THE OREGON STATE DRUG REVIEW© AN EVIDENCE BASED DRUG THERAPY RESOURCE http://pharmacy.oregonstate.edu/drug-policy/newsletter August 2021 Volume 11 Issue 6 © Copyright 2021 Oregon State University. All Rights Reserved Therapeutic Uses for Cannabinoids Kathy Sentena, PharmD, Oregon State University Drug Use Research and Management Group Cannabis (e.g., hemp, marijuana) and synthetic cannabinoids vaporization. THC activates CB 1 receptors in the brain have a long history of therapeutic, as well as recreational, uses. which results in psychoactive effects, which are not While over 100 different cannabinoids have been isolated from associated with CBD. CBD has numerous putative biological cannabis, ∆-9-tetrahydrocannabinol (THC) and cannabidiol targets and has been proposed to act as a negative (CBD) are the most well-known.1 Many patients request allosteric modulator of cannabinoid receptors.4 Lack of information from providers on the benefits and risks of quality control and unknown bioavailability of cannabinoid cannabinoid products. This newsletter will present the evidence products complicate the predictability of pharmacological for potential uses of THC and CBD products as well as legal effects of non-Food and Drug Administration (FDA) restrictions, drug interactions and safety precautions. approved products (e.g., edibles, vapors, purified liquids). Cannabinoid Legal Implications Therapeutic Effects of Cannabinoids There are several factors that determine the regulations that Cannabinoids are anecdotally used for a multitude of apply to cannabinoid products. Hemp-derived products are not ailments (e.g., muscle relaxant, analgesia, appetite considered federally controlled substances if they contain 0.3% stimulation). There are only three FDA-approved products. or less of THC (by dry weight).1 CBD products from hemp can The THC-based synthetic product, dronabinol (Marinol®, be used in cosmetics and some states allow consumable CBD Syndros®), is approved for use in adults for anorexia products. Laws governing the use of cannabinoids depends on associated with weight loss in patients with Acquired the state in which you live and the plant that was the basis of Immunodeficiency Syndrome (AIDS) and nausea and the product (hemp vs. marijuana). The product may require a vomiting associated with cancer chemotherapy for patients prescription or be available online or at a dispensary or smoke who have failed standard antiemetic regimens.5 The third shop. In Oregon, individuals 21 years or older can purchase up approved product is a CBD derivative, cannabidiol to one ounce of cannabis. The Oregon Medical Marijuana Act (Epidiolex®), approved for patients aged 1 year or older for also allows for the use of marijuana for conditions listed in the treatment of seizures associated with Lennox-Gastaut Table 1.2 Patients that qualify for a medical marijuana may pay syndrome, Dravet syndrome or tuberous sclerosis complex.6 lower costs, be able to purchase more potent products and grow additional plants compared to those individuals using The therapeutic effects of cannabinoids, vary between marijuana for recreational purposes only. At this time medical products and routes of administration. Food may cause cannabis may only be authorized by an Oregon licensed Doctor erratic absorption of CBD and edible CBD products (e.g., of Medicine (MD) or Doctor of Osteopathic Medicine (DO). gummy bears, brownies) are associated with the least predictable absorption profiles.7 Liquid formulations are more Table 1. Qualifying Medical Marijuana Uses in Oregon.2 predictable with maximum concentrations reported at 3-5 Cancer Glaucoma hours after ingestion. Products that are oil based have the Degenerative or pervasive HIV/AIDs best absorption as cannabis is lipophilic. Vaping has the neurological condition quickest onset of action with maximum concentrations seen 7 Medical condition or Post- at 15-30 minutes. The time it takes to metabolize cannabis treatment for a medical traumatic is also variable. Most urine drug screens test for THC or its condition that produces stress metabolites. Tests may remain positive after a week to 10 one or more of the disorder days after use and up to 6 weeks if the patient is a heavy 1 following: Cachexia, (PTSD) user. CBD and hemp oil do not usually cause a positive test severe pain, severe due to low levels of THC. Rarely CBD may cause a positive 1 nausea, seizures and test with use of impure forms or very high doses. persistent muscle spams Evidence Supporting the Use of Cannabinoids Cannabinoid Pharmacology There is a lack of evidence to draw strong conclusions on CBD and THC have unique targets and therapeutic effects due efficacy for the medicinal use of most cannabinoid products, to a non-enzymatic