Self-administration of cannabinoids by experimental animals and human marijuana smokers

Drug self-administration behavior has been one of the most direct and productive approaches for studying the reinforcing effects of psychoactive drugs, which are critical in determining their abuse potential. Cannabinoids, which are usually abused by humans in the form of marijuana, have become the most frequently abused illicit class of drugs in the United States. The early elucidation of the structure and stereochemistry of delta-9-tetrahydrocannabinol (THC) in 1964, which is now recognized as the principal psychoactive ingredient in marijuana, activated cannabinoid research worldwide. This review examines advances in research on cannabinoid self-administration behavior by humans and laboratory animals. There have been numerous laboratory demonstrations of the reinforcing effects of cannabinoids in human subjects, but reliable self-administration of cannabinoids by laboratory animals has only recently been demonstrated. It has now been shown that strong and persistent self-administration behavior can be maintained in experimentally and drug-na?ve squirrel monkeys by doses of THC comparable to those in marijuana smoke inhaled by humans. Furthermore, reinforcing effects of some synthetic CB1 cannabinoid agonists have been recently reported using intravenous and intracerebroventricular self-administration procedures in rats and mice. These findings support previous conclusions that THC has a pronounced abuse liability comparable to other drugs of abuse under certain experimental conditions. Self-administration of THC by squirrel monkeys provides the most reliable animal model for human marijuana abuse available to date. This animal model now makes it possible to study the relative abuse liability of other natural and synthetic cannabinoids and to preclinically assess new therapeutic strategies for the treatment or prevention of marijuana abuse in humans.     

Cannabinoids: reward,dependence, and underlying neurochemical mechanisms—a review of recent preclinical data

Background and rationale Starting with the discovery of an endogenous brain cannabinoid system with specific receptors and endogenous ligands, research in the cannabinoid field has accelerated dramatically over the last 15 years. Cannabis is the most used illicit psychotropic substance in the world but only recently have reliable preclinical models become available for investigating the rewarding and dependence-producing actions of its psychoactive constituent, ⁹-tetrahydrocannabinol (THC).Objectives The goal of this review is to examine the various animal models currently available that are being used to facilitate our understanding of the rewarding and dependence-producing actions of cannabinoids, which are central to their abuse liability, and of the neurochemical mechanisms that may underlie these actions of cannabinoids.Results and conclusions Recent demonstrations that strong and persistent intravenous self-administration behavior can be obtained in squirrel monkeys using a range of THC doses that are in agreement with the total intake and the single doses of THC normally self-administered by humans smoking marijuana cigarettes provides a reliable and direct tool for assessing the reinforcing effects of THC that are central to its abuse liability. In addition, recent demonstrations of persistent intravenous self-administration of synthetic cannabinoid CB1 receptor agonists by rats and mice and the development of genetically modified mice lacking specific cannabinoid receptors provide convenient rodent models for exploring underlying neurochemical mechanisms. Repeated demonstrations in rats that THC and synthetic CB1 agonists can induce conditioned place preferences or aversions, depending on details of dose and spacing, can reduce the threshold for intracranial self-stimulation behavior under certain conditions, and can serve as effective discriminative stimuli for operant behavior provide less direct, but more rapidly established, measures for investigating the rewarding effects of cannabinoids. Finally, there have been numerous recent reports of major functional interactions between endogenous cannabinoid, opioid, and dopaminergic neurotransmitter systems in areas such as analgesia, physical dependence and tolerance development, and drug reinforcement or reward. This provides an opportunity to search for drugs with the beneficial therapeutic effects of currently available cannabinoids or opioids but without undesirable adverse effects such as abuse liability.     

Endocannabinoid system involvement in brain reward processes related to drug abuse.

Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in humans and non-human primates. Over the last several decades, an endogenous system comprised of cannabinoid receptors, endogenous ligands for these receptors and enzymes responsible for the synthesis and degradation of these endogenous cannabinoid ligands has been discovered and partly characterized. Experimental findings strongly suggest a major involvement of the endocannabinoid system in general brain reward functions and drug abuse. First, natural and synthetic cannabinoids and endocannabinoids can produce rewarding effects in humans and laboratory animals. Second, activation or blockade of the endogenous cannabinoid system has been shown to modulate the rewarding effects of non-cannabinoid psychoactive drugs. Third, most abused drugs alter brain levels of endocannabinoids in the brain. In addition to reward functions, the endocannabinoid cannabinoid system appears to be involved in the ability of drugs and drug-related cues to reinstate drug-seeking behavior in animal models of relapse. Altogether, evidence points to the endocannadinoid system as a promising target for the development of medications for the treatment of drug abuse.     

Synthetic cannabinoids are substrates and inhibitors of multiple drug-metabolizing enzymes

Synthetic cannabinoids, a new class of psychoactive substances, are potent agonists of cannabinoid receptors, which mimic the psychoactive effects of the principal psychoactive component of cannabis, ?9-tetrahydrocannabinol. Despite governmental scheduling as illicit drugs, new synthetic cannabinoids are being produced. The abuse of synthetic cannabinoids with several drugs containing different chemical groups has resulted in large numbers of poisonings. This has increased the urgency for forensic and public health laboratories to identify the metabolites of synthetic cannabinoids and apply this knowledge to the development of analytical methods and for toxicity prediction. It is necessary to determine whether synthetic cannabinoids are involved in drug-metabolizing enzyme-mediated drug–drug interactions. This review describes the metabolic pathways of 13 prevalent synthetic cannabinoids and various drug-metabolizing enzymes responsible for their metabolism, including cytochrome P450 (CYP), UDP-glucuronosyltransferases (UGTs), and carboxylesterases. The inhibitory effects of synthetic cannabinoids on CYP and UGT activities are also reviewed to predict the potential of synthetic cannabinoids for drug–drug interactions. The drug-metabolizing enzymes responsible for metabolism of synthetic cannabinoids should be characterized and the effects of synthetic cannabinoids on CYP and UGT activities should be determined to predict the pharmacokinetics of synthetic cannabinoids and synthetic cannabinoid-induced drug–drug interactions in the clinic.     

The opioid antagonist naltrexone reduces the reinforcing effects of Δ9-tetrahydrocannabinol (THC) in squirrel monkeys

Rationale Experimental evidence from animal studies suggests reciprocal functional interactions between endogenous brain cannabinoid and opioid systems. There is recent evidence for a role of the opioid system in the modulation of the reinforcing effects of synthetic cannabinoid CB1 receptor agonists in rodents. Since ⁹–tetrahydrocannabinol (THC), the natural psychoactive ingredient in marijuana, is actively and persistently self-administered by squirrel monkeys, this provides an opportunity to directly study involvement of opioid systems in the reinforcing effects of THC in non-human primates.Objectives To study the effects of naltrexone, an opioid antagonist, on THC self-administration behavior in squirrel monkeys.Methods Monkeys pressed a lever for intravenous injections of THC under a ten-response, fixed-ratio (FR) schedule with a 60-s time-out after each injection. Effects of pre-session treatment with naltrexone (0.03–0.3 mg/kg intramuscularly, 15 min before session) for 5 consecutive days on self-administration of different doses of THC (2–8 µg/kg per injection) were studied.Results Self-administration responding for THC was significantly reduced by pretreatment with 0.1 mg/kg naltrexone for five consecutive daily sessions. Naltrexone pretreatment had no significant effect on cocaine self-administration responding under identical conditions.Conclusions Self-administration behavior under a fixed-ratio schedule of intravenous THC injection was markedly reduced by daily pre-session treatment with naltrexone, but remained above saline self-administration levels. These findings demonstrate for the first time the modulation of the reinforcing effects of THC by an opioid antagonist in a non-human primate model of marijuana abuse.     

Cannabis: discrimination of "internal bliss"?

