A mixed methods analysis of cannabis use routines for chronic pain management

Background The wide heterogeneity of available cannabis products makes it difficult for physicians to appropriately guide patients. In the current study, our objective was to characterize naturalistic cannabis use routines and explore associations between routines and reported benefits from consuming cannabis. Methods We performed a mixed methods analysis of n=1087 cross-sectional survey responses from adults with self-reported chronic pain using cannabis for symptom management in the USA and Canada. First, we qualitatively analyzed responses to an open-ended question that assessed typical cannabis use routines, including administration routes, cannabinoid content, and timing. We then sub-grouped responses into categories based on inhalation (smoking, vaporizing) vs. non-inhalation (e.g., edibles). Finally, we investigated subgroups perceptions of how cannabis affected pain, overall health, and use of medications (e.g., substituting for opioids, benzodiazepines). Substitutions were treated as a count of medication classes, while responses for both pain and health were analyzed continuously, with − 2 indicating health declining a lot or pain increasing a lot and 2 indicating that health improved a lot or pain decreased a lot. Results Routines varied widely in terms of administration routes, cannabinoid content, and use timing. Overall, 18.8%, 36.2%, and 45% used non-inhalation, inhalation, and non-inhalation + inhalation routes, respectively. Those who used inhalation routes were younger (mean age 46.5 [inhalation] and 49.2 [non-inhalation + inhalation] vs. 56.3 [inhalation], F=36.1, p<0.001), while a higher proportion of those who used non-inhalation routes were female (72.5% non-inhalation vs. 48.3% inhalation and 65.3% non-inhalation + inhalation, X2=59.6, p<0.001). THC-rich products were typically used at night, while CBD-rich products were more often used during the day. While all participants reported similarly decreased pain, participants using non-inhalation + inhalation administration routes reported larger improvements in health than the non-inhalation (mean difference = 0.32, 95% CI: 0.07–0.37, p<0.001) and inhalation subgroups (mean difference = 0.22, 95% CI: 0.07–0.37, p=0.001). Similarly, the non-inhalation + inhalation group had significantly more medication substitutions than those using non-inhalation (mean difference = 0.62, 95% CI: 0.33–0.90, p<0.001) and inhalation administration routes (mean difference = 0.45, 95% CI: 0.22–0.69, p<0.001), respectively. Conclusions Subgrouping medical cannabis patients based on administration route profile may provide useful categories for future studies examining the risks and benefits of medical cannabis.

Case report: Medical cannabis—warfarin drug-drug interaction

Aim A case of an 85-year-old patient with concurrent use of warfarin and medical cannabis containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is described. Warfarin continues to be a cornerstone of anticoagulation treatment despite the recent addition of FDA-approved anticoagulant agents. It is well known that warfarin has numerous drug interactions; however, much remains unknown about its interaction with THC and CBD. A literature review was conducted to identify documented cases of possible interactions between cannabis and warfarin. The case reports we identified noted that cannabis may potentially increase warfarin’s effect. Therefore, we aimed to determine why an effect was not seen on our patient’s warfarin dose despite daily use of medical cannabis. Case This case report describes an 85-year-old patient who despite starting an oromucosal medical cannabis regimen of THC and CBD (which provided 0.3 mg of THC and 5.3 mg CBD once daily and an additional 0.625 mg of THC and 0.625 mg CBD once daily as needed) had minimal INR fluctuations from October 2018 to September 2019. Conclusion Despite the introduction and use of medical cannabis therapy, with both THC and CBD components, an elderly patient with concurrent warfarin use did not see major INR fluctuations, in contrast to published literature. The potential for warfarin and THC/CBD interactions may be dependent on route of administration and dose of the cannabis product.

