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Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N-alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N-alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common. Adamantane-derived SCRAs have consistently appeared throughout the market since 2011, and as such, a systematic set of these derivatives was synthesized and pharmacologically evaluated. Deuterated and fluorinated adamantane derivatives were prepared to evaluate typical hydrogen bioisosteres, as well as evaluation of the newly detected AFUBIATA.
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Agonistas de Receptores de Canabinoides , Halogenação , Indazóis , Indóis , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/síntese química , Relação Estrutura-Atividade , Animais , Indazóis/farmacologia , Indazóis/química , Indazóis/síntese química , Humanos , Indóis/farmacologia , Indóis/química , Adamantano/análogos & derivados , Adamantano/farmacologia , Adamantano/química , Deutério , Camundongos , Valina/análogos & derivadosRESUMO
Hand osteoarthritis (OA) is an irreversible degenerative condition causing chronic pain and impaired functionality. Existing treatment options are often inadequate. Cannabidiol (CBD) has demonstrated analgesic and anti-inflammatory effects in preclinical models of arthritis. In this open-label feasibility trial, participants with symptomatically active hand OA applied a novel transdermal CBD gel (4% w/w) three times a day for four weeks to their most painful hand. Changes in daily self-reported pain scores were measured on a 0-10 Numeric Pain Rating Scale (NPRS). Hand functionality was determined via daily grip strength measures using a Bluetooth equipped squeeze ball and self-report questionnaire. Quality of life (QoL) ratings around sleep, anxiety, stiffness and fatigue were also measured. All self-report measures and grip strength data were gathered via smartphone application. Urinalysis was conducted at trial end to determine systemic absorption of CBD. Eighteen participants were consented and 15 completed the trial. Pain ratings were significantly reduced over time from pre-treatment baseline including current pain (- 1.91 ± 0.35, p < 0.0001), average pain (- 1.92 ± 0.35, p < 0.0001) and maximum pain (- 1.97 ± 0.34, p < 0.0001) (data represent mean reduction on a 0-10 NPRS scale ± standard error of the mean (SEM)). A significant increase in grip strength in the treated hand (p < 0.0001) was observed although self-reported functionality did not improve. There were significant (p < 0.005) improvements in three QoL measures: fatigue, stiffness and anxiety. CBD and its metabolites were detected at low concentrations in all urine samples. Measured reductions in pain and increases in grip strength seen during treatment reverted back towards baseline during the washout phase. In summary, pain, grip strength and QoL measures, using smartphone technology, was shown to improve over time following transdermal CBD application suggesting feasibility of this intervention in relieving osteoarthritic hand pain. Proof of efficacy, however, requires further confirmation in a placebo-controlled randomised trial.Trial registration: ANZCTR public trials registry (ACTRN12621001512819, 05/11/2021).
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Administração Cutânea , Canabidiol , Estudos de Viabilidade , Força da Mão , Mãos , Osteoartrite , Qualidade de Vida , Humanos , Canabidiol/administração & dosagem , Osteoartrite/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Mãos/fisiopatologia , Medição da Dor , Resultado do TratamentoRESUMO
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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Maconha Medicinal , Humanos , Maconha Medicinal/uso terapêutico , Austrália/epidemiologia , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Inquéritos e Questionários , IdosoRESUMO
Cannabis and its major constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being widely used to treat sleep disturbances. However, THC can cause acute cognitive and psychomotor impairment and there are concerns that driving and workplace safety might be compromised the day after evening use. Here, we examined possible 'next day' impairment following evening administration of a typical medicinal cannabis oil in adults with insomnia disorder, compared to matched placebo. This paper describes the secondary outcomes of a larger study investigating the effects of THC/CBD on insomnia disorder. Twenty adults [16 female; mean (SD) age, 46.1 (8.6) y] with physician-diagnosed insomnia who infrequently use cannabis completed two 24 h in-laboratory visits involving acute oral administration of combined 10 mg THC and 200 mg CBD ('THC/CBD') or placebo in a randomised, double-blind, crossover trial design. Outcome measures included 'next day' (≥9 h post-treatment) performance on cognitive and psychomotor function tasks, simulated driving performance, subjective drug effects, and mood. We found no differences in 'next day' performance on 27 out of 28 tests of cognitive and psychomotor function and simulated driving performance relative to placebo. THC/CBD produced a small decrease (-1.4%, p=.016, d=-0.6) in accuracy on the Stroop-Colour Task (easy/congruent) but not the Stroop-Word Task (hard/incongruent). THC/CBD also produced a small increase (+8.6, p=.042, d=0.3) in self-ratings of Sedated at 10 h post-treatment, but with no accompanying changes in subjective ratings of Alert or Sleepy (p's>0.05). In conclusion, we found a lack of notable 'next day' impairment to cognitive and psychomotor function and simulated driving performance following evening use of 10 mg oral THC, in combination with 200 mg CBD, in an insomnia population who infrequently use cannabis.
