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New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, \"dark net\") as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ(9)-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with \"Spice\" use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds.

On January 22nd 2009, the German Health Authorities prohibited several non-traditional cannabinoids, that proved to be the active components in popular “Bio-Designer-Drugs” like “Spice” and analogous products. The recent detection of CP 47,497-C8 in Europe and Japan documents that these products have already spread world wide. We synthesized several potentially interesting alkylaminoindoles (alkylchain C 3 to C 7) and isolated CP 47,497-C8 from “Spice Gold”. The compounds were purified and characterized by NMR and mass spectrometry methods. With the aid of these authentic references we were able to detect and quantify added psychoactive compounds in different herbal blends. All samples that were acquired before the prohibition in December 2008 contained either CP 47,497-C8 (5.4–11.0 mg/g) or JWH-018 (2.3 mg/g). Some samples acquired in March 2009, 4 weeks after the prohibition took place, still contained CP 47,497-C8 (3.0–3.3 mg/g) but JWH-018 was not detected anymore. Instead it was replaced by its non-regulated C 4-homolog JWH-073 (5.8–22.9 mg/g). Furthermore some of the new products did not contain any non-traditional cannabinoids. To our knowledge this is the first report of the appearance JWH-073 as a new designer drug. The data and method presented here will facilitate and accelerate the detection of these compounds in complex matrices.

3-(1-Naphthalenylmethyl)-1-pentyl-1H-indole (JWH-175) is a synthetic cannabinoid illegally marketed for its psychoactive cannabis-like effects. This study aimed to investigate and compare in vitro and in vivo pharmacodynamic activity of JWH-175 with that of 1-naphthalenyl (1-pentyl-1H-indol-3-yl)-methanone (JWH-018), as well as evaluate the in vitro (human liver microsomes) and in vivo (urine and plasma of CD-1 male mice) metabolic profile of JWH-175. In vitro binding studies showed that JWH-175 is a cannabinoid receptor agonist less potent than JWH-018 on mouse and human CB1 and CB2 receptors. In agreement with in vitro data, JWH-175 reduced the fESPS in brain hippocampal slices of mice less effectively than JWH-018. Similarly, in vivo behavioral studies showed that JWH-175 impaired sensorimotor responses, reduced breath rate and motor activity, and increased pain threshold to mechanical stimuli less potently than JWH-018. Metabolic studies demonstrated that JWH-175 is rapidly bioactivated to JWH-018 in mice blood, suggesting that in vivo effects of JWH-175 are also due to JWH-018 formation. The pharmaco-toxicological profile of JWH-175 was characterized for the first time, proving its in vivo bio-activation to the more potent agonist JWH-018. Thus, it highlighted the great importance of investigating the in vivo metabolism of synthetic cannabinoids for both clinical toxicology and forensic purposes.

•JWH-018 and its 3-hydroxylated metabolite toxicity was evaluated on human cells.•JWH-018 metabolite is toxic for cells, in contrast to its parent substance.•Annexin/PI test show that the JWH-018 metabolite induces cell death through necrosis.•The JWH-018 metabolite impact on cells suggests a non-CB1 mediated toxicity mechanism.•Metabolites toxic profiles might be a key to study side effects of these substances. The emergence and abuse of synthetic cannabinoids has been increasing as an alternative to cannabis, mainly among youth. As their appearance on the drug market has been recent, the pharmacological and toxicological profiles of these psychoactive substances are poorly understood. Current studies suggest that they have stronger effects compared to their natural alternatives and their metabolites retain affinity towards CB1 receptors in CNS. Since studies on its toxicological properties are scarce, the effects of the drug in human derived cell lines were investigated. The present study was designed to explore the toxicological impact of parent drug versus phase I metabolites of synthetic cannabinoids on human cells with and without CB1 receptor. The human cell line of neuroblastoma SH-SY5Y and human kidney cell line HEK-293T were exposed to JWH-018 and to its N-(3-hydroxypentyl) metabolite. Cell toxicity was evaluated using the MTT and LDH assay. Additionally, a dual staining methodology with fluorescent Annexin V-FITC and propidium iodide was performed to address the question of whether JWH-018 N-(3-hydroxypentyl) metabolite is inducing cell death through apoptosis or necrosis, in HEK293T and SH-SY5Y cell lines. The obtained results show that JWH-018 does not cause a statistically significant decrease in cell viability, in contrast to its N-(3-hydroxypentyl) metabolite, which at ≥25μM causes a significant decrease in cell viability. Both cell lines are affected by JWH-018 metabolite. Our results point to higher toxicity of JWH-018 metabolite when compared to its parent drug, suggesting a non-CB1 receptor mediated toxicological mechanism. Comparing the results from Annexin V/PI with MTT and LDH assays of SH-SY5Y and HEK293T in the presence of the synthetic cannabinoid metabolite, emerges the picture that cellular viability decreases and associated death is occurring through necrosis.

JWH-018 is the most known compound among synthetic cannabinoids (SCs) used for their psychoactive effects. SCs-based products are responsible for several intoxications in humans. Cardiac toxicity is among the main side effects observed in emergency departments: SCs intake induces harmful effects such as hypertension, tachycardia, chest pain, arrhythmias, myocardial infarction, breathing impairment, and dyspnea. This study aims to investigate how cardio-respiratory and vascular JWH-018 (6 mg/kg) responses can be modulated by antidotes already in clinical use. The tested antidotes are amiodarone (5 mg/kg), atropine (5 mg/kg), nifedipine (1 mg/kg), and propranolol (2 mg/kg). The detection of heart rate, breath rate, arterial oxygen saturation (SpO2), and pulse distention are provided by a non-invasive apparatus (Mouse Ox Plus) in awake and freely moving CD-1 male mice. Tachyarrhythmia events are also evaluated. Results show that while all tested antidotes reduce tachycardia and tachyarrhythmic events and improve breathing functions, only atropine completely reverts the heart rate and pulse distension. These data may suggest that cardiorespiratory mechanisms of JWH-018-induced tachyarrhythmia involve sympathetic, cholinergic, and ion channel modulation. Current findings also provide valuable impetus to identify potential antidotal intervention to support physicians in the treatment of intoxicated patients in emergency clinical settings.

