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BACKGROUND: Cannabis was legalised for medical purposes in 2016. Uptake was initially slow, but since 2019 there has been a large increase in the number of Australians who have been prescribed cannabis for medical reasons. Yet a significant number of consumers continue to treat their medical conditions via illicitly-sourced cannabis. Little is known about how these two groups of medical cannabis consumers differ. METHODS: The anonymous Cannabis-As-Medicine Survey 2022-2023 (CAMS-22) was available for completion online from December 2022 to April 2023 to adult Australians who had used cannabis to treat a medical condition in the previous year. Recruitment occurred through social media, consumer forums, and medical practices. Questions included demographic characteristics, patterns of cannabis use, conditions treated, and self-rated effectiveness. RESULTS: Of the 3323 respondents included in these analyses, 2352 (73%) mainly used prescribed medical cannabis, 871 (27%) mainly used illicit. Prescribed users were significantly more likely than illicit users to have had their health condition diagnosed (OR = 1.7, 95% CI 1.3, 2.2), to consume their cannabis via oral (OR = 1.9; CI 1.5, 2.4) or vaporised (OR = 5.2; CI 4.0, 6.8) routes, and to be sure of the composition of their medical cannabis (OR = 25.0; CI 16.7, 50.0). Prescribed users were significantly less likely to have used cannabis non-medically before medical use (OR = 0.6, CI 0.5, 0.7), consume cannabis via smoked routes (OR = 0.2, CI 0.1, 0.2), and to report any side effects (OR = 0.1; CI 0.1, 0.2). The most common conditions among both prescribed and illicit users were pain (37%), mental health (36%), and sleep (15%) conditions. Prescribed users were significantly more likely to use cannabis to mainly treat a pain (OR = 1.3; CI 1.1, 1.5) or sleep condition (OR = 1.4; CI 1.1, 1.7) and less likely to treat a mental health condition (OR = 0.8; CI 0.7, 0.9). There were no between-group differences in effectiveness with 97% saying medical cannabis had improved their symptoms. CONCLUSIONS: From a harm-reduction perspective there is much to recommend prescribed medical cannabis; it has fewer side-effects than illicit, is used more safely (oral or vaporised versus smoked routes), gives consumers greater certainty regarding the composition and quality of their medicine, and does not risk exposure to the criminal justice system. Of concern, however, is the apparent willingness of prescribers to prescribe for indications for which there is limited evidence of efficacy, such as mental health and sleep conditions.

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Road safety is an important concern amidst expanding worldwide access to legal cannabis. The present study reports on the driving-related subsection of the Cannabis as Medicine Survey 2020 (CAMS-20) which surveyed driving-related behaviors, attitudes, and perceptions among Australian medical cannabis (MC) users. Of the 1063 respondents who reported driving a motor vehicle in the past 12 months, 28% (297/1063) reported driving under the influence of cannabis (DUIC). Overall, 49-56% of respondents said they typically drive within 6 h of MC use, depending on the route of administration (oral or inhaled). Non-medical cannabis (NMC) was perceived to be more impairing for driving than MC. Binary logistic regression revealed associations between likelihood of DUIC and (1) inhaled routes of cannabis administration, (2) THC-dominant products, (3) illicit rather than prescribed use, (4) believing NMC does not impair driving, and (5) not being deterred by roadside drug testing. Overall, these findings suggest there is a relatively low perception of driving-related risk among MC users. Targeted education programs may be needed to highlight the potential risks associated with DUIC, and further research is needed to determine whether driving performance is differentially affected by MC and NMC.

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Background: Anxiety is a condition for which current treatments are often limited by adverse events (AEs). Components of medicinal cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC), have been proposed as potential treatments for anxiety disorders, specifically posttraumatic stress disorder (PTSD). Objective: To evaluate quality-of-life outcomes after treatment with various cannabis formulations to determine the effectiveness and associated AEs. Methods: An interim analysis of data collected between September 2018 and June 2021 from the CA Clinics Observational Study. Patient-Reported Outcomes Measurement Information System-29 survey scores of 198 participants with an anxiety disorder were compared at baseline and after treatment with medicinal cannabis. The data of 568 anxiety participants were also analyzed to examine the AEs they experienced by the Medical Dictionary for Regulatory Activities organ system class. Results: The median doses taken were 50.0 mg/day for CBD and 4.4 mg/day for THC. The total participant sample reported significantly improved anxiety, depression, fatigue, and ability to take part in social roles and activities. Those who were diagnosed with PTSD (n = 57) reported significantly improved anxiety, depression, fatigue, and social abilities. The most common AEs reported across the whole participant cohort were dry mouth (32.6%), somnolence (31.3%), and fatigue (18.5%), but incidence varied with different cannabis formulations. The inclusion of THC in a formulation was significantly associated with experiencing gastrointestinal AEs; specifically dry mouth and nausea. Conclusions: Formulations of cannabis significantly improved anxiety, depression, fatigue, and the ability to participate in social activities in participants with anxiety disorders. The AEs experienced by participants are consistent with those in other studies.