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Canabidiol , Estudos Cross-Over , Dronabinol , Maconha Medicinal , Desempenho Psicomotor , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Feminino , Masculino , Método Duplo-Cego , Dronabinol/administração & dosagem , Dronabinol/efeitos adversos , Dronabinol/farmacologia , Projetos Piloto , Adulto , Pessoa de Meia-Idade , Canabidiol/administração & dosagem , Canabidiol/efeitos adversos , Canabidiol/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Maconha Medicinal/administração & dosagem , Maconha Medicinal/efeitos adversos , Maconha Medicinal/uso terapêutico , Maconha Medicinal/farmacologia , Administração Oral , Cognição/efeitos dos fármacos , Condução de Veículo , Afeto/efeitos dos fármacosRESUMO
BACKGROUND: Exercise is known to improve health. However, it can be unpleasant, often inducing negative feelings, or 'affect'. Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has been reported to enhance the subjective experience of exercise; specifically, in trained individuals performing fixed-intensity endurance activity. Here, we investigated the effects of CBD on subjective responses to exercise under more ecologically valid conditions; namely, in recreationally active individuals performing self-paced endurance activity. METHODS: A randomised, double-blind, placebo-controlled, crossover trial was conducted at Griffith University between July 17 and August 28, 2023. Griffith University students studying sports nutrition were invited to take part, with eligible volunteers ≥ 18 years of age and able to perform endurance exercise. Participants ingested placebo or 150 mg CBD in two soft-gel capsules 90 min before completing a self-paced 25-lap (10 km) run around an outdoor athletics track (400 m, synthetic). The primary outcomes were affective valence during exercise, assessed on completion of laps 6, 12, 18 and 24 using the 'Feelings Scale', and positive and negative affect, assessed at baseline, pre-run and post-run using the 'Positive and Negative Affect Schedule'. Exercise enjoyment, motivation and self-efficacy, the core features of the 'runner's high' (i.e., euphoria, pain, anxiety, sedation), perceived exertion and run time were also assessed. RESULTS: Fifty-two participants were randomised and 51 were included in the final sample (n = 22 female; 22 [21-25] years). Exercise induced negative affect (i.e., at the time of undertaking) and increased pain. CBD did not counteract either response. In fact, CBD had no significant effects on any of the outcomes measured. In contrast, exercise, once completed, increased positive affect, and decreased negative affect and anxiety. CONCLUSIONS: CBD (150 mg, oral) does not appear to enhance the subjective experience of self-paced endurance exercise in recreationally active individuals. Nor, however, does it appear to compromise it. These findings suggest that CBD use is safe under exercise conditions and unlikely to impede physical activity participation. Our study also reaffirms the powerful mood-enhancing effects of exercise. TRIAL REGISTRATION: Registered with the Australian New Zealand Clinical Trials Registry ( www.anzctr.org.au ) on May 31, 2023 (Trial ID: ACTRN12623000593639).
