Explainable Machine Learning Analysis Reveals Gender Differences in the Phenotypic and Neurobiological Markers of Cannabis Use Disorder

Background: Cannabis Use Disorder (CUD) has been linked to environmental, personality, mental health, neurocognitive and neurobiological risk factors. While many studies have revealed gender differences in CUD, the relative importance of these complex factors by gender has not been described. Methods: We conducted a data-driven examination of gender differences in CUD in a community sample of young adults (Human Connectome Project [HCP]; n = 1204, 54% female). We employed state-of-the-art machine learning methods [gradient tree boosting, XGBoost] in combination with novel factor ranking tools [SHapley's Additive exPlanations (SHAP)] as an 'explainable machine learning approach' in the multimodal data collected by the HCP (phenotypic and brain data). Results: We were able to successfully classify both cannabis dependence and cannabis use levels. Previously identified environmental, personality, mental health, neurocognitive, and brain factors highly contributed to the classification. Predominantly-male risk factors included personality (high openness), mental health (high externalizing, high childhood conduct disorder, high fear somaticism), neurocognitive (impulsive delay discounting, slow working memory performance) and brain (low hippocampal volume) factors. Conversely, predominantly-female risk factors included environmental (low education level, low instrumental support) factors. Conclusions: Our data-driven analysis of gender differences in the multimodal risk factors underlying cannabis dependence and use levels demonstrate that environmental factors contribute more strongly to CUD in women, whereas individual factors such as personality, mental health and neurocognitive factors have a larger importance in men. This warrants further investigations, and suggests the importance of understanding how these differences relate to the development of effective treatment approaches.

Association patterns of cannabis abuse and dependence with risk of problematic non-substance-related dysregulated and addictive behaviors

Co-occurrence of drug misuse with other dysregulated behaviors is common. This study was aimed at exploring the associations between the risk of presenting a clinically relevant condition involving non-substance-related addictive or dysregulated behaviors (as measured by the MultiCAGE CAD-4 screening), and cannabis abuse/dependence (CAST/SDS) scores, and the role of gender therein. Participants were recruited using stratified probabilistic sampling at the University of Granada. Mann-Whitney’s U tests were used to compare male and female students in SDS and CAST scores. Associations between gender and MultiCAGE scores were estimated using the γ ordinal correlation index, and tested with χ2. For each MultiCAGE dimension, a Poisson-family mixed-effects model was built with either SDS or CAST as the main input variable, while controlling for nicotine and alcohol dependence, and relevant sociodemographic variables. Incidence rate ratios (IRR) were computed for SDS/CAST effects, and the significance threshold was family-wise Bonferroni-corrected. Gender differences were significant for cannabis dependence/abuse and all MultiCAGE scores for non-substance-related conditions, with males showing higher risk scores for excessive gambling, excessive internet use, excessive video gaming, and hypersexuality, and females presenting higher scores in dysregulated eating and compulsive buying. Cannabis dependence and abuse were significantly associated with a higher risk of problematic video gaming. These associations were mostly driven by males. Importantly, although risk of problematic video gaming was specifically associated with cannabis abuse/dependence, there was only a weak non-significant association between problematic video gaming and alcohol use scores. Risk of alcohol use problems, in turn, was strongly associated with all other non-substance-related problems (problematic gambling, excessive Internet use, dysregulated eating, compulsive buying, and hypersexuality). These differential associations can cast light on the etiological similarities and dissimilarities between problematic substance use and putative addictive behaviors not involving drugs.

The Alerting and Orienting Systems of Attention Are Modified by Cannabis Dependence

Attention allows us to select relevant information from the background. Although several studies have described that cannabis use induces deleterious effects on attention, it remains unclear if cannabis dependence affects the attention network systems differently.Objectives:To evaluate whether customary consumption of cannabis or cannabis dependence impacts the alerting, orienting, and executive control systems in young adults; to find out whether it is related to tobacco or alcohol dependence and if cannabis use characteristics are associated with the attention network systems.Method:One-hundred and fifty-four healthy adults and 102 cannabis users performed the Attention Network Test (ANT) to evaluate the alerting, orienting, and executive control systems.Results:Cannabis use enhanced the alerting system but decreased the orienting system. Moreover, those effects seem to be associated with cannabis dependence. Out of all the cannabis-using variables, only the age of onset of cannabis use significantly predicted the efficiency of the orienting and executive control systems.Conclusion:Cannabis dependence favors tonic alertness but reduces selective attention ability; earlier use of cannabis worsens the efficiency of selective attention and resolution of conflicts.

