Is cannabis a gateway drug? Testing hypotheses about the relationship between cannabis use and the use of other illicit drugs

We outline and evaluate competing explanations of three relationships that have consistently been found between cannabis use and the use of other illicit drugs, namely, (1) that cannabis use typically precedes the use of other illicit drugs; and that (2) the earlier cannabis is used, and (3) the more regularly it is used, the more likely a young person is to use other illicit drugs. We consider three major competing explanations of these patterns: (1) that the relationship is due to the fact that there is a shared illicit market for cannabis and other drugs which makes it more likely that other illicit drugs will be used if cannabis is used; (2) that they are explained by the characteristics of those who use cannabis; and (3) that they reflect a causal relationship in which the pharmacological effects of cannabis on brain function increase the likelihood of using other illicit drugs. These explanations are evaluated in the light of evidence from longitudinal epidemiological studies, simulation studies, discordant twin studies and animal studies. The available evidence indicates that the association reflects in part but is not wholly explained by: (1) the selective recruitment to heavy cannabis use of persons with pre-existing traits (that may be in part genetic) that predispose to the use of a variety of different drugs; (2) the affiliation of cannabis users with drug using peers in settings that provide more opportunities to use other illicit drugs at an earlier age; (3) supported by socialisation into an illicit drug subculture with favourable attitudes towards the use of other illicit drugs. Animal studies have raised the possibility that regular cannabis use may have pharmacological effects on brain function that increase the likelihood of using other drugs. We conclude with suggestions for the type of research studies that will enable a decision to be made about the relative contributions that social context, individual characteristics, and drug effects make to the relationship between cannabis use and the use of other drugs.     

COVID-19 and the health of people who use drugs: What is and what could be?

SARS-CoV-2, the virus that causes COVID-19, has changed the world as we know it, and continues to do so. How COVID-19 affects people who use drugs, the environments in which they live, and capacities of response, warrants immediate attention. This special issue begins to map how COVID-19 is altering the health of people who use drugs, including in relation to patterns of drug use, service responses, harms that may relate to drug use, interventions to reduce risk of harms, COVID-19 health, and drug policies. We emphasise the need to envisage COVID-19 and its effects as a matter of intersecting ‘complex adaptive systems’: that is, the impacts of COVID-19 extend beyond the virus and related illness conditions to encompass multiple social, cultural, economic, policy and political effects; and these affect the health of people who use drugs directly as well as indirectly by altering the risk and enabling environments in which they live. We synthesize emergent evidence on the impact of COVID-19 on the health of people who use drugs. A key concern we identify is how to sustain policy and service delivery improvements prompted by COVID-19. We need to maintain an ethos of emergent adaptation and experimentation towards the creation of safer environments in relation to the health of people who use drugs.     

Future antidepressants: what is in the pipeline and what is missing?

Monoamine reuptake inhibitors still reign in the treatment of major depression, but possibly not for long. While medicinal chemists have been able to reduce the side effects of these drugs, their delayed onset of action and considerable non-response rate remain problematic. Of late, serious questions have been raised regarding the efficacy of monoamine reuptake inhibitors. The present review presents an inventory of what is (and until recently was) in the antidepressant pipeline of pharmaceutical companies. Novel antidepressant compounds can be categorised into four groups depending on their target(s): (i) monoamine receptors; (ii) non-monoamine receptors; (iii) neuropeptide receptors; and (iv) hormone receptors. Other possible targets include components of post-receptor intracellular processes and elements of the immune system; to date, however, compounds specifically aimed at these targets have not been the subject of clinical trials. Development of several compounds targeted at monoamine receptors has recently been discontinued. At least five neurokinin-1 (NK(1)) receptor antagonists were until recently in phase II of clinical testing. However, the apparent interest in the NK(1) receptor should not be interpreted as representing a departure from the monoamine hypothesis since neurokinins also modulate monoaminergic systems. In the authors' view, development of future antidepressants will continue to rely on the serendipity-based monoamine hypothesis. However, an alternative approach, based on the hypothesis that chronic stress precipitates depressive symptoms, might be more productive. Unfortunately, clinical results using drugs targeted at components of the HPA axis have not been very encouraging to date. In the short run, the authors believe that augmentation strategies offer the best hope for improving the efficacy of antidepressant treatment. Several approaches to improve the efficacy of SSRIs are conceivable, such as concurrent blockade of monoamine autoreceptors and the addition of antipsychotics, neuromodulators or hormones (HPA axis and gender related). In the long-term, however, construction of a scientifically verified conceptual framework will be needed before more effective antidepressants can be developed. It can be argued that it is not depression itself that should be treated, but rather that its duration should be reduced by pharmacological means. Animal models that take this concept into consideration and identify mechanisms for acceleration of recovery from the effects of stress need to be developed.     