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INTRODUCTION: The non-intoxicating plant-derived cannabinoid, cannabidiol (CBD), has demonstrated therapeutic potential in a number of clinical conditions. Most successful clinical trials have used relatively high (≥300 mg) oral doses of CBD. Relatively few studies have investigated the efficacy of lower (<300 mg) oral doses, typical of those available in over-the-counter CBD products. METHODS: We present a protocol for a randomised, double-blind, placebo-controlled, parallel-group clinical trial investigating the effects of a low oral dose (150 mg) of CBD on acute psychosocial stress, situational anxiety, motion sickness and cybersickness in healthy individuals. Participants (n=74) will receive 150 mg of CBD or a matched placebo 90 min before completing three virtual reality (VR) challenges (tasks) designed to induce transient stress and motion sickness: (a) a 15 min 'Public Speaking' task; (b) a 5 min 'Walk the Plank' task (above a sheer drop); and (c) a 5 min 'Rollercoaster Ride' task. The primary outcomes will be self-reported stress and nausea measured on 100 mm Visual Analogue Scales. Secondary outcomes will include salivary cortisol concentrations, skin conductance, heart rate and vomiting episodes (if any). Statistical analyses will test the hypothesis that CBD reduces nausea and attenuates subjective, endocrine and physiological responses to stress compared with placebo. This study will indicate whether low-dose oral CBD has positive effects in reducing acute psychosocial stress, situational anxiety, motion sickness and cybersickness. ETHICS AND DISSEMINATION: The University of Sydney Human Research Ethics Committee has granted approval (2023/307, version 1.6, 16 February 2024). Study findings will be disseminated in a peer-reviewed journal and at academic conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12623000872639).
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Canabidiol , Enjoo devido ao Movimento , Humanos , Canabidiol/uso terapêutico , Austrália , Ansiedade/tratamento farmacológico , Náusea/tratamento farmacológico , Método Duplo-Cego , Enjoo devido ao Movimento/tratamento farmacológico , Estresse Psicológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Anorexia nervosa (AN) is an eating disorder (ED) with high mortality rates and limited response to existing treatments, prompting the need to identify effective agents and adjuncts. There is evidence for an emerging role for the neuropeptide oxytocin (OT) in the pathophysiology of AN, with studies showing a perturbed oxytocinergic system in patients with AN. Preliminary evidence has demonstrated that intranasal OT (IN-OT) can produce anxiolytic effects in AN, as well as reducing concern about eating, and dysfunctional attentional biases related to the disorder. IN-OT is a non-invasive treatment option for AN that requires investigation as an adjunct to nutritional rehabilitation. METHODS: This multi-site study (Trial Registration:ACTRN1261000897460) sought to replicate and extend a previous randomised placebo-controlled pilot trial of repeated dose IN-OT in patients with AN hospitalised for nutritional rehabilitation. Patients with AN (N=61) received daily IN-OT (18 IU twice per day) or placebo for four weeks, whilst undergoing inpatient hospital treatment. Outcome measures included ED psychopathology (primary) as measured by the Eating Disorder Examination (EDE) and Body Mass Index (BMI; secondary). Participants were assessed pre- and post-treatment, and at six months following the intervention. The effects of the first and last doses of IN-OT on responses (anxiety ratings and salivary cortisol) to a high-energy snack were also examined. RESULTS: Sixty-one female inpatients (Mage=24.36,SD=7.87) with an average BMI of 16.24 (range: 11.43-18.55), were recruited into the study. No significant differences were found between placebo and OT groups at any of the time points on the outcomes of interest, but significant improvements in almost all psychological parameters in both groups were evident over time. IN-OT did not significantly reduce anxiety nor salivary cortisol in response to a high-calorie snack. CONCLUSION: This is the largest randomised placebo-controlled trial of repeated dose intranasal OT in people with AN, during refeeding. The therapeutically promising findings of the pilot study were not replicated. Limitations and reasons for the non-replication included relatively large variance, baseline psychopathology scores being higher in this patient group, potential ceiling effects in BMI and ED psychopathology as well as differing comorbidities.