Identifying archetypal cannabis consumers to inform drug policy design: a Q-sort assessment of young adults’ attitudes in Mexico City’s metropolitan area

Background As the legalization of cannabis moves forward in many countries, it is important to highlight the potential harm that excessive use can cause on young consumers. Crafting effective policy interventions to reduce the harm stemming from excessive use requires an understanding of the attitudes and motivations of young consumers. Methods This article uses Q methodology to study four aspects of cannabis use among young adults from Mexico City’s metropolitan area: motivations for use, perceived consequences of use, reasons that would increase willingness to reduce consumption, and attitudes towards government regulation. A total of 110 cannabis users between 18 and 21 years old were recruited using chain-referral sampling. Using a Q methodology, we captured the relative importance that participants assigned to a series of statements and identified archetypal profiles of young adults who use cannabis for each of the four aspects mentioned above. Results The sample for this research study included 76 men and 34 women. The average age of participants was 20 years old, and the average age when cannabis consumption started was 15 years old. For each of the four Q-sort factor analyses, we identified 4 distinct factors based on explained variance and interpretability. The Q factor analysis indicated that attenuation of a negative affect (i.e., anxiety, stress) and relaxation were primary motivations for cannabis use. Understood consequences of cannabis use ranged across aspect-archetype, reflecting legal (i.e., interacting with law enforcement), financial, familial (i.e., disappointing family members), and educational performance concerns. Participants indicated that finding alternative relaxation strategies, receiving credible evidence of the health harms of cannabis use, increased financial burden of purchasing, and increased inaccessibility of cannabis products would motivate reductions in use. Across archetypes, participants indicated a willingness to comply with cannabis policies which are simple and easy to understand, which do not lead to discrimination or law enforcement involvement, and which provide for legal places to purchase and use safe (i.e., free of adulterants) cannabis products. Conclusions We posit that these archetypes could be useful to inform cannabis policy design. As the study reveals, participants’ cannabis use was primarily motivated by perceived improvements to mental health. Furthermore, participant responses indicated that they viewed cannabis use as a health matter, not a criminal one. Policies which aim to promote alternative mental health wellness and relaxation mechanisms, which aim to improve communication of potential health harms of cannabis, and which allow for the safe and legal purchase and use of cannabis may be effective in reducing cannabis-associated harms. Though our findings shed light on important aspects of cannabis users’ attitudes and perspectives, the sample size does not allow for a generalization of the findings and the drawing of conclusions about the population under scrutiny. Further research should consider the application of the Q methodology used in this article to a larger and more representative sample of cannabis users.

UK Medical Cannabis Registry palliative care patients cohort: initial experience and outcomes

Introduction Palliative care aims to improve quality of life through optimal symptom control and pain management. Cannabis-based medicinal products (CBMPs) have a proven role in the treatment of chemotherapy-induced nausea and vomiting. However, there is a paucity of high-quality evidence with regards to the optimal therapeutic regimen, safety, and effectiveness of CBMPs in palliative care, as existing clinical trials are limited by methodological heterogeneity. The aim of this study is to summarise the outcomes of the initial subgroup of patients from the UK Medical Cannabis Registry who were prescribed CBMPs for a primary indication of palliative care, cancer pain and chemotherapy-induced nausea and vomiting, including effects on health-related quality of life and clinical safety. Methods A case series from the UK Medical Cannabis Registry of patients, who were receiving CBMPs for the indication of palliative care was undertaken. The primary outcome consisted of changes in patient-reported outcome measures including EQ-5D-5L, General Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), Pain Visual Analog Scale (VAS) and the Australia-Modified Karnofsky Performance Scale at 1 and 3 months compared to baseline. Secondary outcomes included the incidence and characteristics of adverse events. Statistical significance was defined by p-value< 0.050. Results Sixteen patients were included in the analysis, with a mean age of 63.25 years. Patients were predominantly prescribed CBMPs for cancer-related palliative care (n = 15, 94%). The median initial CBD and THC daily doses were 32.0 mg (Range: 20.0–384.0 mg) and 1.3 mg (Range: 1.0–16.0 mg) respectively. Improvements in patient reported health outcomes were observed according to SQS, EQ-5D-5L mobility, pain and discomfort, and anxiety and depression subdomains, EQ-5D-5L index, EQ-VAS and Pain VAS validated scales at both 1-month and 3-months, however, the changes were not statistically significant. Three adverse events (18.75%) were reported, all of which were either mild or moderate in severity. Conclusion This small study provides an exploratory analysis of the role of CBMPs in palliative care in the first cohort of patients since CBMPs legalisation in the UK. CBMPs were tolerated with few adverse events, all of which were mild or moderate and resolved spontaneously. Further long-term safety and efficacy studies involving larger cohorts are needed to establish CBMPs role in palliative care, including comparisons with standard treatments.