Cannabis and psychosis: what is the link?

Growing evidence supports the hypothesis that cannabis consumption is a risk factor for the development of psychotic symptoms. Nonetheless, controversy remains about the causal nature of the association. This review takes the debate further through a critical appraisal of the evidence. An electronic search was performed, allowing to identify 622 studies published until June 1st 2005. Longitudinal studies and literature reviews were selected if they addressed specifically the issues of the cannabis/psychosis relationship or possible mechanisms involved. Ten epidemiological studies were relevant: three supported a causal relationship between cannabis use and diagnosed psychosis; five suggested that chronic cannabis intake increases the frequency of psychotic symptoms, but not of diagnosed psychosis; and two showed no causal relationship. Potential neurobiological mechanisms were also identified, involving dopamine, endocannabinoids, and brain growth factors. Although there is evidence that cannabis use increases the risk of developing psychotic symptoms, the causal nature of this association remains unclear. Contributing factors include heavy consumption, length and early age of exposure, and psychotic vulnerability. This conclusion should be mitigated by uncertainty arising from cannabis use assessment, psychosis measurement, reverse causality and control of residual confounding.     

Vitamins and cognition: what is the evidence?

Vitamin supplements are consumed for their purported health benefits by a large segment of the populations of developed countries. Several indirect strands of evidence suggest that increasing levels of vitamins may improve brain function. These include evidence that individual vitamins are intrinsically involved in the cellular and physiological processes underpinning brain function; that small proportions of the population exhibit biochemical deficiencies in each individual vitamin, suggesting that a much larger proportion have less than optimal overall micronutrient status; and that epidemiological research suggests a relationship between individual vitamins (or the potentially neurotoxic amino acid homocysteine, which is related to B vitamin status), and cognitive function and mood. The related question as to whether direct supplementation with vitamins can therefore improve psychological functioning in cognitively intact individuals has been addressed in a number of studies. The evidence reviewed here suggests that, whereas studies involving supplementation with single vitamins, or restricted ranges of vitamins, have demonstrated equivocal results, evidence from studies involving the administration of broader ranges of vitamins, or multivitamins, suggest potential efficacy in terms of cognitive and psychological functioning. In contrast to the literature investigating restricted ranges of vitamins, most of the evidence regarding multivitamins was collected from healthy, non-elderly samples, suggesting that more research in this population is warranted.     

Tricyclic antidepressants and fibromyalgia: what is the mechanism of action?

Fibromyalgia is a chronic pain disorder of which other clinical features, such as persistent fatigue and disordered sleep, may be a secondary consequence. The initial pharmacological approach to treating the disorder is the management of the pain. Tricyclic antidepressants are the most effective drugs in use so far, especially when administered in combination with other therapies (e.g., selective serotonin re-uptake inhibitors), which suggests modulation of the neurotransmitters serotonin and noradrenaline. The effectiveness of amitriptyline and related tricyclic antidepressants, however, is consistent with the involvement of mechanisms, such as potassium channel modulation and NMDA receptor antagonism, in addition to or in place of the modulation of monoamine neurotransmitters. Investigation of the importance of each of the pharmacological properties of amitriptyline and related molecules in the management of fibromyalgia could provide clues for the rational design of new drugs.     

Does cannabis use increase the risk of death? Systematic review of epidemiological evidence on adverse effects of cannabis use