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Anorexia Nervosa , Transtornos da Alimentação e da Ingestão de Alimentos , Feminino , Humanos , Administração Intranasal , Anorexia Nervosa/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Hidrocortisona , Ocitocina , Projetos PilotoRESUMO
Point-of-collection testing (POCT) devices are widely used in roadside and workplace drug testing to identify recent cannabis use by measuring the presence of Δ9 -tetrahydrocannabinol (THC) in oral fluid (OF). However, the performance of POCT devices with oral medicinal cannabis products remains poorly described. In a randomised, double-blinded, crossover trial, adults with insomnia disorder (n = 20) received a single (2 mL) oral dose of oil containing 10 mg THC + 200 mg cannabidiol, or placebo, prior to sleep. Participants were tested with the Securetec DrugWipe® 5S (10 ng/mL THC cut-off) and Dräger DrugTest® 5000 (25 ng/mL THC cut-off) POCT devices at baseline (pre-treatment) and then at 0.5, 10, and 18 h post-treatment. An OF sample, taken at each time point, was also analysed using liquid chromatography-tandem mass spectrometry. Large individual variability in OF THC concentrations was observed 0.5 h post-treatment (range: 0-425 ng/mL; mean (SD) 48.7 (107.5) ng/mL). Both the Securetec DrugWipe® 5S and DrugTest® 5000 demonstrated poor sensitivity to THC at 0.5 h post-treatment (25% and 50%, respectively). At 10 and 18 h post-treatment, all participant OF THC concentrations were below screening cut-offs, and all test results were negative. These findings highlight the relatively poor sensitivity of both devices in detecting recent use of an oral medicinal cannabis product. They also suggest a low probability of obtaining a positive THC result the morning after ('one-off') use. Further research is required to establish the probability of obtaining a positive THC result with regular medicinal cannabis use.
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INTRODUCTION: Prescribed medicinal cannabis (MC) is an increasingly common prescription in Australia for treating pain, anxiety, and sleep disorders. Prescribed MC products generally contain tetrahydrocannabinol (THC) and/or cannabidiol (CBD) in a variety of dose levels and forms. It is unclear whether THC and CBD products are used by patients with different characteristics and for different conditions. OBJECTIVES: To examine consumer experiences of using THC- and CBD-containing prescribed MC products to better understand how they are being used within the Australian context. METHODS: We utilised data collected from an online anonymous cross-sectional survey of individuals (CAMS-20 survey), consisting of Australian residents using cannabis for therapeutic reasons. We focused on a subgroup of participants (N = 546) receiving prescribed MC products. We utilised linear, logistic, and multinomial regression modelling to analyse responses to survey questions based on the cannabinoid profile of the prescribed product. RESULTS: Participants prescribed THC-dominant MC products were statistically more likely to be younger, male, and to prefer inhaled routes of administration than participants using CBD-dominant products who were older, female, and preferred oral routes of administration. Pain and mental health were the most common reasons for all types of prescribed MC, but were more likely to be treated with THC than CBD despite the significantly higher risk of mild to severe drowsiness, dry mouth and eye irritation. Consumer reported effectiveness of prescribed MC was very positive, particularly for THC-containing products. Consumers on opioids and antipsychotics were statistically more likely to be prescribed THC-containing products than products containing CBD only, despite the greater risk of impairment. CONCLUSIONS: This Australia-wide study found clear differences in consumer-reported experiences of prescribed THC- and CBD-containing products. Current prescriptions of these products do not always align with relevant clinical guidance. Educating prescribers around cannabinoid products is essential to ensure optimal prescribing practices and to prevent avoidable drug side effects and interactions.