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Introduction: Sleep disorders are the third most common indication for the prescription of medical cannabis products in Australia, after pain and anxiety. While the use of cannabis for medical purposes is growing in Australia, underlying consumer behaviours and patterns of use, particularly around sleep disorders, are poorly understood. Methods: We conducted a subanalysis of the cross-sectional "Cannabis as Medicine Survey" 2020-2021 (CAMS-20) (N = 1600), to explore the characteristics of a sample of Australians who were using prescribed and/or illicit medical cannabis to treat a self-reported sleep disorder. Results: When asked to specify up to seven different conditions they were treating with medical cannabis, a total of 1030 (64%) respondents [mean (SD) 44.9 (13.6) years] selected a sleep disorder, with "insomnia disorder" (85.5%), 'sleep-related movement disorders' (26%) and 'sleep-related breathing disorders' (11.1%) the most common subtypes. Only 165 (16.8%) respondents selected a self-reported sleep disorder as the main health condition being treated. Relative to other health conditions, use of medical cannabis for a self-reported sleep disorder was associated with younger age, increased likelihood of using both prescribed and illicit forms of medical cannabis, inhaled routes of administration, and THC-dominant products. Most respondents reported a reduction in the use of benzodiazepines and alcohol since starting medical cannabis. Binary logistic regression showed that respondents who predominantly used inhaled routes of administration, and concomitant use of medical cannabis for pain, mental health and/or substance use disorder, or a gastrointestinal disorder, were significantly more likely to also use medical cannabis to treat a self-reported sleep disorder. Conclusion: Overall, these results suggest that self-reported sleep disorders are often being treated with medical cannabis alongside other health conditions (often pain or a mental health disorder) and that use of inhaled methods, THC-dominant products, and illicit sources of medical cannabis are common among people with self-reported sleep disorders in Australia.

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BACKGROUND: Australia has had a framework for legal medicinal cannabis since 2016, yet prior online surveys in 2016 and 2018 indicated that most consumers continued to use illicit medical cannabis products. Regulatory data indicate an increase in the prescription of medicinal cannabis since 2019, and this survey examines consumer experiences of prescribed and illicit medical cannabis (MC) use in Australia. METHODS: A cross-sectional anonymous online survey was administered September 2020 to January 2021. Recruitment via social media, professional and consumer forums, and medical practices. Participant eligibility: ≥ 18 years; used a cannabis product for self-identified medical reason(s) in the past year, and resident in Australia. Outcome measures included consumer characteristics, conditions treated, source and patterns of MC use, and perspectives on accessing MC. RESULTS: Of the 1600 participants (mean age 46.4 ± 14.3 years, 53% male), 62.4% (n = 999) reported using only illicit and 37.6% (n = 601) used prescribed MC in the past year. MC was used on a median of 28 (IQR: 12, 28) of the past 28 days and cost $AUD 74 ± 72 weekly (median = $40, IQR: $7, $100). Prescribed participants were more likely to treat pain conditions than those using illicit MC (52% v 40%, OR = 1.7, 1.3-2.1) and less likely to treat sleep conditions (6% v 11%, OR = 0.5, 0.3-0.8), with mental health conditions also a common indication in both groups (26%, 31%). Prescribed MC was consumed predominately by oral routes (72%), whereas illicit MC was most commonly smoked (41%). Prescribed MC was 'mainly THC' (26%), 'equal THC/CBD' (40%), 'mainly CBD' (31%) and 'uncertain' (3%), while 34% of those using illicit MC were 'uncertain' of the cannabinoid profile. Cost and difficulties finding medical practitioners to prescribe remain significant barriers to accessing prescribed MC, and few (10.8%) described the existing model for accessing prescribed MC as 'straightforward or easy'. CONCLUSIONS: There has been a notable shift from illicit to prescribed MC by many consumers compared to prior surveys. Consumers using prescribed MC reported a range of advantages compared to illicit MC, including safer routes of administration, and greater certainty regarding access and composition of products.