Delta-8-THC: Delta-9-THC’s nicer younger sibling?

Background Products containing delta-8-THC became widely available in most of the USA following the 2018 Farm Bill and by late 2020 were core products of hemp processing companies, especially where delta-9-THC use remained illegal or required medical authorization. Research on experiences with delta-8-THC is scarce, some state governments have prohibited it because of this lack of knowledge. Objective We conducted an exploratory study addressing a broad range of issues regarding delta-8-THC to inform policy discussions and provide directions for future systematic research. Methods We developed an online survey for delta-8-THC consumers, including qualities of delta-8-THC experiences, comparisons with delta-9-THC, and open-ended feedback. The survey included quantitative and qualitative aspects to provide a rich description and content for future hypothesis testing. Invitations to participate were distributed by a manufacturer of delta-8-THC products via social media accounts, email contact list, and the Delta8 Reddit.com discussion board. Participants (N = 521) mostly identified as White/European American (90%) and male (57%). Pairwise t tests compared delta-8-THC effect rating items; one-sample t tests examined responses to delta-9-THC comparison items. Results Most delta-8-THC users experienced a lot or a great deal of relaxation (71%); euphoria (68%) and pain relief (55%); a moderate amount or a lot of cognitive distortions such as difficulty concentrating (81%), difficulties with short-term memory (80%), and alerted sense of time (74%); and did not experience anxiety (74%) or paranoia (83%). Participants generally compared delta-8-THC favorably with both delta-9-THC and pharmaceutical drugs, with most participants reporting substitution for delta-9-THC (57%) and pharmaceutical drugs (59%). Participant concerns regarding delta-8-THC were generally focused on continued legal access. Conclusions Delta-8-THC may provide much of the experiential benefits of delta-9-THC with lesser adverse effects. Future systematic research is needed to confirm participant reports, although these studies are hindered by the legal statuses of both delta-8-THC and delta-9-THC. Cross-sector collaborations among academics, government officials, and representatives from the cannabis industry may accelerate the generation of knowledge regarding delta-8-THC and other cannabinoids. A strength of this study is that it is the first large survey of delta-8 users, limitations include self-report data from a self-selected convenience sample.

Olivetolic acid, a cannabinoid precursor in Cannabis sativa, but not CBGA methyl ester exhibits a modest anticonvulsant effect in a mouse model of Dravet syndrome

Objective Cannabigerolic acid (CBGA), a precursor cannabinoid in Cannabis sativa, has recently been found to have anticonvulsant properties in the Scn1a+/- mouse model of Dravet syndrome. Poor brain penetration and chemical instability of CBGA limits its potential as an anticonvulsant therapy. Here, we examined whether CBGA methyl ester, a more stable analogue of CBGA, might have superior pharmacokinetic and anticonvulsant properties. In addition, we examined whether olivetolic acid, the biosynthetic precursor to CBGA with a truncated (des-geranyl) form, might possess minimum structural requirements for anticonvulsant activity. We also examined whether olivetolic acid and CBGA methyl ester retain activity at the epilepsy-relevant drug targets of CBGA: G-protein-coupled receptor 55 (GPR55) and T-type calcium channels. Methods The brain and plasma pharmacokinetic profiles of CBGA methyl ester and olivetolic acid were examined following 10 mg/kg intraperitoneal (i.p.) administration in mice (n = 4). The anticonvulsant potential of each was examined in male and female Scn1a+/- mice (n = 17–19) against hyperthermia-induced seizures (10–100 mg/kg, i.p.). CBGA methyl ester and olivetolic acid were also screened in vitro against T-type calcium channels and GPR55 using intracellular calcium and ERK phosphorylation assays, respectively. Results CBGA methyl ester exhibited relatively limited brain penetration (13%), although somewhat superior to that of 2% for CBGA. No anticonvulsant effects were observed against thermally induced seizures in Scn1a+/- mice. Olivetolic acid also showed poor brain penetration (1%) but had a modest anticonvulsant effect in Scn1a+/- mice increasing the thermally induced seizure temperature threshold by approximately 0.4°C at a dose of 100 mg/kg. Neither CBGA methyl ester nor olivetolic acid displayed pharmacological activity at GPR55 or T-type calcium channels. Conclusions Olivetolic acid displayed modest anticonvulsant activity against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome despite poor brain penetration. The effect was, however, comparable to the known anticonvulsant cannabinoid cannabidiol in this model. Future studies could explore the anticonvulsant mechanism(s) of action of olivetolic acid and examine whether its anticonvulsant effect extends to other seizure types.