Cannabis Use in People With Obsessive-Compulsive Symptomatology: Results From a Mexican Epidemiological Sample

Recent studies suggest that the endocannabinoid system could play an important role in the physiopathology of obsessive-compulsive disorder (OCD). There are reports of effective treatment with derivatives of tetrahydrocannabinol (THC). The study of the genetic factor associated with psychiatric disorders has made possible an exploration of its contribution to the pharmacological response. However, very little is known about the genetic factor or the prevalence of cannabis use in the Mexican population with OCD. The objective of this study is to compare the prevalence of use and dependence on cannabis in individuals with obsessive-compulsive symptomatology (OCS) with that of individuals with other psychiatric symptoms (psychosis, depression, and anxiety), and to explore the association between genetic risk and use. The study includes a total of 13,130 individuals evaluated in the second stage of the 2016 National Survey of Drug, Alcohol, and Tobacco Use (Encodat 2016), with genetic analysis (polygenic risk scoring) of a subsample of 3,521 individuals. Obsessive symptomatology had a prevalence of 7.2% and compulsive symptomatology a prevalence of 8.6%. The proportion of individuals with OCS who had ever used cannabis was 23.4%, and of those with cannabis dependency was 2.7%, the latter figure higher than that in individuals with other psychiatric symptoms (hypomania, 2.6%; anxiety, 2.8%; depression, 2.3%), except psychosis (5.9%). Individuals with OCS who reported using cannabis had an increased genetic risk for cannabis dependence but not for OCD. We thus cannot know how the increased genetic risk of cannabis dependence in people with OCD is influenced by their pharmacological response to derivatives of THC. The results, however, suggest paths for future studies.

Cannabis based medicines and cannabis dependence: A critical review of issues and evidence

Cannabis has been legalised for medical use in an ever-increasing number of countries. A growing body of scientific evidence supports the use of medical cannabis for a range of therapeutic indications. In parallel with these developments, concerns have been expressed by many prescribers that increased use will lead to patients developing cannabis use disorder. Cannabis use disorder has been widely studied in recreational users, and these findings have often been projected onto patients using medical cannabis. However, studies exploring medical cannabis dependence are scarce and the appropriate methodology to measure this construct is uncertain. This article provides a narrative review of the current research to discern if, how and to what extent, concerns about problems of dependence in recreational cannabis users apply to prescribed medical users. We focus on the main issues related to medical cannabis and dependence, including the importance of dose, potency, cannabinoid content, pharmacokinetics and route of administration, frequency of use, as well as set and setting. Medical and recreational cannabis use differs in significant ways, highlighting the challenges of extrapolating findings from the recreational cannabis literature. There are many questions about the potential for medical cannabis use to lead to dependence. It is therefore imperative to address these questions in order to be able to minimise harms of medical cannabis use. We draw out seven recommendations for increasing the safety of medical cannabis prescribing. We hope that the present review contributes to answering some of the key questions surrounding medical cannabis dependence.

CANreduce 2.0 – the effects of adherence-focused guidance for Internet self-help among cannabis misusers: results of a three-arm randomized controlled trial (Preprint)

BACKGROUND Despite increasing demand for treatment among cannabis misusers in many countries, most misusers are not in treatment. Internet-based self-help offers an alternative for those hesitant to seek face-to-face therapy, though low-effectiveness and adherence issues often arise. Through adherence-focused guidance enhancement (AFGE), we aimed to increase adherence to, and the effectiveness of Internet-based self-help among cannabis misusers. OBJECTIVE A three-arm randomized controlled trial was conducted comparing the effectiveness of (1) an AFGE Internet-based self-help intervention with social presence (AFGE-SP), (2) a similar intervention with an impersonal service team (AFGE-ST), and (3) Internet access as usual (IAU, controls). METHODS From July 2016—May 2019, 575 cannabis misusers (70.6% males, mean age=28.3) not otherwise in treatment were recruited from the general population. The primary outcome was cannabis-use days over the preceding 30 days. Secondary outcomes included cannabis-dependence severity, changes in cannabis misuse disorder (CMD) symptoms, and intervention adherence. RESULTS All groups exhibited reduced cannabis-use days after 3 months (AFGE-SP: -8.2; AFGE-ST: -9.8; IAU: -4.2). AFGE-ST participants reported significantly fewer cannabis-use days than IAU controls (P = .01, d = .60); a similar reduction in the AFGE-SP (d=.40) group failed to achieve significance (P =.07). There was no significant difference between the two intervention groups. AFGE-ST patients also exhibited superior improvements in cannabis-use disorder, cannabis-dependence severity, and general anxiety symptoms after three months. CONCLUSIONS Adding an impersonal service team to the AFGE Internet-based self-help intervention significantly reduced cannabis use, cannabis use disorder, dependence severity, and general anxiety symptoms. CLINICALTRIAL http://www.isrctn.com/ISRCTN11086185

