The initiation of personalized medicine has come with the potential for improving the efficacy and safety of medications. Variations in the genes in any of the involved pathways might impact a patient’s prognosis, pharmacological response, and adverse effects of therapy. Knowledge of the pharmacogenomics (PGx) of cannabinoids is necessary for effective and safe dosing and to avoid treatment failure and severe complications.

Cannabis is regulated as a schedule 1 substance by the U.S. federal government. However, 37 states, the District of Columbia, Guam, Puerto Rico, and the U.S. Virgin Islands have comprehensive medical marijuana programs with indications for a range of chronic illnesses. In addition, the remaining 13 states allow the use of cannabidiol (CBD) for medical reasons in limited situations [1].

The medicinal use of cannabis in ancient China dates to about 2700 BC [2,3]. Cannabis has a wide range of clinical applications and the list of diseases in which cannabis/cannabinoids are used as a treatment is constantly increasing. Studies in experimental models and humans have suggested anti-inflammatory, neuroprotective, anxiolytic, and antipsychotic properties of chemicals extracted from cannabis [4]. Cannabis contains more than 100 cannabinoids, where CBD and THC are the subjects of most studies [5,6]. THC is the main psychoactive constituent and can produce neuroprotective, analgesic, antiemetic, and antiglaucoma effects [7,8]. CBD decreases THC psychoactivity and exhibits anti-inflammatory, antioxidant, anticonvulsant, and neuroprotective effects [6,9,10,11]. CBD (Epidiolex) has been FDA and EMA approved for Dravet and Lennox–Gastaut syndromes [4]. Another cannabis medication, Sativex (THC:CBD, 1:1 ratio), is used to treat symptoms of multiple sclerosis [4]. Moreover, a synthetic pharmaceutical-grade THC (dronabinol and nabilone) has been FDA approved for the treatment of chemotherapy-induced nausea and vomiting in patients who failed to respond to traditional antiemetic therapy. Dronabinol has also been approved as a therapy for anorexia in patients with AIDS [12]. Other cannabinoids including cannabidivarin also contribute to the medicinal effects of cannabis. Cannabidivarin, also known as cannabidivarol or CBDV, has recently gained significant attention. CBDV is the propyl analog of CBD and is similar to CBD structurally and functionally. CBDV is a nonpsychotropic phytocannabinoid with anti-inflammatory and anticonvulsant activities [13]. In October 2017, CBDV was given an orphan designation by the EMA for use in Rett syndrome and in February 2018 for the treatment of fragile X syndrome [14]. In 2020, the FDA also granted an orphan designation to CBDV for fragile X and Rett syndromes. Recently, a few clinical trials with CBDV were announced to assess the efficacy and safety of CBDV in the treatment of autism spectrum disorder (ASD) and Prader–Willi syndrome (PWS) [15].

Treatment by cannabis and cannabinoids is a part of innovative medicine. The list of medical disorders in which cannabinoids are used as a therapy is rapidly growing. However, knowledge of the medicinal effects as well as the incidences and severity of the side/adverse effects of cannabinoids is still lacking. Pharmacogenomics can help predict both positive and negative effects of cannabinoids and precisely identify the best treatment and dose for each individual, thereby reducing the complications, hospitalizations, and treatment cost. More recently, the importance of characterizing synonymous single-nucleotide variants (sSNVs) with respect to their role in regulatory functions exhibited in health and disease has gained focus [47]. A valuable resource that can be accessed for information relating human genetic variation and response to medications is the PharmGKB database [48].

Recent studies have started to elucidate the potential benefit for using pharmacogenomic testing to ascertain which individuals will derive positive effects from cannabis use and which individuals will encounter adverse events. Thus far, studies have been reported for pain management, epilepsy, and cannabis distribution, and consultation in community pharmacies.

With the increase in the use of cannabis in recent times, several positive attributes associated with its use have been identified. However, correspondingly, adverse effects have also been observed with some individuals. Interestingly, inter-individual variability has been observed with cannabis users and suggests that pharmacogenomic testing may help predict response. To assess the potential for pharmacogenomics to inform cannabis pharmacotherapy, a study by Poli et al. (2022) focused on the use of cannabis in a population of chronic pain patients [438]. A total of 600 Italian patients were recruited to participate in an open label, multi-center non-randomized observational study to assess the association between cannabis treatment and chronic pain treatment. Participating patients were segmented into five groups based on their disease state: (1) central nervous disease; (2) arthritis and autoimmune diseases; (3) headache and migraine; (4) neuropathic; and (5) cancer. Six selected SNPs were selected for testing based on a TaqMan assay. The study demonstrated a 20% reduction in pain during the first month, with an overall decrease in pain to 43% after one year. However, a significant number of participants dropped out of the study due to poor or no pain reduction and/or side effects. There was a significant association between dropout and the polymorphism of the gene CNR1. The Poli study is the first reported study to demonstrate that certain polymorphic genes may be associated with a cannabis effect, both in terms of pain management as well as side effects.

Although several treatment options are available for epilepsy, some epilepsies are associated with seizures that are resistant to existing treatment methods. Pharmacotherapy for pediatric epilepsy is particularly challenging; more effective therapies are needed to avoid short-term and long-term neurological disorders. Cannabis has been used to treat disease dating back to ancient times. Cannabis components, CBD and THC, are potential therapeutic options in epilepsy treatment. CBD has been shown to have an anticonvulsant effect in clinical studies. THC is the major psychoactive component of cannabis that contributes to the reduction in epileptic seizures. Concerns regarding the use of cannabis include the lack of standardization and regulation, imprecise dosing, possible adverse side effects, and drug interactions [439].

In the United States, approximately 3.5 million people have epilepsy [440], of these, twenty-five percent of the patients have treatment resistant epilepsy (TRE) [441]. Clearly, effective therapeutics are needed [442]. The use of pharmacogenomics should be able to identify predictors of CBD response. In a recent study, an open-label CBD study for TRE was executed using the Affymetrix Drug Metabolizing Enzymes and Transporters plus array [443]. A total of 113 patients participated in the study. The study demonstrated that genetic variation in pharmacogenes is associated with CBD response as well as the onset of adverse events in TRE.

In order to assess the potential of pharmacogenomic testing informing on the safe use of cannabis in the community pharmacy, a pilot study was performed at two urban pharmacies in Canada [194]. Twenty patients were pharmacogenomically profiled. Consultation was provided by pharmacists to the participants subsequent to testing. A total of 75% of the patients reported a high value in the pharmacist consultation. Additional studies will likely improve patient safety and allow individuals to make informed decisions regarding the use of cannabis.