Effects of short-term environmental stresses on the onset of cannabinoid production in young immature flowers of industrial hemp (Cannabis sativa L.)

Backgrounds Cannabis sativa L. produces at least 120 cannabinoids. Although genetic variation is the main factor in cannabinoid production, the effects of short-term environmental stresses in the early flowering stage remains largely unknown. Methods To investigate the effects of short-term environmental stresses on the onset of cannabinoid production in young immature flowers, a hemp variety, Green-Thunder (5–8% CBD/mg of dry weight), was treated with mechanical damage, insect herbivory, extreme heat, or drought stress for 5–7 days during the first 2 weeks of flowering. Three hemp tissues, including flowers, leaves, and stems, were collected from hemp grown under these stress conditions at multiple time points during the first 2 weeks after transition to the short photoperiod and analyzed using high pressure liquid chromatography to quantify phytocannabinoids including cannabigerolic acid (CBGA), cannabigerol (CBG), cannabidiolic acid (CBDA), cannabidiol (CBD), Δ-tetrahydrocannabinolic acid (THCA), Δ-tetrahydrocannabinol (THC), and cannabinol (CBN). Results The 5 days of mechanical wounding did not affect the production of any of the cannabinoids during the initial stage of flowering. However, after 5 days of herbivore treatment, there was a significant difference in concentration between day 1 and day 6 of CBGA (control: 308 μg/g; treatment – 24 μg/g), CBG (control: 69 μg/g; treatment: 52 μg/g), and CBD (control: 755 μg/g; treatment: 194 μg/g) between the control and treatment plants. The 7 days of heat treatment at 45–50 oC significantly reduced the production of CBGA during this observed window (control: 206 μg/g; treatment: 182 μg/g) and CBG (control: 21 μg/g; treatment: − 112 μg/g). Notably, the largest change was observed after 7 days of drought stress, when plants showed a 40% greater accumulation of CBG (control: 336 μg/g; treatment: 622 μg/g), and a significant decrease (70–80%) in CBD (control: 1182 μg/g; treatment: 297 μg/g) and THC amounts (control: 3927 μg/g; treatment: 580 μg/g). Conclusions Although this observation is limited in the early flowering stage, the common field stresses are adequate to induce changes in the cannabinoid profiles, particularly drought stress being the most impactful stress for hemp flower initiation with the altering the cannabinoid production by decreasing CBD and THC accumulation while increasing CBG by 40%.

CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature

Introduction Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. Objective In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. Materials and methods The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3–2 mg/kg/day). The median duration of treatment was 6.5 months (3–28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. Results The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20–70% of the patients. Conclusion Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

Unsubstantiated health claims for COVID-19 infections are led by cannabidiol: return of snake oil medicine