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Canabidiol , Canabinoides , Cannabis , Alucinógenos , Maconha Medicinal , Humanos , Masculino , Feminino , Canabinoides/efeitos adversos , Canabinoides/análise , Maconha Medicinal/efeitos adversos , Estudos Transversais , Austrália , Dor/induzido quimicamente , Agonistas de Receptores de Canabinoides , Dronabinol/efeitos adversosRESUMO
The aim of this study was to systematically review prior research investigating the effects of contact/collision sport participation on neurometabolite levels in the absence of concussion. Four online databases were searched to identify studies that measured neurometabolite levels in contact/collision sport athletes (without concussion) using proton (1 H) or phosphorus (31 P) magnetic resonance spectroscopy (MRS). All study designs were acceptable for inclusion. Meta-analytic procedures were used to quantify the effect of contact/collision sport participation on neurometabolite levels and explore the impact of specific moderating factors (where sufficient data were available). Narrative synthesis was used to describe outcomes that could not be meta-analysed. Nine observational studies involving 300 contact/collision sport athletes were identified. Six studies (providing 112 effect estimates) employed longitudinal (cohort) designs and three (that could not be meta-analysed) employed case-control designs. N-acetylaspartate (NAA; g = -0.331, p = 0.013) and total creatine (tCr; creatine + phosphocreatine; g = -0.524, p = 0.029), but not glutamate-glutamine (Glx), myo-inositol (mI) or total choline (tCho; choline-containing compounds; p's > 0.05), decreased between the pre-season and mid-/post-season period. Several moderators were statistically significant, including: sex (Glx: 6 female/23 male, g = -0.549, p = 0.013), sport played (Glx: 22 American football/4 association football [soccer], g = 0.724, p = 0.031), brain region (mI: 2 corpus callosum/9 motor cortex, g = -0.804, p = 0.015), and the MRS quantification approach (mI: 18 absolute/3 tCr-referenced, g = 0.619, p = 0.003; and tCho: 18 absolute/3 tCr-referenced, g = 0.554, p = 0.005). In case-control studies, contact/collision sport athletes had higher levels of mI, but not NAA or tCr compared to non-contact sport athletes and non-athlete controls. Overall, this review suggests that contact/collision sport participation has the potential to alter neurometabolites measured via 1 H MRS in the absence of concussion. However, further research employing more rigorous and consistent methodologies (e.g. interventional studies with consistent 1 H MRS pulse sequences and quantifications) is required to confirm and better understand the clinical relevance of observed effects.
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Concussão Encefálica , Creatina , Humanos , Masculino , Feminino , Concussão Encefálica/diagnóstico por imagem , Espectroscopia de Ressonância Magnética/métodos , Colina , Receptores de Antígenos de Linfócitos T , Ácido Aspártico , InositolRESUMO
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: The current review broadly summarises the evidence base for pharmacotherapies and adjunctive and alternative therapies in the treatment of eating disorders and disordered eating. METHODS: This paper forms part of a Rapid Review series examining the evidence base in the field of eating disorders. This was conducted to inform the Australian National Eating Disorder Research and Translation Strategy 2021-2030. ScienceDirect, PubMed and Ovid/Medline were searched for included studies published between 2009 and 2021 in English. High-level evidence such as meta-analyses, large population studies and randomised control trials were prioritised, and grey literature excluded. Data from included studies relating to pharmacotherapy, and to adjunctive and alternative therapies in eating disorders, were synthesised and disseminated in the current review. RESULTS: A total of 121 studies were identified, relating to pharmacotherapy (n = 90), adjunctive therapies (n = 21) and alternative therapies (n = 22). Some of the identified studies involved combinations of the above (e.g. adjunctive pharmacotherapy). Evidence of efficacy of interventions across all three categories was very limited with few relevant high quality clinical trials. There was a particular scarcity of evidence around effective treatments for anorexia nervosa (AN). With treatment of bulimia nervosa (BN), fluoxetine has exhibited some efficacy leading to regulatory approval in some countries. With binge eating disorder (BED), recent evidence supports the use of lisdexamfetamine. Neurostimulation interventions show some emerging efficacy in the treatment of AN, BN and BED but some, such as deep brain stimulation can be highly invasive. CONCLUSION: Despite widespread use of medications, this Rapid Review has identified a lack of effective medications and adjunctive and alternative therapies in the treatment of EDs. An intensification of high-quality clinical trial activity and drug discovery innovation are required to better assist patients suffering from EDs.
Eating disorders have the highest mortality rates and treatment costs of all mental health conditions. This rapid review summarises the evidence around the use of medications and various alternative therapies in the treatment of eating disorders. The review highlights a lack of effective interventions for the treatment of anorexia nervosa with an urgent need to trial new treatments for this condition. Two medications show some efficacy in treating other eating disorders: the antidepressant drug fluoxetine for the treatment of bulimia nervosa, and the stimulant drug lisdexamfetamine for binge eating disorder. There is some positive evidence emerging from novel therapies that involve brain stimulation technologies. Overall, more high-quality research is needed to discover and develop new medications, and other alternative therapies, to better assist patients with eating disorders.
