Sex Differences in Medical Cannabis-Related Adverse Effects

Joshua Aviram; Gil M. Lewitus; Yelena Vysotski; Paula Berman; Anna Shapira; Shiri Procaccia; David Meiri


Pain. 2022;163(5):975-983. 

In This Article


Israeli Medical Cannabis Regulations

Owing to the Israeli Ministry of Health (IMOH) regulations of cannabis use for medical purposes, there are specific indications for which a physician can request a license for a patient. Chronic noncancer pain is a qualifying condition for MC license. Generally, MC application is received by one of the board members of the medical cannabis unit (MCU) that would reply to the physician if his request is approved or declined.[16]

In Israel, at the time the study was conducted (2015-2019), any physician with any expertise could apply to the IMOH to request an MC license for his or her patients. These physicians decide in collaboration with the patient on the route of administration that is approved by the MCU, either inflorescence for smoking and vaporizing or oil extracts for sublingual use. The monthly dose of MC is decided by the physician, with a starting monthly dose generally indicated as 20 g by the MCU and any increase subjected to its approval. Physicians provide consultation for the selection of a specific MC cultivar or combinations of cultivars. However, the final decision on the MC cultivar or cultivars selected is in the hands of the patient. After approval, the patients' contact details were transferred to 1 of 9 licensed cultivators for treatment instructions, cultivar selection (ie, THC:CBD ratio and sativa or indica dominance), and payment. Every patient goes through a personal trial-and-error process to find the cultivar or the combination of cultivars that best meets his or her therapeutic needs. Titration guidelines of MC treatment (starting dose, doses per day, guidelines for increasing or decreasing of the dose, or maximum dose allowed) are recommended by the physicians but are not enforced. Patients paid a fixed monthly price of about $100 regardless of the amount or the number of cultivars.

Mentionable, no specific information on the prescribing physicians was published by the IMOH at the time the study was conducted. However, Sharon et al. published a generalizable survey in which 95% of 50 Israeli pain specialist physicians applied for MC licenses for their patients.[21]

Inclusion criteria

Patients were eligible to participate if they were aged > 18 years, read Hebrew, were diagnosed for CNCP by a physician, and had standing MC license for the treatment of CNCP.


Study Questionnaires. Data collection was performed online by secure survey technology Qualtrics (Provo, Utah; version 12018).[19] Demographic information included age, sex, body mass index, and tobacco and alcohol consumption habits. Data on pain characteristics included the least, average, and worst weekly pain intensities and pain etiology. Specifically, patients were given the list of pain etiologies with examples for each (eg, "chronic neuropathic pain—such as herniated disc with radiating pain, postherpetic neuralgia, etc."). Specific information on the pharmaceutical analgesics consumption was also reported. Validated questionnaires included the quality of life (QoL) questionnaire, EuroQol (EQ5),[11] and sleep timing section of the Pittsburgh sleep quality index.[22] In addition, patients reported on their MC treatment characteristics and related adverse effects, including administration route, cultivator brand, cultivar name, total monthly dose (grams), and monthly dose of each specific cultivar names (grams), as well as adverse effects that patients attributed directly to the MC treatment based on the most frequent AEs in a previously published list of MC related–AEs.[4] In the AEs report section, there was an option to report on "other" AEs patients may have experienced, with an open text. After a report of a specific AE, the patients were transferred to a section with questions regarding the frequency (rarely, frequently, or constantly) and severity (mild, moderate, or severe).

Phytocannabinoid Profiling of Cannabis Chemovars. During December 2015 and October 2019, air-dried MC cultivars were obtained from several Israeli MC cultivators. Reagents, analytical standards, and general methodologies for phytocannabinoid and terpenoids extraction and analysis from Cannabis were according to our previously published methods.[6,7]

For each phytocannabinoid, the concentrations of the acid and its neutral counterpart were summed and reported as the total content. For example, the concentration of total Δ-9-tetrahydrocannabinol (Δ9-THC) was calculated as Total Δ9 – THC = Δ9 – THCA × 0.877 + Δ – THC, with 0.877 being the molar ratio between the 2 compounds that corrects for a change in the mass of (–)-Δ9-trans-tetrahydrocannabinol acid (Δ9-THCA) as a result of decarboxylation. For compounds with no absolute identification, neutral or acid concentrations were used.

For terpenoid analysis, 10 mg of ground cannabis flowers were weighed in a 20 mL amber HS–rounded bottom vial and immediately sealed with a magnetic 32 mm Polytetrafluoroethylene (PTFE) septa cap. Terpenoids were separated using a Trace 1310 gas chromatograph (Thermo Scientific, Bremen, Germany) coupled to a TSQ 8000 Evo triple quadrupole mass spectrometer (Thermo scientific), equipped with a DB-35 MS UI capillary column (30 m × 0.25 mm x 0.25 μm, Agilent Technologies, Palo Alto, CA). A Pal RTC autosampler CTC-Pal (Analytics AG, Zwingen, Switzerland) for automated static headspace injections was used; 1 mL of a sample's gas phase, prepared after 30 minutes agitation of a flower sample with 140°C temperature, was injected in the GC injection port with a split ratio of 1:50. The identification and absolute quantification of terpenoids was performed in MS/MS mode by external calibrations as described by Shapira et al. (2019).[20]

Because the inflorescences were analyzed in their natural form, monthly consumption of phytocannabinoid doses was calculated using total phytocannabinoid concentrations. This calculation corrects for any differences that may arise in phytocannabinoid profiles as a result of decarboxylation because of mishandling or storage of the MC inflorescences. The median phytocannabinoid concentrations of few separate batches for each cultivar were used in our analyses.

To reduce the variability between analyzed cultivars, only phytocannabinoids and terpenoids with minimum average concentrations of 0.1 g and 400 ppm, respectively, were reported.

Study Procedure

The data for this cross-sectional study were gathered from 2017 through 2019 after approval by the Institutional Ethics Committee of the Technion, Institute of Technology, Haifa, Israel (#011-2016). From an existing database of Israeli patients with preexisting MC license for various indications, we selected patients who agreed electronically to disclose their email address for future studies. Those who reported having a diagnosis of CNCP were sent an email with an explanation on the study design and a link to the online questionnaire. Electronic informed consent was obtained from patients who agreed to participate in the study. No financial compensation was offered to participating patients. While questionnaire data were being collected, the most prominent and most frequently administered cultivars from various approved cultivators in Israel were analyzed for phytocannabinoid content by Electrospray ionization-liquid chromatography (ESI-LC) or mass spectrometry (MS). Importantly, the chemical analyses were performed on the inflorescence of cultivars received from the cultivators and not directly from the patients.

Statistical Analysis

R software (V.1.1.463) with tidyverse[29] and atable[26] packages were used to analyze differences in outcome measures by the Pearson χ 2 test for categorical measures and the Kruskal–Wallis rank-sum test for numeric measures. For the effect size and confidence interval (CI), the Cohen d test was used. The Shapiro–Wilk test of normality demonstrated a nonnormal distribution for all measures; thus, data are presented as median and lower and upper quartiles (interquartile range). Differences were considered significant at the P < 0.05 level. Incidences are presented as number and percentage of patients.