, more research is required to determine whether these molecular effects manifest in toxicity at tissue/system level.

Cannabinoid receptors type 1 (CB1) and type 2 (CB2) are promising targets for a number of diseases, including obesity, neuropathic pain, and multiple sclerosis, among others. Upon ligand-mediated activation of these receptors, multiple receptor conformations could be stabilized, resulting in a complex pattern of possible intracellular effects. Although numerous compounds have been developed and widely used to target cannabinoid receptors, their mode of action and signaling properties are often only poorly characterized. From a drug development point of view, unraveling the underlying complex signaling mechanism could offer the possibility to generate medicines with the desired therapeutic profile. Recently, an increased interest has emerged for the development of agonists that are signaling pathway-selective and thereby do not evoke on-target adverse effects. This phenomenon, in which specific pathways are preferred upon receptor activation by certain ligands, is also known as 'biased signaling'. For a particular group of cannabinoid receptor ligands (i.e. CB1/CB2 agonists), namely the synthetic cannabinoid receptor agonists (SCRAs), the research on biased signaling is still in its infancy and interesting outcomes are only recently being revealed. Therefore, this review aims at providing insights into the recent knowledge about biased agonism mediated by SCRAs so far. In addition, as these outcomes are obtained using a distinct panel of functional assays, the accompanying difficulties and challenges when comparing functional outcomes are critically discussed. Finally, some guidance on the conceptualization of ideal in vitro assays for the detection of SCRA-mediated biased agonism, which is also relevant for compounds belonging to other chemical classes, is provided.

BACKGROUND AND PURPOSEThe morbidity and mortality associated with recreational use of synthetic cannabinoid receptor agonists (SCRAs) is a major health concern, and may involve over-activation of CB1 receptors. Thus, we sought to determine the efficacy of 13 SCRAs at CB1 using receptor depletion with the irreversible CB1 antagonist AM6544 followed by fitting the curve with the Black and Leff operational model to calculate efficacy.EXPERIMENTAL APPROACHReceptor depletion in mouse AtT-20 neuroblastoma cells stably expressing human CB1 was achieved by pre-treatment of cells with AM6544 (10 µM, 60 mins). The CB1-mediated hyperpolarisation of AtT20 cells was measured using membrane potential dye. From data fit to the operational model, the efficacy (tau) and affinity (KA) parameters were obtained for each drug.KEY RESULTSAM6544 did not affect the potency or maximal effect of native somatostatin receptor-induced hyperpolarisation (Control, pEC50 9.13 ± 0.05, Emax 38 ± 1%; AM6544 treated pEC50 9.18 ± 0.04, Emax 39 ± 0.7%). The tau value of ∆9-THC was 70-fold less than the reference CB-agonist CP55940, and 240-fold less than the highest efficacy SCRA, 5F-MDMB-PICA. Most of the SCRAs had about 50% of the efficacy of CP55940. There was no correlation between the tau and KA values for any SCRA.CONCLUSION AND IMPLICATIONSAll the SCRA tested showed substantially higher agonist activity at CB1 than ∆9-THC, which may contribute to the adverse effects seen with these drugs but not ∆9-THC, although the mechanisms underlying SCRA toxicity are still poorly defined.

BACKGROUND AND AIMS The Psychoactive Surveillance Consortium and Analysis Network (PSCAN) is a national network of academic emergency departments (ED), analytical toxicologists and pharmacologists that collects clinical data paired with biological samples to identify and improve treatments of medical conditions arising from use of new psychoactive substances (NPS). The aim of this study was to gather clinical data with paired drug identification from NPS users who presented to EDs within PSCAN during its first year (2016-17). DESIGN Observational study involving patient records and biological samples. SETTING Seven academic emergency medical centers across the United States. PARTICIPANTS ED patients (n = 127) > 8 years of age with possible NPS use who were identified and enrolled in PSCAN by clinical providers or research personnel. MEASUREMENTS Clinical signs, symptoms and treatments were abstracted from the patients' health records. Biological samples were collected from leftover urine, serum and whole blood. Biological and drug samples, when available, were tested for drugs and drug metabolites via liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS). FINDINGS Patients in whom synthetic opioids were detected (n = 9) showed higher rates of intubation (four of nine), impaired mental status (four of nine) and respiratory acidosis (five of nine) compared with the rest of the cohort (nine of 118, P-value

We describe the validation of a method for the simultaneous analysis of 29 synthetic cannabinoids (SCs) and metabolites, 4 amphetamines, and 2 cannabinoids in human whole blood. This method enables one analysis to cover what previously required multiple analyses for these classic and novel drugs-of-abuse with diverse physicochemical properties. The scope of targeted analytes was based on the most prevalent drugs-of-abuse and SCs encountered at the New Zealand border in 2017 and included parent compounds and metabolites belonging to the indole and indazole carboxamide, quinolinyl indole carboxylate, and naphthoylindole classifications. Samples were prepared by supported-liquid-extraction (SLE) followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis with positive electrospray ionization (ESI). The method was validated with respect to selectivity, matrix effects, process efficiency, sensitivity, repeatability, extract stability, and carryover for qualitative confirmation. Linearity as well as accuracy and precision data at target decision concentrations were also evaluated. The limits of detection and confirmation ranged from 0.1 to 6.0 ng/mL and 1.0 to 6.0 ng/mL, respectively. The described method was successfully applied to the analysis of 564 ante- and post-mortem blood samples in 2018. There were 132 cases (23%) with positive findings of at least one SC, with the five most commonly detected SCs being AMB-FUBINACA and/or acid (61%), 5F-ADB and/or acid (40%), ADB-FUBINACA (11%), 5F-MDMB-PICA acid (6%), and MDMB-FUBINACA acid (6%). The results also demonstrate the predominant presence of metabolites at higher levels than the unchanged parent SCs in blood, highlighting the need to maintain forensic screening methods capable of the simultaneous detection of both parent compounds and metabolites.

Cannabis ( Cannabis sativa) is the most widely used illicit drug in the world, with an estimated 192 million users globally. The main psychoactive component of cannabis is (-)- trans-Δ

Neuropathic pain is caused by a lesion or dysfunction in the nervous system, and it may arise from illness, be drug-induced or caused by toxin exposure. Since the discovery of two G-protein-coupled cannabinoid receptors (CB(1) and CB(2)) nearly three decades ago, there has been a rapid expansion in our understanding of cannabinoid pharmacology. This is currently one of the most active fields of neuropharmacology, and interest has emerged in developing cannabinoids and other small molecule modulators of CB(1) and CB(2) as therapeutics for neuropathic pain. This short review article provides an overview of the chemotypes currently under investigation for the development of novel neuropathic pain treatments targeting CB(1) receptors.

To the EditorSynthetic cannabinoid receptor agonists (SCRA’s) encompass a diverse class of direct endogenous cannabinoid receptor agonists [1] with various clinical effects including: altered menta...