A broader view on deriving a reference dose for THC traces in foods

An Acute Reference Dose (ARfD) of 1 µg of delta-9-tetrahydrocannabinol (THC) per kilogram (kg) of body weight (bw) per day was recommended by the European Food Safety Authority (EFSA) for its assessment of possible acute health risks from the intake of industrial hemp food products. The scientific basis for this opinion, such as their choice of a Point of Departure for identification of the Lowest Observed Adverse Effect Level (LOAEL) for THC on the central nervous system, and the seeming absence of an experimental No Observed Adverse Effect Level (NOAEL), is critically reviewed. Moreover, the risk assessment for an ARfD derivation for THC is then reconsidered. In contrast to the EFSA Scientific Opinion of 2015, a higher LOAEL is presently identified from pharmacokinetic and pharmacodynamic studies, and forensic data, in representative cohorts of healthy humans after oral administrations of low THC doses. A NOAEL for THC is derived through this combination of results, demonstrating a threshold for impairment of psychomotor function only after intake of an oral THC bolus beyond 2.5 mg for the average healthy adult. This 2.5 mg dose produces mean THC blood serum levels of <2 ng/mL, as well as do two doses when taken daily within a time interval of ≥6 h. The forensic threshold of THC that is correlated with the impairment of psychomotor function is known to be between 2 and 5 ng/mL in blood serum for adults. For an appropriately spaced intake of 2 x 2.5 mg THC per day, an adult can therefore be regarded as being at the NOAEL. Applying a default uncertainty factor of 10 for intraspecies variability to a NOAEL of 2 x 2.5 mg (over ≥6 hours) for THC, yields a “daily dose of no concern” or a “tolerable upper intake level” of 0.50 mg, corresponding to 7 µg/kg bw. Starting with a NOAEL of only 2.5 mg, consumed as a single bolus, the lowest possible daily ARfD of THC would therefore be 0.25 mg, or 3.5 µg/kg bw for healthy adults, as the absolutely most conservative estimate. Other justifiable estimates have ranged up to 14 µg/kg bw per day

Effects of cannabis ingestion on endometriosis-associated pelvic pain and related symptoms

Background: The use of cannabis for symptoms of endometriosis was investigated utilising retrospective archival data from Strainprint Technologies Ltd., a Canadian data technology company with a mobile phone application that tracks a range of data including dose, mode of administration, chemovar and their effects on various self-reported outcomes, including pelvic pain. Methods: A retrospective, electronic record-based cohort study of StrainprintTM users with selfreported endometriosis was conducted. Self-rated cannabis efficacy, defined as a function of initial and final symptom ratings, was investigated across the included symptom clusters of cramps, pelvic pain, gastrointestinal pain, nausea, depression, and low libido. Cannabis dosage form, dose and cannabinoid ratio information was also recorded. Results: A total number of 252 participants identifying as suffering endometriosis recorded 16193 sessions using cannabis between April 2017 and February 2020. The most common method of ingestion was inhalation (n = 10914, 67.4%), with pain as the most common reported symptom being treated by cannabis (n = 9281, 57.3%). Gastrointestinal symptoms, though a less common reason for cannabis usage (15.2%), had the greatest self-reported improvement after use. Inhaled forms had higher efficacy for pain, while oral forms were superior for mood and gastrointestinal symptoms. Dosage varied across ingestion methods, with a median dose of 9 inhalations (IQR 5 to 11) for inhaled dosage forms and 1 mg/mL (IQR 0.5 to 2) for other ingested dosage forms. The ratio of THC to CBD had a statistically significant, yet clinically small, differential effect on efficacy, depending on method of ingestion. Conclusions: Cannabis appears to be effective for pelvic pain, gastrointestinal issues and mood, with effectiveness differing based on method of ingestion. The greater propensity for use of an inhaled dosage delivery may be due to the rapid onset of pain-relieving effects versus the slower onset of oral products. Oral forms appeared to be superior compared to inhaled forms in the less commonly reported mood or gastrointestinal categories. Clinical trials investigating the tolerability and effectiveness of cannabis for endometriosis pain and associated symptoms are urgently required

LC-MS/MS quantitation of phytocannabinoids and their metabolites in biological matrices

Marijuana (i.e., cannabis) and its derivatives are considered the most commonly used of illicit drugs. Within the last two decades, phytocannabinoids and their synthetic analogues have emerged as potential medicines for the treatment of various disorders via targeting of the endocannabinoid system. Recently, some countries have legalized (medicinal/recreational) cannabis, which now allows for more research to be conducted. Accordingly, sensitive and specific analytical assays are required to identify and quantify these compounds in different human matrices. These analytical approaches were developed using mass spectrometric detection, where LC–MS/MS specifically has become the mainstay for the quantitative analysis of tetrahydrocannabinol and other cannabinoids. This is due to its superior selectivity and sensitivity, and ability to determine free and conjugate analytes within the same analysis. This tabular review of such methods is prefaced by a short overview of the major cannabinoids and some of their physiological actions