Issues. To conduct a comprehensive search of the peer‐reviewed literature to assess risk of cannabis‐related mortality. Approach. Systematic peer‐reviewed literature searches were conducted in Medline, EMBASE and PsycINFO to identify data on mortality associated with cannabis use. Search strings for cannabis and mortality were used. Searches were limited to human subjects and the publication timeframe of January 1990 to January 2008. Reference lists of review articles and of specific studies deemed important by colleagues were searched to identify additional studies. A list of the selected articles was emailed to experts in the field asking for comment on completeness. Key Findings. There is insufficient evidence, particularly because of the low number of studies, to assess whether the all‐cause mortality rate is elevated among cannabis users in the general population. Case–control studies suggest that some adverse health outcomes may be elevated among heavy cannabis users, namely, fatal motor vehicle accidents, and possibly respiratory and brain cancers. The evidence is as yet unclear as to whether regular cannabis use increases the risk of suicide. Conclusions. There is a need for long‐term cohort studies that follow cannabis using individuals into old age, when the likelihood of any detrimental effects of cannabis use are more likely to emerge among those who persist in using cannabis into middle age and older. Case–control studies of cannabis use and various causes of mortality are also needed.[Calabria B, Degenhardt L, Hall W, Lynskey M. Does cannabis use increase the risk of death? Systematic review of epidemiological evidence on adverse effects of cannabis use. Drug Alcohol Rev 2010]     

Detectability of cannabinoids in the serum samples of cannabis users: Indicators of recent cannabis use? A follow-up study

Forensic toxicologists are frequently required to predict the time of last cannabis consumption. Several studies suggested the utility of minor cannabinoids as indicators of recent cannabis use. Because several factors influence blood cannabinoid concentrations, the interpretation of serum cannabinoid concentrations remains challenging. To assess the informative value of serum cannabinoid levels in cannabis users (in total N = 117 patients, including 56 patients who stated an exact time of last cannabis use within 24 h before blood sampling), the detectability of cannabinoids, namely, delta-9-tetrahydrocannabinol (delta-9-THC), 11-hydroxy-delta-9-THC, 11-nor-9-carboxy-delta-9-THC, cannabichromene (CBC), cannabidiol (CBD), cannabinol (CBN), cannabidivarin, tetrahydrocannabivarin, cannabigerol (CBG), cannabicyclol, delta-8-THC, tetrahydrocannabinolic acid A, cannabichromenic acid, cannabidiolic acid (CBDA), cannabigerolic acid, cannabicyclolic acid (CBLA), 11-nor-9-carboxy-THCV (THCVCOOH), and 11-nor-CBN-9-COOH, was investigated. Excluding CBDA and CBLA, all investigated cannabinoids were detected in at least one analyzed sample. The interval between cannabis consumption and sample collection (reported by the patients) was not correlated with cannabinoid concentrations. Minor cannabinoids tended to be more easily detected in samples obtained shortly after consumption. However, some samples tested positive for minor cannabinoids despite an interval of several hours or even days between consumption and sampling (according to patients' statements). For instance, CBC, CBG, THCVCOOH, CBD, and CBN in certain cases could be detected more than 24 h after the last consumption of cannabis. Thus, findings of minor cannabinoids should always be interpreted with caution.     

Treatment of cognitive impairment in multiple sclerosis: is the use of acetylcholinesterase inhibitors a viable option?

Approximately half of all patients with multiple sclerosis (MS) experience cognitive impairment, most commonly with regard to new learning and memory. Cognitive dysfunction is a leading cause of disability in MS and it can have profound social and economic consequences for patients and their families.Research on treatment for cognitive impairment in MS is still in the early stages, as it is for most neurological conditions. The available disease-modifying therapies in MS may provide some modest benefit to cognition, but patients with MS clearly need better treatment for cognitive dysfunction. A number of studies have assessed symptomatic treatments of cognition in MS, and the results of these small, underpowered studies have been mixed. Regardless, acetylcholinesterase inhibitors (AChEIs) have been the most promising class of medications tested in MS to date. Seven of eight studies on AChEIs have shown positive results, although it is difficult to assess their adequacy since only three of the studies have been published in peer reviewed journals, with the rest appearing only as abstracts. The earliest AChEI studies in MS examined physostigmine, but the short half-life and prominent adverse effects of this medication may have limited its use compared with other AChEIs. All of the more recent AChEI studies have used donepezil, which, from the limited data available to date, appears to have been relatively well tolerated among MS patients. The largest randomized controlled trial of donepezil included 69 subjects and found that donepezil improved verbal learning and memory compared with placebo during neuropsychological testing. That study also found that patients receiving donepezil were more likely to report memory improvement than those receiving placebo, and the study clinician also noted a cognitive benefit among those on donepezil as opposed to placebo.There are still many unanswered questions regarding the use of AChEIs in MS, including the effects of their long-term use in a chronic disease such as MS. On the whole, to date the research on AChEIs in MS must be considered preliminary, and it is premature to recommend the clinical use of this class of medications at the present time.     

Can genetics inform the management of cognitive deficits in schizophrenia?