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Objective: Evidence is accumulating that components of the Cannabis sativa plant may have therapeutic potential in treating psychiatric disorders. Medicinal cannabis (MC) products are legally available for prescription in Australia, primarily through the Therapeutic Goods Administration (TGA) Special Access Scheme B (SAS-B). Here we investigated recent prescribing practices for psychiatric indications under SAS-B by Australian doctors. Methods: The dataset, obtained from the TGA, included information on MC applications made by doctors through the SAS-B process between 1st November 2016 and 30th September 2022 inclusive. Details included the primary conditions treated, patient demographics, prescriber location, product type (e.g., oil, flower or capsule) and the general cannabinoid content of products. The conditions treated were categorized according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR). Trends in prescribing for conditions over time were analyzed via polynomial regression, and relationships between categorical variables determined via correspondence analyses. Results: Approximately 300,000 SAS-B approvals to prescribe MC had been issued in the time period under investigation. This included approvals for 38 different DSM-5-TR defined psychiatric conditions (33.9% of total approvals). The majority of approvals were for anxiety disorders (66.7% of psychiatry-related prescribing), sleep-wake disorders (18.2%), trauma- and stressor-related disorders (5.8%), and neurodevelopmental disorders (4.4%). Oil products were most prescribed (53.0%), followed by flower (31.2%) and other inhaled products (12.4%). CBD-dominant products comprised around 20% of total prescribing and were particularly prevalent in the treatment of autism spectrum disorder. The largest proportion of approvals was for patients aged 25-39 years (46.2% of approvals). Recent dramatic increases in prescribing for attention deficit hyperactivity disorder were identified. Conclusion: A significant proportion of MC prescribing in Australia is for psychiatry-related indications. This prescribing often appears somewhat "experimental", given it involves conditions (e.g., ADHD, depression) for which definitive clinical evidence of MC efficacy is lacking. The high prevalence of THC-containing products being prescribed is of possible concern given the psychiatric problems associated with this drug. Evidence-based clinical guidance around the use of MC products in psychiatry is lacking and would clearly be of benefit to prescribers.
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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: T-type Ca2+ channels (Cav3) represent emerging therapeutic targets for a range of neurological disorders, including epilepsy and pain. To aid the development and optimisation of new therapeutics, there is a need to identify novel chemical entities which act at these ion channels. A number of synthetic cannabinoid receptor agonists (SCRAs) have been found to exhibit activity at T-type channels, suggesting that cannabinoids may provide convenient chemical scaffolds on which to design novel Cav3 inhibitors. However, activity at cannabinoid type 1 (CB1) receptors can be problematic because of central and peripheral toxicities associated with potent SCRAs. The putative SCRA MEPIRAPIM and its analogues were recently identified as Cav3 inhibitors with only minimal activity at CB1 receptors, opening the possibility that this scaffold may be exploited to develop novel, selective Cav3 inhibitors. Here we present the pharmacological characterisation of SB2193 and SB2193F, two novel Cav3 inhibitors derived from MEPIRAPIM. Methods: The potency of SB2193 and SB2193F was evaluated in vitro using a fluorometric Ca2+ flux assay and confirmed using whole-cell patch-clamp electrophysiology. In silico docking to the cryo-EM structure of Cav3.1 was also performed to elucidate structural insights into T-type channel inhibition. Next, in vivo pharmacokinetic parameters in mouse brain and plasma were determined using liquid chromatography-mass spectroscopy. Finally, anticonvulsant activity was assayed in established genetic and electrically-induced rodent seizure models. Results: Both MEPIRAPIM derivatives produced potent inhibition of Cav3 channels and were brain penetrant, with SB2193 exhibiting a brain/plasma ratio of 2.7. SB2193 was further examined in mouse seizure models where it acutely protected against 6 Hz-induced seizures. However, SB2193 did not reduce spontaneous seizures in the Scn1a +/- mouse model of Dravet syndrome, nor absence seizures in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Surprisingly, SB2193 appeared to increase the incidence and duration of spike-and-wave discharges in GAERS animals over a 4 h recording period. Conclusion: These results show that MEPIRAPIM analogues provide novel chemical scaffolds to advance Cav3 inhibitors against certain seizure types.