Cannabis use, a self-management strategy among Australian women with endometriosis : results from a national online survey

Objective: This study sought to determine the prevalence, tolerability, and self-reported effectiveness of cannabis in women with endometriosis. Methods: A cross-sectional online survey was conducted between October and December 2017. Recruitment targeted women with endometriosis through social media postings from endometriosis advocacy groups. Women aged 18 to 45, living in Australia, and with surgically confirmed endometriosis were eligible to participate. Survey questions investigated the types of self-management used, change in symptoms or medication use, costs, and adverse events. Results: A total of 484 responses were included for analysis, with 76% of the women reporting the use of general self-management strategies within the last 6 months. Of those using self management, 13% reported using cannabis for symptom management. Self-reported effectiveness in pain reduction was high (7.6 of 10), with 56% also able to reduce pharmaceutical medications by at least half. Women reported the greatest improvements in sleep and in nausea and vomiting. Adverse effects were infrequent (10%) and minor. Conclusion: Australian law currently requires legal medicinal cannabis use to follow specific, regulated pathways that limit prescription by this method; however, self-reported illicit use of cannabis remains relatively common in Australian women with endometriosis. Women report good efficacy of cannabis in reducing pain and other symptoms, with few adverse effects reported. Further clinical research is warranted to determine the effectiveness of cannabis in managing endometriosis symptoms. In locations where medicinal cannabis is more accessible, there remains a paucity of evidence for its clinical efficacy with endometriosis-associated symptoms

Phytocannabinoid drug-drug interactions and their clinical implications

Cannabis is a plant with a long history of human pharmacological use, both for recreational purposes and as a medicinal remedy. Many potential modern medical applications for cannabis have been proposed and are currently under investigation. However, its rich chemical content implies many possible physiological actions. As the use of medicinal cannabis has gained significant attention over the past few years, it is very important to understand phytocannabinoid dispositions within the human body, and especially their metabolic pathways. Even though the complex metabolism of phytocannabinoids poses many challenges, a more thorough understanding generates many opportunities, especially regarding possible drug-drug interactions (DDIs). Within this context, computer simulations are most commonly used for predicting substrates and inhibitors of metabolic enzymes. These predictions can assist to identify metabolic pathways by understanding individual CYP isoform specificities to a given molecule, which can help to predict potential enzyme inhibitions and DDIs. The reported in vivo Phase I and Phase II metabolisms of various phytocannabinoids is herein reviewed, accompanied by a parallel in silico analysis of their predicted metabolism, highlighting the clinical importance of such understanding in terms of DDIs and clinical outcomes

[In Press] Cannabis use for endometriosis : clinical and legal challenges in Australia and New Zealand

Introduction: Endometriosis is a difficult to manage condition associated with a significant disease burden. High levels of illicit cannabis use for therapeutic purposes have been previously reported by endometriosis patients in Australia and New Zealand (NZ). Although access to legal medicinal cannabis (MC) is available through medical prescription via multiple federal schemes, significant barriers to patient access remain. Methods: An anonymous cross-sectional online survey was developed and distributed through social media via endometriosis advocacy groups worldwide. Respondents were asked about legal versus illicit cannabis usage, their understanding of access pathways and legal status, and their interactions with health care professionals. Results: Of 237 respondents who reported cannabis use with a medical diagnosis of endometriosis, 186 (72.0%) of Australian and 51 (88.2%) NZ respondents reported self-administering cannabis illicitly. Only 23.1% of Australian and 5.9% of NZ respondents accessed cannabis through a doctor’s prescription, with 4.8% of Australian and no NZ respondents reporting to legally self-administer cannabis. Substantial substitution effects (> 50% reduction) were observed in users of nonopioid analgesia (63.1%), opioid analgesia (66.1%), hormonal therapies (27.5%), antineuropathics (61.7%), antidepressants (28.2%) and antianxiety medications (47.9%). Of Australian respondents, 18.8% and of NZ respondents, 23.5% reported not disclosing their cannabis use to their medical doctor, citing concern over legal repercussions, societal judgment, or their doctors’ reaction and presumed unwillingness to prescribe legal MC. Conclusions: Respondents self-reported positive outcomes when using cannabis for management of endometriosis, demonstrating a therapeutic potential for MC. Despite this, many are using cannabis without medical supervision. While evidence for a substantial substitution effect by cannabis was demonstrated in these data, of particular concern are the clinical consequences of using cannabis without medical supervision, particularly with regard to drug interactions and the tapering or cessation of certain medications without that supervision. Improving doctor and patient communication about MC use may improve levels of medical oversight, the preference for legal MC adoption over acquisition via illicit supply and reducing cannabis-associated stigma