There is no doubt that schizophrenia has a significant genetic component and a number of candidate genes have been identified for this debilitating disorder. Of note, several of these are implicated in cognition. Cognitive deficits constitute core symptoms of schizophrenia, and while current antipsychotic treatment strategies aim to help psychosis-related symptomatology, the cognitive symptom domain is largely inadequately treated. A number of other pharmacological approaches (e.g. using drugs that target specific neurotransmitter systems) have also been attempted for the amelioration of cognitive deficits in this population; however, these too have had limited success so far. Psychological interventions appear promising, though there has been speculation regarding whether or not these produce long-term functional improvements. Pharmacogenetic studies of the cognitive effects of currently available antipsychotics, although in relatively early stages, suggest that the treatment of cognitive deficits in schizophrenia may be advanced by focusing on genetic variants associated with specific cognitive dysfunctions in the general population and using this to match the most relevant pharmacological and/or psychological interventions with the genetic and cognitive profiles of the target population. Such a strategy would encourage bottom-up advances in drug development and provide a platform for individualised treatment of cognitive deficits in schizophrenia.     

Pitavastatin and carbohydrate metabolism: what is the evidence?

Statins are the cornerstone of hypolipidemic treatment but recently have been associated with increased risk of developing diabetes mellitus. However, the risk of incident diabetes is not the same among statins. Pitavastatin lowers low-density lipoprotein cholesterol and increases high-density lipoprotein cholesterol but also seems to be neutral in terms of risk of incident diabetes. Clinical and experimental evidence shows that pitavastatin increases adiponectin levels and reduces oxidative stress, effects that seem to be implicated in the beneficial effect of the drug on carbohydrate metabolism variables. Pitavastatin is a useful hypolipidemic drug, which is promising for patients with increased diabetes risk or established diabetes.     

Antiangiogenesis and radiotherapy: what is the role of combined modality treatment?

The formation of new blood vessels is a prerequisite for the growth of primary and metastatic tumour. Thus, strategies that aim at the inhibition of tumour angiogenesis have gained considerable interest in recent years. Furthermore, there is a need to identify the role of antiangiogenic agents in conjunction with conventional anticancer modalities like chemotherapy or radiotherapy. It is the objective of this review to summarise experimental data for different antiangiogenic agents used for combined modality experiments with radiotherapy. Promising data have been reported for a series of antiangiogenic agents for combined modality treatment with radiotherapy using tumour growth delay as the primary end-point. Yet, the results from different agents with various tumour lines are contradictory in part. Furthermore, enhancement of local tumour control, the main objective of curative radiotherapy, has so far been demonstrated for only two agents (DC101 and CA4DP), while experiments using TNP-470 even revealed a reduction of local tumour control when combined with irradiation. Finally, detailed studies investigating the modulation of normal tissue reactions for the combination of radiotherapy and inhibitors of angiogenesis are pending so far. Thus, experimental data currently available do not consistently support the beneficial effects of combined modality treatment with inhibitors of angiogenesis and radiotherapy. We therefore conclude that there is still a long way to go until we know which antiangiogenic agent will clinically be suitable for what tumour entity for combined treatment of radiotherapy and inhibitors of angiogenesis.     

Opioids and the immune system: what is their mechanism of action?

There is a significant amount of literature showing that morphine and other opioids modulate immune responses. The findings support many mechanisms by which this may occur. In vitro experiments provide evidence for direct actions of opioids on immune cells using a variety of functional end points. When these drugs are given in vivo, a plethora of immune parameters are also altered. The paper in this issue of the journal by Zhang et al. provides new information on morphine alteration of immune cell subsets in the spleen and thymus of mice and the potential role of glucocorticoids in these observed phenomena. This Commentary reviews the in vitro activities of morphine on leucocytes, as well as other documented mechanisms by which morphine can alter immune function in vivo.     

Legal cannabis laws,home cultivation,and use of edible cannabis products: A growing relationship?