Rationale AKB48 and its fluorinate derivate 5F-AKB48 are two novel synthetic cannabinoids belonging to a structural class with an indazole core structure. They are marketed as incense, herbal preparations or chemical supply for their psychoactive Cannabis-like effects. Objectives The present study was aimed at investigating the in vitro and in vivo pharmacological activity of AKB48 and 5F-AKB48 in male CD-1 mice and comparing their in vivo effects with those caused by the administration of Δ 9 -THC and JWH-018. Results In vitro competition binding experiments performed on mouse and human CB 1 and CB 2 receptors revealed a nanomolar affinity and potency of the AKB48 and 5F-AKB48. In vivo studies showed that AKB48 and 5F-AKB48, induced hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promoted aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of AKB48 and 5F-AKB48 stimulated dopamine release in the nucleus accumbens. Behavioural, neurological and neurochemical effects were fully prevented by the selective CB 1 receptor antagonist/inverse agonist AM 251. Conclusions For the first time, the present study demonstrates the overall pharmacological effects induced by the administration of AKB48 and 5F-AKB48 in mice and suggests that the fluorination can increase the power and/or effectiveness of SCBs. Furthermore, this study outlines the potential detrimental effects of SCBs on human health.

With respect to the continuous emergence of new synthetic cannabinoids on the market since 2008, evaluation of the metabolism of these compounds and the development of analytical methods for the detection of these drugs including their respective metabolites in biological fluids have become essential. Other than JWH-018 or JWH-073, AM-2201 is one of the frequently identified synthetic cannabinoids in Korea. Recently, in our laboratory, several JWH-018 metabolites have been detected in some urine samples obtained from subjects who were arrested for the possession of herbal mixtures containing only AM-2201 or from those who confessed AM-2201 abuse. In the present study, we identified major urinary metabolites of AM-2201 and several metabolites of JWH-018, i.e., N -5-hydroxylated and carboxylated metabolites from rats administered AM-2201 and found that the metabolic profile in rats was similar to those in human subjects in this study. Analytical results of the urine samples from suspects who had a considerable possibility of AM-2201 or JWH-018 intake were also compared to distinguish between AM-2201 and JWH-018 abuse. The presence of 6-indole hydroxylated metabolites of each drug and N -4-hydroxy metabolite of AM-2201 was found to contribute to the decisive differences in the metabolic patterns of the two drugs. In addition, the concentration ratio of the N -(5-hydroxypentyl) metabolite to the N -(4-hydroxypentyl) metabolite of JWH-018 may be used as a criterion to differentiate between AM-2201 and JWH-018 abuse.

Smoking mixtures containing the cannabimimetic indoles may still be available over-the-counter in several countries. Due to the high affinity of these compounds to the cannabinoid receptors, their effective dose is lower than that of the marijuana products resulting in a low concentration of the excreted metabolites accompanied by a higher psychoactive potency. Up to now the in vivo metabolism of the cannabimimetic indoles seems to be insufficiently investigated and no data have been published on an assay of JWH-018 in urine. In this publication the urinary metabolites of JWH-018 are reported. Using gas and liquid chromatography combined with tandem mass spectrometry two main monohydroxylated metabolites were identified in the forensic urine samples. Based on the differences in their electron ionization MS/MS spectra it is supposed that one is formed by hydroxylation of the indole ring whilst the other by hydroxylation of the N-alkyl chain. The main metabolites are almost completely glucuroconjugated, whereas minor ones ( N-despentyl hydroxy-, carboxy-, dihydroxy-, and reduced di- and trihydroxy metabolites) were also present in the free fraction. The parent compound was not detected in urine.

The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket but that WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3 lysine. The Huffman laboratory identified strategies to establish CB2 receptor selectivity among cannabimimetic indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as “Alkyl Indole” receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB1 receptor have found their way into the market as “Spice” or “K2”. The sale of these alleged “herbal products” evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines.

This study investigates the impact of SCs consumption by assessing the effects of three novel synthetic cannabinoids (SCs); MDMB-CHMINACA, 5F-ADB-PINACA, and APICA post-drug treatment. SCs are known for their rapid onset (<1 min) and prolonged duration (≥5 h). Therefore, this research aimed to assess behavioral responses and their correlation with endocannabinoids (ECs) accumulation in the hippocampus, and EC’s metabolic enzymes alteration at different timeframes (1-3-5-h) following drug administration. Different extents of locomotive disruption and sustained anxiety-like symptoms were observed throughout all-encompassing timeframes of drug administration. Notably, MDMB-CHMINACA induced significant memory impairment at 1 and 3 h. Elevated levels of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were detected 1 h post-MDMB-CHMINACA and 5F-ADB-PINACA administration. Reduced mRNA expression levels of fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) (AEA and 2-AG degrading enzymes, respectively), and brain-derived neurotrophic factor (BDNF) occurred at 1 h, with FAAH levels remaining reduced at 3 h. These findings suggest a connection between increased EC content and decreased BDNF expression following SC exposure. Cognitive disruption, particularly motor coordination decline and progressive loss manifested in a time-dependent manner across all the analyzed SCs. Our study highlights the importance of adopting a temporal framework when assessing the effects of SCs.