The recent discovery of arachidonylethanolamide (anandamide), an endogenous ligand for cannabinoid receptors, and the synthesis of SR141716A, a cannabinoid antagonist selective for brain cannabinoid (CB1) receptors, have provided new tools to explore the mechanisms underlying cannabis abuse and dependence. Drug discrimination is the animal model with the most predictive validity and specificity for investigation of the psychoactive effects of cannabinoids related to their abuse potential, because, unlike many other drugs of abuse, delta9-tetrahydrocannabinol (delta9-THC), the major psychoactive ingredient of marijuana, is not self-administered by animals. Results of delta9-THC discrimination studies have revealed that the subjective effects of cannabis intoxication are pharmacologically selective for centrally active cannabinoid compounds, and that cannabis action at CB1 receptors is involved in medication of these effects. Less clear is the role of endogenous cannabinoid system(s) in cannabis intoxication. Anandamide, named for a Sanskrit word for "internal bliss," unreliably substitutes for delta9-THC. Further, substitution, when it is observed, occurs only at doses that also significantly decrease response rates. In contrast, delta9-THC and other structurally diverse cannabinoids fully substitute for delta9-THC at doses that do not substantially affect response rates. Attempts to train animals to discriminate anandamide (or SR141716A) have so far been unsuccessful. Preliminary evidence from drug discrimination studies with more metabolically stable anandamide analogs have suggested that these differences in the discriminative stimulus effects of delta9-THC and anandamide-like cannabinoids are not entirely due to pharmacokinetic factors, but the exact role of "internal bliss" in cannabis intoxication and dependence is still not completely understood.     

Neurobiology of marijuana abuse.

Marijuana has a long history of abuse yet, as described here by Mary Abood and Billy Martin, there is little evidence that animals will self-administer the primary psychoactive constituent, tetrahydrocannabinol, or that marijuana stimulates brain reward pathways. While marked tolerance develops to marijuana, it has been difficult to demonstrate physical dependence, and until recently the mechanisms by which cannabinoids produced their behavioral effects were poorly defined. The development of new synthetic analogs played a critical role in the characterization and cloning of the cannabinoid receptor. Insight into cannabinoid receptors may lead to a better understanding of marijuana abuse in humans and provide new therapeutic strategies for several disorders.     

Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation

The endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA) produces most of its pharmacological effects by binding and activating CB₁ and CB₂ cannabinoid receptors within the CNS and periphery. However, the actions of AEA are short lived because of its rapid catabolism by fatty acid amide hydrolase (FAAH). Indeed, FAAH knockout mice as well as animals treated with FAAH inhibitors are severely impaired in their ability to hydrolyze AEA as well as a variety of noncannabinoid lipid signaling molecules and consequently possess greatly elevated levels of these endogenous ligands. In this mini review, we describe recent research that has investigated the functional consequences of inhibiting this enzyme in a wide range of animal models of inflammatory and neuropathic pain states. FAAH-compromised animals reliably display antinociceptive and anti-inflammatory phenotypes with a similar efficacy as direct-acting cannabinoid receptor agonists, such as Δ⁹-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa. Importantly, FAAH blockade does not elicit any apparent psychomimetic effects associated with THC or produce reinforcing effects that are predictive of human drug abuse. The beneficial effects caused by FAAH blockade in these models are predominantly mediated through the activation of CB₁ and/or CB₂ receptors, though noncannabinoid mechanisms of actions can also play contributory or even primary roles. Collectively, the current body of scientific literature suggests that activating the endogenous cannabinoid system by targeting FAAH is a promising strategy to treat pain and inflammation but lacks untoward side effects typically associated with Cannabis sativa.     

The impact of the 2016 Psychoactive Substances Act on synthetic cannabinoid use within the homeless population: Markets,content and user harms

