Psychedelics elicit prosocial, antidepressant and anxiolytic effects via neuroplasticity, neurotransmission and neuro-immunomodulatory mechanisms. Whether psychedelics affect the brain endocannabinoid system and its extended version, the endocannabinoidome (eCBome) or the gut microbiome, remains unknown. Adult C57BL/6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7...
The use of the intoxicating cannabinoid delta‐8‐tetrahydrocannabinol (Δ8‐THC) has grown rapidly over the last several years. There have been dozens of Δ8‐THC studies dating back over many decades, yet no review articles have comprehensively covered these findings. In this review, we summarize the pharmacological studies of Δ8‐THC, including receptor binding, cell signalling, in vivo...
Deschloroketamine (DCK), a structural analogue of ketamine, has recently emerged on the illicit drug market as a recreational drug with a modestly long duration of action. Despite it being widely used by recreational users, no systematic research on its effects has been performed to date. Pharmacokinetics, acute effects, and addictive potential in a series of behavioural tests in Wistar rats...
Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment‐resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic...
Methoxphenidine is a dissociative-based novel psychoactive designer drug. Although fatal accidents from methoxphenidine abuse have been reported, recreational use of the drug continues. We aim to provide scientific supportfor legal regulation of recreational abuse of methoxphenidine by demonstrating its the pharmacological action. Addictive potential of methoxphenidine was examined using...
Adolescent cannabis use is associated with adult psychopathology. When Δ9 -tetrahydrocannabinol (THC), mainly in high doses, is administered to adolescence rats there are also long lasting effects in adults. This study aims to determine the specific adult bio-behavioural profile after adolescent low-dose THC, which better mirrors adolescent recreational cannabis use. Adolescent male...
Adolescents are regularly exposed to ∆9 -tetrahydrocannabinol (THC) via smoking and, more recently, vaping cannabis extracts. Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behaviour and lasting tolerance in response...
(R)-Ketamine (arketamine) may have utility as a rapidly acting antidepressant. While (R)-ketamine has lower potency than (R,S)-ketamine to inhibit NMDA receptors in vitro, the extent to which (R)-ketamine shares the NMDA receptor-mediated adverse effects of (R,S)-ketamine in vivo has not been fully characterised. Furthermore, (R)-ketamine is metabolised to (2R,6R)-hydroxynorketamine (HNK),...
It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of Δ9 -tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB1 /CB2 receptor agonists or produces these pharmacological effects on its own. The effects of THC or the CB1 /CB2 receptor full agonist WIN55212...
BACKGROUND AND PURPOSE: Synthetic cannabinoids (often sold as Spice or K2) have become a very popular alternative to cannabis due to their easy access and portrayed safety. Controlled studies on the behavioural effects of synthetic cannabinoids are currently lacking, which hampers risk assessments of these compounds. EXPERIMENTAL APPROACH: This is a first attempt to assess the influence of a...
Methoxetamine (MXE) is a novel psychoactive substance that is emerging on the Internet and induces dissociative effects and acute toxicity. Its pharmacological effects have not yet been adequately investigated. We examined a range of behavioural effects induced by acute administration of MXE (0.5-5 mg·kg-1 ; i.p.) in rats and whether it causes rapid neuroadaptive molecular changes. MXE (0.5-5...
Today, there is continued, and in some cases growing, availability of not only psychoactive substances, including treatments for mental health disorders such as cognitive enhancers, which can enhance or restore brain function, but also 'recreational' drugs such as novel psychoactive substances (NPS). The use of psychoactive drugs has both benefits and risks: whilst new drugs to treat cognitive...
It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ(9) -tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC. However, our understanding of CBD and THC interactions is limited and the brain circuitry mediating interactions between CBD and THC are...
The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic...
Background and Purpose Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro . Experimental Approach We assessed the effects of the benzofurans 5‐ APB , 5‐ APDB , 6‐ APB , 6‐ APDB , 4‐ APB , 7‐ APB , 5‐ EAPB and 5‐ MAPDB and benzodifuran 2 C ‐ B ‐ FLY on the human...
Acute activation of κ opioid (KOP) receptors results in anticocaine-like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar...
BACKGROUND AND PURPOSE: Synthetic cathinones, commonly referred to as 'bath salts', are a group of amphetamine-like drugs gaining popularity worldwide. 4-Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the UK, and exerts its effects by acting as a substrate-type releaser at monoamine transporters. Similar to other cathinone-related compounds, MEPH has a...
(R,S)-ketamine produces rapid and significant antidepressant effects in approximately 65% of patients suffering from treatment-resistant bipolar depression (BD). The genetic, pharmacological and biochemical differences between ketamine responders and non-responders have not been identified. The purpose of this study was to employ a metabolomics approach, a global, non-targeted determination of...
The substituted β‐keto amphetamine mephedrone (4‐methylmethcathinone) was banned in the UK in A pril 2010 but continues to be used recreationally in the UK and elsewhere. Users have compared its psychoactive effects to those of 3,4‐methylenedioxymethamphetamine ( MDMA , ‘ecstasy’). This review critically examines the preclinical data on mephedrone that have appeared over the last 2–3 years and,...
Background and Purpose Many young people consume ecstasy as a recreational drug and often in combination with cannabis. In this study, we aimed to mimic human consumption patterns and investigated, in male and female animals, the long‐term effects of Δ 9 ‐tetrahydrocannabinol ( THC ) and 3,4‐methylenedioxymethamphetamine ( MDMA ) on diverse neuroinflammation and neurotoxic markers. Experimental...
Background and Purpose The cardiovascular effects produced by 3,4‐methylenedioxymethamphetamine ( MDMA ; ‘ E cstasy’) contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats. Experimental Approach Radiotelemetry was employed to evaluate the...
BACKGROUND AND PURPOSE: Cannabis is the most popular drug used in the European Union, closely followed by cocaine. Whereas cannabis impairs neurocognitive function in occasional cannabis users, such impairments appear less prominent in heavy users, possibly as a result of tolerance. The present study was designed to assess whether the impairing effects of Δ(9) -tetrahydrocannabinol (THC) in...
We greatly appreciate the comments offered by Drs Rolle, Takematsu and Hoffman and the opportunity to put our work into a wider perspective. We share the view that our work does not reflect the clinical situation but rather provides a proof of mechanism study, which aims to help to translate preclinical findings (Sprague et al., 2005) into the clinic. As we noted in the discussion of our work...
Background and Purpose Recreational users report that mephedrone has similar psychoactive effects to 3,4‐methylenedioxymethamphetamine ( MDMA ). MDMA induces well‐characterized changes in body temperature due to complex monoaminergic effects on central thermoregulation, peripheral blood flow and thermogenesis, but there are little preclinical data on the acute effects of mephedrone or other...
BACKGROUND: Ecstasy use is commonly linked with memory deficits in abstinent ecstasy users. Similar impairments are being found during ecstasy intoxication after single doses of ± 3,4 metylenedioxymethamphetamine (MDMA). The concordance of memory impairments during intoxication and abstinence suggests a similar neuropharmacological mechanism underlying acute and chronic memory impairments. The...