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Background: Medicinal cannabis (MC) is an increasingly utilized treatment option for various refractory diseases. While robust clinical evidence supporting MC efficacy in inflammatory bowel disease (IBD) is lacking, many IBD patients report using MC to obtain symptomatic relief. Understanding this use and associated outcomes may help inform future clinical trials. Methods: A cross-sectional anonymous online survey was conducted involving Australians with IBD. It examined attitudes and experiences with MC in relation to IBD management. The survey included validated sub-questionnaires assessing quality of life, medication adherence, IBD severity, and functional impairment. Results: A total of 838 responses were obtained. Results showed 25.3% (n = 212) of respondents were current or previous users of MC (18.1% current, 7.2% previous). Half of the current users also consumed cannabis recreationally although less frequently than for medicinal purposes. Cannabis consumption was via smoking (joints 34.2%; water pipe/bongs 14.5%) or as an oral liquid (19.7%) with products obtained from recreational dealers (44.6%), friends/family (26.1%), or self-grown (9.8%). Only 3 respondents reported using legally accessed products. Clinical ratings of IBD severity did not differ according to cannabis use although users reported more hospitalizations, less engagement with specialist services, and lower medication adherence. IBD symptoms reported as positively affected by cannabis included abdominal pain, stress, sleep, cramping, and anxiety. Most users (92.7%) endorsed cannabis as effective in symptom management. Cannabis-using ulcerative colitis patients reported better quality of life than nonusers on some measures. Conclusion: Many patients in Australia are using illicit MC to manage their IBD. Further clinical trials are required to validate, or refute, patient claims around MC efficacy for symptom control in IBD.

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Background: Medicinal cannabis (MC) is being used for symptomatic relief by many patients with inflammatory bowel disease (IBD), often independently of clinical guidance. Such use presents challenges for supporting clinicians. The aim of this study was to determine the current attitudes, knowledge, and experience of gastroenterologists toward patient use of MC for symptom management in IBD. Methods: Australian gastroenterologists (n = 70) and trainees (n = 23) completed an anonymous, 30-item questionnaire, probing their knowledge, attitudes, and experience with MC in managing IBD. Survey data were collected between April and August 2019. Results: Thirty-nine percent of survey respondents reported having patients using MC; however, only a minority supported use of MC in IBD (21%) or expressed a desire to prescribe (28%). Only 6% claimed good understanding of current patient access pathways and only 31% felt comfortable discussing MC with their patients. Some respondents (20%) cited adverse side effects as a reason for not wanting to prescribe, with driving impairment (64%) and impacts on the developing brain (56%) cited as significant concerns. Nonetheless, MC was ranked as less hazardous than corticosteroids, immunomodulators, and biologics by most respondents, and many (53%) were encouraging of patient participation in future clinical trials. Conclusions: Specialist support for the use of MC in IBD patients is relatively low, potentially reflecting the lack of experience and knowledge with MC, uncertain evidence for efficacy, and the often-unorthodox nature of current MC use in patients. This situation may change rapidly with increased familiarity, evidence development, and education around MC prescribing.

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OBJECTIVE: Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. METHODS: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a+/- mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a+/- mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together. RESULTS: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation. SIGNIFICANCE: Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.

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P-glycoprotein (P-gp) is an ABC transporter expressed at the blood brain barrier and regulates the brain uptake of various xenobiotics and endogenous mediators including glucocorticoid hormones which are critically important to the stress response. Moreover, P-gp is expressed on microglia, the brain's immune cells, which are activated by stressors and have an emerging role in psychiatric disorders. We therefore hypothesised that germline P-gp deletion in mice might alter the behavioral and microglial response to stressors. Female P-gp knockout mice displayed an unusual, frantic anxiety response to intraperitoneal injection stress in the light-dark test. They also tended to display reduced conditioned fear responses compared to wild-type (WT) mice in a paradigm where a single electric foot-shock stressor was paired to a context. Foot-shock stress reduced social interaction and decreased microglia cell density in the amygdala which was not varied by P-gp genotype. Independently of stressor exposure, female P-gp deficient mice displayed increased depression-like behavior, idiosyncratic darting behavior, age-related social withdrawal and hyperactivity, facilitated sensorimotor gating and altered startle reactivity. In addition, P-gp deletion increased microglia cell density in the CA3 region of the hippocampus, and the microglial cells exhibited a reactive, hypo-ramified morphology. Further, female P-gp KO mice displayed increased glucocorticoid receptor (GR) expression in the hippocampus. In conclusion, this research shows that germline P-gp deletion affected various behaviors of relevance to psychiatric conditions, and that altered microglial cell activity and enhanced GR expression in the hippocampus may play a role in mediating these behaviors.

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