BackgroundOn 26 May 2016, the UK introduced the Psychoactive Substances Act. The Act made it an offence to produce, supply, or offer to supply, any psychoactive substance likely to be used for its psychoactive effects. While a Home Office review of the Act in 2018 proclaimed that the Act had been successful in achieving its main goal of preventing the open sale of psychoactive substances, significantly, the review acknowledged that high levels of synthetic cannabinoid use remain amongst vulnerable user groups, in particular the homeless population.MethodsThe research adopted an innovative interdisciplinary approach drawing on sociology and chemistry. The sociological element involved 82 face-to-face qualitative semi-structured interviews with 37 homeless synthetic cannabinoid users, 45 stakeholders, and over 100 h of fieldwork observations. The chemical analysis element involved the testing (using Gas Chromatography-Mass Spectrometry) of 69 synthetic cannabinoid street samples obtained by a local police force.ResultsThe introduction of the Act was associated with a number of significant changes to the synthetic cannabinoid market, including the integration of synthetic cannabinoids into the existing illicit street market, new dealers, the adoption of more targeted and aggressive supply practices, and variability in the content and potency of synthetic cannabinoids. Combined, these changes have increased the risk of harm to homeless users and homeless sector staff and resulted in a concomitant increase in the demand on emergency services.ConclusionThe foreseen concerns that the Act would result in detrimental market changes and increased harms to vulnerable user groups have been manifested in the homeless population. The failure of the Act to reduce synthetic cannabinoid use within this group, combined with the increased risk of individual and societal harm, highlights the importance of reducing the demand for synthetic cannabinoids.     

Cannabinoid agonists but not inhibitors of endogenous cannabinoid transport or metabolism enhance the reinforcing efficacy of heroin in rats.

Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforcing effects of heroin. In rats intravenously self-administering heroin, we investigated effects of cannabinoid CB1 receptor agonists and compounds that block transport or metabolism of the endogenous cannabinoid anandamide. The natural cannnabinoid CB1 receptor agonist delta-9-tetrahydrocannabinol (THC, 0.3-3 mg/kg i.p.) did not alter self-administration of heroin under a fixed-ratio one (FR1) schedule, except at a high 3 mg/kg dose which decreased heroin self-administration. Under a progressive-ratio schedule, however, THC dose-dependently increased the number of 50 mug/kg heroin injections self-administered per session and the maximal ratio completed (break-point), with peak increases at 1 mg/kg THC. In addition, 1 mg/kg THC increased break-points and injections self-administered over a wide range of heroin injection doses (25-100 microg/kg), indicating an increase in heroin's reinforcing efficacy and not its potency. The synthetic cannabinoid CB1 receptor agonist WIN55,212-2 (0.3-3 mg/kg i.p.) had effects similar to THC under the progressive-ratio schedule. In contrast, AM-404 (1-10 mg/kg i.p.), an inhibitor of transport of anandamide, and URB-597 (0.01-0.3 mg/kg i.p.), an inhibitor of the enzyme fatty acid amide hydrolase (FAAH) that degrades anandamide, or their combination, did not increase reinforcing efficacy of heroin at any dose tested. Thus, activation of cannabinoid CB1 receptors facilitates the reinforcing efficacy of heroin and this appears to be mediated by interactions between cannabinoid CB1 receptors and mu-opioid receptors and their signaling pathways, rather than by an opioid-induced release of endogenous cannabinoids.     

Cannabinoids and pain

Recent advances have dramatically increased our understanding of cannabinoid pharmacology: the psychoactive constituents of Cannabis sativa have been isolated, synthetic cannabinoids described and an endocannabinoid system identified, together with its component receptors, ligands and their biochemistry. Strong laboratory evidence now underwrites anecdotal claims of cannabinoid analgesia in inflammatory and neuropathic pain. Sites of analgesic action have been identified in brain, spinal cord and the periphery, with the latter two presenting attractive targets for divorcing the analgesic and psychotrophic effects of cannabinoids. Clinical trials are now required, but are hindered by a paucity of cannabinoids of suitable bioavailability and therapeutic ratio.     

Spicing things up: synthetic cannabinoids

Rationale

Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally.

Objectives

The availability, acute subjective effects—including self-reports posted on Erowid—laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed.

Results

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.

Conclusions

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.     

‘Synthetic cannabis’: A dangerous misnomer

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.     

Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions

In addition to their classical known effects, such as analgesia, impairment of cognition and learning and appetite enhancement, cannabinoids have also been related to the regulation of cardiovascular responses and implicated in cardiovascular pathology. Elevated levels of endocannabinoids have been related to the extreme hypotension associated with various forms of shock as well as to the cardiovascular abnormalities that accompany cirrhosis. In contrast, cannabinoids have also been associated with beneficial effects on the cardiovascular system, such as a protective role in atherosclerosis progression and in cerebral and myocardial ischaemia. In addition, it has also been suggested that the pharmacological manipulation of the endocannabinoid system may offer a novel approach to antihypertensive therapy. During the last decades, the tremendous increase in the understanding of the molecular basis of cannabinoid activity has encouraged many pharmaceutical companies to develop more potent synthetic cannabinoid analogues and antagonists, leading to an explosion of basic research and clinical trials. Consequently. not only the synthetic THC dronabinol (Marinol) and the synthetic THC analogue nabilone (Cesamet) have been approved in the United States, but also the standardized cannabis extract (Sativex) in Canada. At least three strategies can be foreseen in the future clinical use of cannabinoid-based drugs: (a) the use of CB(1) receptor antagonists, such as the recently approved rimonabant (b) the use of CB(2)-selective agonists, and (c) the use of inhibitors of endocannabinoid degradation. In this context, the present review examines the effects of cannabinoids and of the pharmacological manipulation of the endocannabinoid system, in cardiovascular pathophysiology.     

Cannabinoids in clinical practice

Cannabis has a potential for clinical use often obscured by unreliable and purely anecdotal reports. The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (delta9-THC); others include cannabidiol (CBD) and cannabigerol (CBG). Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this. The mechanism of action is still not fully understood, although cannabinoid receptors have been cloned and natural ligands identified. Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasm and pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor. Most of the controlled studies have been carried out with THC rather than cannabis herb and so do not mimic the usual clincal situation. Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and antiinflammatory effects, indicating that there is scope for developing drugs which do not have the psychoactive properties of THC. Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety. Cannabinoids are effective in chemotherapy-induced emesis and nabilone has been licensed for this use for several years. Currently, the synthetic cannabinoid HU211 is undergoing trials as a protective agent after brain trauma. Anecdotal reports of cannabis use include case studies in migraine and Tourette's syndrome, and as a treatment for asthma and glaucoma. Apart from the smoking aspect, the safety profile of cannabis is fairly good. However, adverse reactions include panic or anxiety attacks, which are worse in the elderly and in women, and less likely in children. Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatric hospital admissions found no evidence of this, however, it may exacerbate existing symptoms. The relatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks, especially driving and operating machinery; although driving impairment with cannabis is only moderate, there is a significant interaction with alcohol. Natural materials are highly variable and multiple components need to be standardised to ensure reproducible effects. Pure natural and synthetic compounds do not have these disadvantages but may not have the overall therapeutic effect of the herb.     

Modelling of the concentration--effect relationship of THC on central nervous system parameters and heart rate -- insight into its mechanisms of action and a tool for clinical research and development of cannabinoids

Pharmacokinetics after pulmonary administration of delta-9-tetrahydrocannabinol (THC) and its major metabolites 11-OH-THC and 11-nor-9-COOH-THC was quantified. Additionally, the relationship between THC and its effects on heart rate, body sway and several visual analogue scales was investigated using pharmacokinetic-pharmacodynamic (PK-PD) modelling. This provided insights useful for the research and development of novel cannabinoids and the physiology and pharmacology of cannabinoid systems. First, the PK-PD model gave information reflecting various aspects of cannabinoid systems. The delay between THC concentration and effect was quantified in equilibration half-lives of 7.68 min for heart rate and from 39.2 to 84.8 min for the CNS responses. This suggests that the effect of THC on the different responses could be due to different sites of action or different physiological mechanisms. Differences in the shape of the concentration-effect relationship could indicate various underlying mechanisms. Second, the PK-PD model can be used for prediction of THC concentration and effect profiles. It is illustrated how this can be used to optimise studies with entirely different trial designs. Third, many new cannabinoid agonists and antagonists are in development. PK-PD models for THC can be used as a reference for new agonists or as tools to quantitate the pharmacological properties of cannabinoid antagonists.     