Deep Cerebellar Transcranial Electrical Stimulation: Hypothesis and Theory for Cannabis Use Disorder

Cannabis is the most widely cultivated, trafficked and abused illicit drug (“WHO | Cannabis,” n.d.; “World Drug Report 2020,” n.d.). In 2018, an estimated 192 million people aged 15-64 years used cannabis for nonmedical purposes globally (Degenhardt et al., 2013). The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated that, across the globe, there were more than 22·1 million people with cannabis dependence (Degenhardt et al., 2018). Moreover, the same study calculated that cannabis dependence could be accounted for 646 thousand Disability Adjusted Life Years, globally. Importantly, cannabis dependence mostly affects young adults (20-24 years), and thus has significant negative impact on the growth and productivity of not only these individuals but also to the societies and nations (Degenhardt et al., 2013). In addition to the dependence syndrome, cannabis use is associated with increased risk of psychosis, cognitive dysfunction, academic problems, and road side accidents (Volkow et al., 2014). A review showed a fairly consistent associations between cannabis use and both lower educational attainment and increased reported use of other illicit drugs (Macleod et al., 2004). In the United States, Cannabis Use Disorder (CUD) is an escalating problem in young adults by legalization (Cerdá et al., 2020) where National Survey on Drug Use and Health reported increased prevalence from 5.1% in 2015 to 5.9% in 2018 in 18-25 year olds (“2019 NSDUH Detailed Tables | CBHSQ Data,” n.d.). The psychoactive effects are due to type 1 cannabinoid receptor (CB1), the cannabinoid binding protein, that are highly expressed in the cerebellar cortex (Marcaggi, 2015). CB1 is primarily found in the molecular layer at the most abundant synapse type in the cerebellum (Marcaggi, 2015) that can shape the spike activity of cerebellar Purkinje cell (Brown et al., 2019). Moreover, granule cell to Purkinje cell synaptic transmission can trigger endocannabinoid release (Alger and Kim, 2011), which may be important for information processing by cerebellar molecular layer interneurons (Dorgans et al., 2019). This suggests that endocannabinoids could be essential to neurocognitive aspects of cerebellar function (Di Marzo et al., 2015),(Marcaggi, 2015),(Alger and Kim, 2011). Accumulating evidence also suggests cerebellar modulation of the reward circuitry and social behaviour, via direct cerebellar innervation of the ventral tegmental area (VTA) including dopamine cell bodies (A1) in the VTA (Carta et al., 2019). The VTA-dopamine (DA) signalling in the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC) (Lohani et al., 2019) play a key role in motivatedbehaviours and cognition. Cerebellar neuropathological changes can result in aberrant dopaminergic activity in the NAc and mPFC (ROGERS et al., 2011),(Lohani et al., 2019). Therefore, there is a critical need to determine how cerebellum modulate limbic VTA-DA signalling. Cerebellar Non-Invasive Brain Stimulation (NIBS) is postulated to be most relevant in CUD since endocannabinoids are essential to cerebellar function that includes reward-related behaviours, information processing, and cognitive control. (Di Marzo et al., 2015),(Marcaggi, 2015),(Alger and Kim, 2011). Furthermore, cerebellar NIBS can facilitate training of cognitive control in CUD during a during visual cue reactivity paradigm using a mobile virtual reality (VR) interface that can also allow remote delivery of cerebellar NIBS in conjunction with VR-based cognitive training for home-based intervention. Specifically, transcranial electrical stimulation (tES) can be translatable to low-cost (<$150) mobile devices that can be used in a low resource home-based setting (Carvalho et al., 2018).