BackgroundOver half of U.S. states have enacted legal cannabis laws (LCL). In parallel, edible cannabis products (i.e., edibles) have presented new regulatory challenges. LCL provisions that dictate access to cannabis (e.g., home cultivation (HC) or dispensaries (DSP)) may impact edible production and use. This study examined relationships among HC and DSP provisions, cannabis cultivation, and edible use.MethodsAn online cannabis use survey was distributed using Facebook. Data were collected from 1813 cannabis-using adults. U.S. states were classified as states without LCL (Non-LCL) or LCL states that: (1) only permit DSP (LCL DSP-only), (2) only permit HC (LCL HC-only), or (3) permit HC and DSP (LCL HC + DSP). Analyses tested associations among these classifications, cannabis growing, and edible use and procurement.ResultsIndividuals in LCL HC-only and LCL HC + DSP states were more likely to report currently growing cannabis at home (OR: 3.3, 95% CI: 1.7, 6.2; OR: 3.9, 95% CI: 2.4, 6.3, respectively) and past-month edible use (OR: 2.1, 95% CI: 1.4, 3.4; OR: 2.9, 95% CI: 2.2, 3.9, respectively) than individuals in LCL DSP-only states. Regardless of state, those who had grown cannabis were more likely to have made edibles than those who had never grown cannabis (OR: 2.2, 95% CI: 1.8, 2.6). Individuals in LCL HC-only states were more likely to have made edibles in the past month than individuals from Non-LCL (OR: 2.75, 95% CI: 1.5, 5.3) and DSP-only states (OR: 2.1, 95% CI: 1.0, 4.4). Individuals in LCL HC + DSP states were more likely to have purchased edibles in the past month than individuals from Non-LCL (OR: 3.7, 95% CI: 2.4, 5.6) and DSP-only states (OR: 3.2, 95% CI: 1.8, 5.5).ConclusionSpecific LCL provisions may differentially affect individuals’ propensity to grow cannabis and make, buy, and use edible cannabis products. Permitting home cultivation contributes to a greater likelihood of growing cannabis. Those who grow cannabis economize the plant by creating homemade edible cannabis products. Conversely, permitting dispensaries increases the likelihood of purchasing edibles. The psychoactive effects of edibles with unknown and variable cannabinoid content will be unpredictable. Policymakers should carefully consider how specific LCL provisions can affect patterns of cannabis edible product access and quality.     

The adverse health effects of cannabis use: What are they,and what are their implications for policy?

Background: The adverse health effects of cannabis are a source of contention in debates about policies towards the drug. Methods: This paper provides a review of epidemiological evidence on the major adverse health effects of cannabis use and considers its implications for policy. Results: The evidence strongly suggests that cannabis can adversely affect some users, especially adolescents who initiate use early and young adults who become regular users. These adverse effects probably include increased risks of: motor vehicle crashes, the development of cannabis dependence, impaired respiratory function, cardiovascular disease, psychotic symptoms, and adverse outcomes of adolescent development, namely, poorer educational outcomes and an increased likelihood of using other illicit drugs. Conclusions: Politically, evidence of adverse health effects favours the status quo in developed countries like Australia where cannabis policy has been framed by the media as a choice between two views: (1) either cannabis use is largely harmless to most users and so we should legalize, or at the very least decriminalize its use; or (2) it harms some of its users so we should continue to prohibit its use.     

Human epicardial fat: what is new and what is missing?

1. Putative physiological functions of human epicardial adipose tissue (EAT) include: (i) lipid storage for the energy needs of the myocardium; (ii) thermoregulation, whereby brown fat components of EAT generate heat by non-shivering thermogenesis in response to core cooling; (iii) neuroprotection of the cardiac autonomic ganglia and nerves; and (iv) regulation of vasomotion and luminal size of the coronary arteries. Under pathophysiological circumstances, EAT may play an adverse paracrine role in cardiac arrhythmias and in lipotoxic cardiomyopathy, but of major current interest is its hypothetical role as an immunological organ contributing to inflammation around coronary artery disease (CAD). 2. The amount of EAT measured either by echocardiographic thickness over the free wall of the right ventricle or as volume by computed tomography expands in patients with obesity both without and with CAD. The mechanisms other than obesity governing the increase in EAT volume in CAD are unknown, but EAT around CAD is infiltrated by chronic inflammatory cells and overexpresses genes for adipokines that have pro- or anti-inflammatory actions and regulate oxidative stress plus angiogenesis. 3. Many cross-sectional studies have shown positive associations between increased EAT mass and stable CAD burden. One prospective population-based epidemiological study suggested that EAT volume at baseline is a predictor of acute myocardial infarction, but was without significant incremental predictive value after adjustment for established cardiovascular risk factors. However, strategies are needed to obtain robust epidemiological, interventional and experimental evidence to prove or disprove the hypothesis that EAT is a cardiovascular risk factor locally contributing to CAD.