decarboxylation process that results in especially those which are not FDA approved. There is differing chemical structures.3 Decarboxylation activates raw limited evidence, beyond anecdotal, to support the use of cannabis into active forms and can be done through heat or CBD and THC for some indications (Table 2). The majority OREGON STATE DRUG REVIEW Page 2 of evidence is low-quality and there is a need for randomized Refractory - FDA-approved Low clinical trials to determine true effects of treatment. Federal seizures in (Epidiolex®) restrictions present a barrier to conducting research in a patients with - PC trial of 171 formalized manner. The National Institute on Drug Abuse Lennox- patients (age 2-55 (NIDA) has adopted a policy to guide researchers to measure Gastaut years, baseline seizure and report findings on cannabis using a standard THC unit of 5 syndrome frequency of 74/month ) mg. This recommendation does not limit use to 5 mg but rather with Lennox-Gastaut standardizes the comparable effects of THC.8 Additional syndrome received oral challenges to the use of cannabinoids are the lack of CBD 20 mg/kg as add consistency between different dosage forms and potency. on therapy which decreased monthly Table 2. Cannabinoid Uses with Limited Evidence. drop seizure frequency Condition Evidence Strength by 17.21% (95% CI, - of 30.32 to -4.09; Evidence P=0.0135) more than CBD (oral) placebo compared to Psychotic Small, non-controlled Low baseline13 episodes in study (n=6) lasting 4 THC (oral) patients with weeks demonstrated Refractory - FDA-approved Low Parkinson’s reductions in BPRS and chemotherapy (Marinol® capsules; disease PPQ with CBD 150 -induced Schedule III) mg/day, compared to nausea and - FDA-approved baseline levels9 vomiting (Syndros® solution; Anxiety Small study (n=24) Low Schedule II) associated randomized patients to - Meta-analysis of 6462 with public CBD 600 mg/day or patients demonstrated speaking placebo demonstrated a complete response reductions in anxiety, with cannabinoids in cognitive impairment, 47% of patients discomfort and alert compared to 20% with levels with CBD10 placebo (OR 3.82; 95% Anxiety Small study (n=72) Low CI, 1.55 to 9.42: P < demonstrated anxiety 0.05) score reduction in 79% THC (oral or inhaled) of patients in the first Appetite - FDA-approved Low month11 stimulant in (Marinol®; Schedule Refractory - FDA-approved Low patients with III)5 seizures in (Epidiolex®; Schedule HIV or AIDs - FDA-approved patients with V) (Syndros® solution; Dravet - PC trial of 120 Schedule II) syndrome children and young Study in 139 patients adults with Dravet showed an syndrome (baseline improvement of 9 seizure rate of points on a visual 14/month) received oral analog scale compared CBD 20 mg/kg which to placebo (p<0.05) for decreased conclusive the outcome of seizures by 22.8% improvement in (95% CI, -41.1 to -5.4; appetite P=0.01) more than Refractory Plant derived Low placebo12 chronic pain cannabinoids were found to reduce pain 40% more than control Oregon DUR Board Newsletter Produced by OSU COLLEGE of PHARMACY DRUG USE RESEARCH & MANAGEMENT Managing Editor: Kathy Sentena [email protected] OREGON STATE DRUG REVIEW Page 3 (OR 1.41, 95% CI, 0.99 Table 3. CBD and THC Drug Interactions1 to 2.00); results not SS Enzyme Drug Recommendation Example (pooled analysis of 7 Characteristic Drugs* trials, n=178)14 Cannabidiol (CBD) Symptom Limited to case reports Low CYP3A4 Moderate to Reduce CBD ritonavir, Strong dose verapamil, Improvement and anecdotal Inhibitors voriconazole evidence1,7 in: CYP2C19 Moderate to Reduce CBD fluconazole, - Tourette Strong dose omeprazole syndrome Inhibitors - PTSD CYP3A4 Inducers Consider carbamazepine, Abbreviations: AIDS – Acquired Immunodeficiency Syndrome; BPRS – increasing CBD St. John’s wort Brief Psychiatric Rating Scale; CBD – cannabidiol; CI – confidence dose interval; HIV – Human Immunodeficiency Syndrome; FDA – Food and CYP2C19 Inducers Consider primidone, Drug Administration; OR – odds ratio; PC – placebo-controlled; PPQ – Personal Problems Questionnaire; PTSD – post-traumatic stress increasing CBD rifampin disorder; RCT – randomized controlled trial; SS – statistically dose significant; THC - ∆-9-tetrahydrocannabinol CYP2C8 Substrates of May increase amiodarone, enzyme drug levels – carbamazepine, Adverse Events Associated with Cannabinoids consider lowering warfarin The use of cannabinoids commonly results in adverse events, dose of drug with an incidence rate of approximately 50%.7 Adverse events CYP2C9 Substrates of May increase amitriptyline, enzyme drug levels – phenytoin are more commonly seen with higher doses and prolonged consider lowering 7 use. CBD may cause decreased appetite and weight loss, dose of drug diarrhea, dizziness,