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Introduction: Cannabis contains cannabidiol (CBD), the main non-psychoactive phytocannabinoid, but also many other phytocannabinoids that have therapeutic potential in the treatment of epilepsy. Indeed, the phytocannabinoids cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA) and cannabichromene (CBC) have recently been shown to have anti-convulsant effects in a mouse model of Dravet syndrome (DS), an intractable form of epilepsy. Recent studies demonstrate that CBD inhibits voltage-gated sodium channel function, however, whether these other anti-convulsant phytocannabinoids affect these classic epilepsy drug-targets is unknown. Voltage-gated sodium (NaV) channels play a pivotal role in initiation and propagation of the neuronal action potential and NaV1.1, NaV1.2, NaV1.6 and NaV1.7 are associated with the intractable epilepsies and pain conditions. Methods: In this study, using automated-planar patch-clamp technology, we assessed the profile of the phytocannabinoids CBGA, CBDVA, cannabigerol (CBG), CBCA and CBC against these human voltage-gated sodium channels subtypes expressed in mammalian cells and compared the effects to CBD. Results: CBD and CBGA inhibited peak current amplitude in the low micromolar range in a concentration-dependent manner, while CBG, CBCA and CBC revealed only modest inhibition for this subset of sodium channels. CBDVA inhibited NaV1.6 peak currents in the low micromolar range in a concentration-dependent fashion, while only exhibiting modest inhibitory effects on NaV1.1, NaV1.2, and NaV1.7 channels. CBD and CBGA non-selectively inhibited all channel subtypes examined, whereas CBDVA was selective for NaV1.6. In addition, to better understand the mechanism of this inhibition, we examined the biophysical properties of these channels in the presence of each cannabinoid. CBD reduced NaV1.1 and NaV1.7 channel availability by modulating the voltage-dependence of steady-state fast inactivation (SSFI, V0.5 inact), and for NaV1.7 channel conductance was reduced. CBGA also reduced NaV1.1 and NaV1.7 channel availability by shifting the voltage-dependence of activation (V0.5 act) to a more depolarized potential, and for NaV1.7 SSFI was shifted to a more hyperpolarized potential. CBDVA reduced channel availability by modifying conductance, SSFI and recovery from SSFI for all four channels, except for NaV1.2, where V0.5 inact was unaffected. Discussion: Collectively, these data advance our understanding of the molecular actions of lesser studied phytocannabinoids on voltage-gated sodium channel proteins.
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Global interest in the non-intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a diversity of health conditions. At present, there is sufficient clinical trial evidence to support the use of high oral doses of CBD (e.g., 10-50 mg/kg) in treating intractable childhood epilepsies. However, a question remains as to whether "low-dose" CBD products confer any therapeutic benefits. This is an important question to answer, as low-dose CBD products are widely available in many countries, often as nutraceutical formulations. The present review therefore evaluated the efficacy and safety of low oral doses of CBD. The review includes interventional studies that measured the clinical efficacy in any health condition and/or safety and tolerability of oral CBD dosed at less than or equal to 400 mg per day in adult populations (i.e., ≥18 years of age). Studies were excluded if the product administered had a Δ9 -tetrahydrocannabinol content greater than 2.0%. Therapeutic benefits of CBD became more clearly evident at doses greater than or equal to 300 mg. Increased dosing from 60 to 400 mg/day did not appear to be associated with an increased frequency of adverse effects. At doses of 300-400 mg, there is evidence of efficacy with respect to reduced anxiety, as well as anti-addiction effects in drug-dependent individuals. More marginal and less consistent therapeutic effects on insomnia, neurological disorders, and chronic pain were also apparent. Larger more robust clinical trials are needed to confirm the therapeutic potential of lower (i.e., <300 mg/day) oral doses of CBD.