Behavioural consequences of maternal exposure to natural cannabinoids in rats

Cannabis sativa preparations (hashish, marijuana) are the most widely used illicit drugs during pregnancy in Western countries. The possible long-term consequences for the child of in utero exposure to cannabis derivatives are still poorly understood. Animal models of perinatal cannabinoid exposure provide a useful tool for examining the developmental effects of cannabinoids. Behavioral consequences of maternal exposure to either cannabis preparations or to its main psychoactive component, ⁹-tetrahydrocannabinol (THC) in rat models are reviewed in this paper. Maternal exposure to cannabinoids resulted in alteration in the pattern of ontogeny of spontaneous locomotor and exploratory behavior in the offspring. Adult animals exposed during gestational and lactational periods exhibited persistent alterations in the behavioral response to novelty, social interactions, sexual orientation and sexual behavior. They also showed a lack of habituation and reactivity to different illumination conditions. Adult offspring of both sexes also displayed a characteristic increase in spontaneous and water-induced grooming behavior. Some of the effects were dependent on the sex of the animals being studied, and the dose of cannabinoid administered to the mother during gestational and lactational periods. Maternal exposure to low doses of THC sensitized the adult offspring of both sexes to the reinforcing effects of morphine, as measured in a conditioned place preference paradigm. The existence of sexual dimorphisms on the developmental effects of cannabinoids, the role of sex steroids, glucocorticoids, and pituitary hormones, the possible participation of cortical projecting monoaminergic systems, and the mediation of the recently described cannabinoid receptors are also analyzed. The information obtained in animal studies is compared to the few data available on the long-term behavioral and cognitive effects on in utero exposure to cannabis in humans.     

CB<Subscript>1</Subscript> cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat

Rationale Addictive drugs have a number of commonalities in animal behavioral models. They lower intracranial self-stimulation (ICSS) thresholds, support self-administration, and produce conditioned place preference (CPP). However, cannabinoids appear atypical as drugs of abuse, since there are controversial data in the literature concerning their reinforcing properties.Objectives The aim of the present study was to examine the effects of cannabinoids on brain reward using the rate–frequency curve shift paradigm of ICSS.Methods Male Sprague–Dawley rats were implanted with electrodes into the medial forebrain bundle (MFB). Rate–frequency functions were determined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding. After brain stimulation reward thresholds stabilized rats received intraperitoneal (IP) injections of the potent CB₁ receptor agonists WIN 55,212-2 (graded doses 0.1, 0.3, 1 and 3 mg/kg), CP 55,940 (graded doses 10, 30, 56 and 100 g/kg), or HU-210 (graded doses 10, 30, 100 g/kg).Results With the exception of the highest dose of all cannabinoid agonists tested, which significantly increased the threshold frequency required for MFB ICSS, all other doses of the tested drugs did not affect ICSS thresholds. The CB₁ receptor antagonist SR141716A reversed the actions of WIN 55,212-2 and CP 55,940, but not HU-210. However, the selective CB₁ cannabinoid receptor antagonist AM 251 counteracted the effect of HU-210. Both CB₁ receptor antagonists, at the doses used in the present study, did not affect reward thresholds by themselves.Conclusions The present results indicate that cannabinoid agonists do not exhibit reinforcing properties in the ICSS paradigm, but rather have an inhibitory influence on reward mechanisms. The results suggest that the anhedonic effects of cannabinoids are probably mediated by cannabinoid CB₁ receptors.     

苯乙胺类物质的滥用危害与管制措施探析

2017年《世界毒品报告》显示:苯乙胺类物质已成为继合成大麻素类、合成卡西酮类之后的第三大合成类毒品.在所有因滥用新精神活性物质导致的临床病例中苯乙胺所占比例高达28.4％[1],苯乙胺类物质因其化学结构灵活多变,由此成为众多非法兴奋剂的演变"载体",加之部分苯乙胺类新精神活性物质兼具兴奋与致幻的双重效应,其危害性较之...