Background The United States Food and Drug Administration (FDA) monitors, inspects, and enforces the promotion of products by companies that claim to mitigate, prevent, treat, diagnose, or cure COVID-19. The introduction of COVID-19-related diagnostics and therapeutics during the pandemic has highlighted the significance of rigorous clinical trials to ensure safety and efficacy of such interventions. The objective of this report is to provide a descriptive review of promotional violations of health products for COVID-19 infection. Methods Warning letters issued by the FDA’s Center for Drug Evaluation and Research were retrieved over an 18 month period (March 6, 2020, to August 30, 2021) to identify promotional violations. FDA violation letters categorized as “Unapproved and Misbranded Products Related to Coronavirus Disease 2019 (COVID-19)” were reviewed. A content analysis was performed for each letter to identify categories for product type, promotional venue, violation type, and country of origin. For cannabidiol-related violations, a content analysis was repeated within its own product category. Results A total of 130 letters were reported. Across all letters, cannabidiol products were the most frequent subject of violation (15/130; 11.5%). Of the cannabidiol letters, all reported the promotion of unapproved products (15/15; 100%), misbranding (15/15; 100%), and/or had claims that lacked scientific substantiation (14/15; 93.3%). All promotional violations were linked to websites (15/15; 100%), along with other mainstream venues: Facebook, Instagram, YouTube, Twitter, LinkedIn, and email. Lastly, the cannabidiol products were described to provide therapeutic benefit to COVID-19, by acting as an anti-viral (5; 33.3%), pro-inflammatory (1; 6.7%), anti-inflammatory (7; 46.7%), immune-booster (5; 40%), immune-suppressor (2; 13.3%), and/or other (2; 13.3%). Conclusion Despite the urgent need for COVID-19 treatments, promotional material by companies must comply with standard regulatory requirements, namely substantiation of claims. As the pandemic persists, the FDA must continue their efforts to monitor, inspect, and enforce violative companies. Cannabidiol-related substances led the spectrum of products with unsubstantiated claims to treat COVID-19 infection. Improving awareness among the public, healthcare providers, and stakeholders highlights the value of drug approval process, while protecting public safety.

Staff awareness of the use of cannabidiol (CBD): a trust-wide survey study in the UK

Introduction Cannabidiol (CBD) is now a legal substance in Europe and is available in ‘high street shops’, usually as CBD oil. However, in the United Kingdom (UK), there is no clear consensus among healthcare professionals and organisations over how to manage CBD use in their patients. This is an important issue as CBD is a constituent of ‘medicinal and recreational cannabis’ and is gaining support in the scientific literature and lay media for use in physical and mental health problems. Given the aforementioned, this study is an exploration of healthcare professionals’ beliefs and attitudes with regard to CBD. Methods In July 2018, we sent requests by email to approximately 2000 clinical staff (including 319 physicians) at a mental health trust in South West London to answer 8 questions in a single survey using Surveyplanet.com, about their beliefs regarding CBD. There was no specific method of choosing the staff, and the aim was to get the email request sent to as many staff as possible on each service line. We did an analysis to see how the attitudes and beliefs of different staff member groups compared. We also gave them space to offer free text responses to illustrate their ideas and concerns. We used chi-squared tests for comparison across groups and used odds ratio for pairwise group comparisons. Results One hundred ninety surveys were received in response, and of these, 180 were included in the final sample. The physician response rate was 17.2% (55/319); the response rate for non-physicians could not be estimated as their total number was not known at outset. 32.2% of the responders had the right to prescribe (58/180) and 52.8% had an experience of working in addiction services (95/180). We found that staff members who can prescribe were 1.99 times as likely to believe CBD has potential therapeutic properties compared to those who do not (OR = 1.99, CI = 1.03, 3.82; p = 0.038) and 2.94 times less likely to think it had dangerous side effects (OR = 0.34, CI = 0.15, 0.75; p = 0.006). Prescribing healthcare professionals were 2.3 times as likely to believe that CBD reduces the likelihood of psychosis (OR = 2.30, CI = 1.10, 4.78; p = 0.024). However, prescribing healthcare professionals with the ability to prescribe were 2.12 times as likely to believe that CBD should be prescription only (OR = 2.12, CI = 1.12, 4.01; p = 0.02). Individuals experienced in addiction services were 2.22 times as likely to be associated with a belief that CBD has therapeutic properties (OR = 2.22, CI = 1.22, 4.04; p = 0.009). Staff in general reported a lack of knowledge about CBD in their free text responses. Conclusions With almost 95% of prescribers being physicians, they appear to demonstrate awareness of potential therapeutic benefit, reduced likelihood of psychosis and seeming lack of dangerous side effects with CBD. However, their higher stringency about the need for prescription implies an attitude of caution. There was also a suggestion that biases about cannabis were influencing responses to questions as well. The external validity of this study could be diminished by sampling bias and limitation to a single mental health trust. Nonetheless, some of the results drew a reasonable comparison with similar studies.