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Canabidiol , Cannabis , Dor Crônica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Adulto , Criança , Humanos , Canabidiol/efeitos adversos , Dor Crônica/tratamento farmacológico , Dronabinol/uso terapêutico , Ensaios Clínicos como AssuntoRESUMO
A growing number of clinical trials (CTs) are investigating the therapeutic potential of cannabidiol (CBD), a non-intoxicating phytocannabinoid found in Cannabis sativa. These CTs often use crossover experimental designs requiring 'washout' (clearance) periods. However, the length of time CBD persists in plasma (its 'window of detection') is unclear and could be significant. Indeed, the structurally related phytocannabinoid, Δ9 -tetrahydrocannabinol (THC), has a long window of detection in plasma. We investigated the extent to which CBD and its major metabolites persist in plasma. Data from three CTs that measured plasma cannabinoid concentrations ≥7 days after administering a single oral dose of CBD were pooled. The CBD doses were as follows: CT #1: 300 mg; CT #2: 200 mg (and 10 mg THC); and CT #3: 15, 300 and 1500 mg (one per treatment session). Thirty-two participants were included in the analysis, 17 of whom (from CT #3) provided repeated measures. Overall, 0% (15 mg), 60% (200 mg), 28% (300 mg) and 100% (1500 mg) of participants had detectable concentrations (i.e., >0.25 ng·ml-1 ) of CBD in plasma ≥7 days post-treatment (some, several weeks post-treatment). A zero-inflated negative binomial mixed-effects regression analysis (R2 m = 0.44; R2 c = 0.73) predicted that, on average, a 13 day washout period would reduce plasma CBD concentrations to 'zero' (i.e., <0.25 ng·ml-1 ) if a single oral dose of 300 mg was consumed. Higher doses require longer washout periods; concomitant medications may also affect clearance. In conclusion, CBD has a long window of detection in plasma. Crossover studies involving CBD should, therefore, be conducted with caution, particularly when higher doses and/or chronic dosing regimens are used.
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Canabidiol , Canabinoides , Cannabis , Humanos , Canabidiol/análise , Dronabinol/análise , Canabinoides/análise , Método Duplo-CegoRESUMO
Background: Δ9-Tetrahydrocannabinol (THC), the main intoxicating component of cannabis, can cause cognitive and psychomotor impairment. Whether this impairment is still present many hours or even days after THC use requires clarification. Possible "next day" effects are of major significance in safety-sensitive workplaces. We therefore conducted a systematic review of studies investigating the "next day" effects of THC. Methods: Studies that measured performance on safety-sensitive tasks (e.g., driving, flying) and/or neuropsychological tests >8 h after THC (or cannabis) use using interventional designs were identified by searching two online databases from inception until March 28, 2022. Risk of bias (RoB) was evaluated using the relevant Cochrane tools. Results were described in terms of whether THC had a significant effect on performance relative to the primary comparator (i.e., placebo or baseline, as appropriate). Results: Twenty studies (n=458) involving 345 performance tests were reviewed. Most studies administered a single dose of THC (median [interquartile range]: 16 [11-26] mg) and assessed performance between >12 and 24 h post-treatment. N=209/345 tests conducted across 16 published studies showed no "next day" effects of THC. Nine of these 16 studies used randomized, double-blind, placebo-controlled designs. Half (N=8) had "some" RoB, and half (N=8) had a "high" RoB. Notably, N=88 of these 209 tests failed to demonstrate "acute" (i.e., <8 h post-treatment) THC-induced impairment. N=12/345 tests conducted across five published studies indicated negative (i.e., impairing) "next day" effects of THC. None of these five studies used randomized, double-blind, placebo-controlled designs and all were published >18 years ago (four, >30 years ago). Three had "some" RoB, and two had a "high" RoB. A further N=121/345 tests indicated "unclear" "next day" effects of THC with insufficient information provided to assess outcomes. The remaining N=3/345 tests indicated positive (i.e., enhancing) "next day" effects of THC. Conclusions: Some lower quality studies have reported "next day" effects of THC on cognitive function and safety-sensitive tasks. However, most studies, including some of higher quality, have found no such effect. Overall, it appears that there is limited scientific evidence to support the assertion that cannabis use impairs "next day" performance. Further studies involving improved methodologies are required to better address this issue.