Re: “Cannabidiol for COVID-19 Patients with Mild to Moderate Symptoms (CANDIDATE Study): A Randomized,Double-Blind,Placebo-Controlled Clinical Trial” by Crippa et al.

Dear Editor,

Clinical research has reported that cannabidiol (CBD) is a molecule that has assumed an almost ubiquitous attribute in the management of inflammatory sequelae. The well-designed and elegantly conducted gold standard study by Crippa et al. ¹ ran counter to a recent in vitro/in vivo (murine model) study ² that strongly suggested that CBD could potentially be a preventative agent for early stage SARS-CoV-2 infections.

There probably was nothing antagonistic with the CBD formulation used in the Crippa study, which has been used in other studies with good effect. The problem may be in the route of administration (sublingual-oral route) and other cohort-specific factors that may have significantly affected CBD absorption. Oral administration of cannabinoids has always been an attractive option for the administration of cannabis-based medicines. The ease for patients to consume provides treating clinicians with optimal dose control and longer systemic exposure; however, the extensive first pass metabolism in the gut leads to variable bioavailability.

Comparative studies between murine and human studies are always difficult to assess. Notwithstanding in a pseudo comparison, the in vivo murine preclinical study by Nguyen et al. ² injected CBD (intraperitoneally at a dose of 20 or 80 mg/kg of body weight b.i.d.) to the mice (with an approximate body weight of the mice est. at 25 g) for 7 days previrus challenge and for an additional 4 days b.i.d. after the challenge. In the Crippa et al. study, patients were dosed with 300 mg/day (i.e., 1 mL or 150 mg per dose, twice a day) for 14 days.

Relevant to the high CBD dose on a per kilogram dose regimen, the murine study mice received 1760 mg/kg of body weight intraperitoneally for the 11 days, whereas in the Crippa study, patients on average received 58 mg/kg of body weight (this based on the standard body weight of a 72 kg man) for 14 days through the sublingual-oral route, which is a 30-fold difference. Furthermore, intraperitoneal administration has a better bioavailability profile for CBD than does any per oral administration, and intraperitoneal administration bypasses first pass metabolism. The latter is expected to result in 10-fold higher CBD plasma levels than its major active metabolite 7-hydroxycannabidiol (7-OH-CBD), whereas the sublingual administration results in plasma levels of 7-OH-CBD greater than or equal to CBD. ³

Contrasting results and the negative result of the Crippa et al. study ¹ could be explained by adverse gut effects that may have been present in the intestinal microbiome of the participants in the clinical trial allocated to the CBD group. The reported results seem to support this contention. Namely, there were participants coded to the CBD group that presented with comorbidities (35%), with the administration of pharmaceutical medicines (18%) with participants presenting with multiple COVID-19–associated symptoms, and with some participants also recorded as alcohol abusers (24%). These combined demographical sequelae can significantly progress intestinal microbiome deficits relevant to abundance and diversity that could have significantly affected the primary outcome in the Crippa study.

There is also the question of subtle pharmaceutical drug–CBD interactions that can go unnoticed. A disrupted intestinal microbiome has important links with susceptibility to COVID-19. ⁴ Recently, Ng and Haran reported that COVID-19 symptoms persisted after clearance of the virus. ⁵ They have reported that at 3 months, 86 of the 106 patients studied who presented with infections had postacute COVID-19 syndrome (PACS)—defined by the researchers as at least one persistent otherwise unexplained symptom, 4 weeks after clearance of the virus. And 81 patients had PACS at 6 months, most commonly fatigue, poor memory, hair loss, anxiety, and trouble sleeping.

The combination of these factors may have adversely affected CBD absorption with an unbalanced endocannabinoid system (ECS) skewed toward a proinflammatory tone in the gut. This is supported by the plasma levels of CBD in this study, which were 30% lower than CBD plasma levels reported by the same research group, ⁶ with the same CBD product and dosage, however, in a chronic occupational stress cohort.

The ECS underlies the effects of cannabis bioactive molecules, plant cannabinoids in various organ systems with reported distribution in locales such as the gastrointestinal system, central and peripheral nervous system, endocrine system, and inflammatory cells. As is known, this system consists of cannabinoid receptors (e.g., cannabinoid receptor subtype 1 and cannabinoid receptor subtype 2), the endogenous ligands that bind to these cannabinoid receptors (e.g., anandamide and 2-arachidonoylglycerol), and enzymes for their biosynthesis and degradation (e.g., fatty acid amide hydrolase and monoacylglycerol lipase). ⁷ The system has important links to the gut and as such is charged with maintaining a regulated inflammatory tone in the intestines ⁷

Cannabis-based medicines have been administered to patients through various routes, including inhalation (smoking and vaporization), transdermal, intranasal, buccal spray, or orally in the form of oil in soft capsules, oil drops, or cookies. ⁸ As such the bioavailability of cannabinoids from pharmacokinetic studies varies significantly according to the mode of administration.^9,10 Bioavailability from application on oral mucous membranes is ∼13% and even lower through the oral route with an approximate bioavailability of 5% because of extensive intestinal first pass metabolism.^11,12

Patients diagnosed with COVID-19 can present with gut dysbiosis ¹³ that may dysregulate and support an imbalance of gut motility, digestion, and proinflammatory immunological responses. ¹⁴ It may be that cannabinoid molecules administered through the sublingual-oral route offer no advantage for efficient CBD absorption. As such the scientific literature has always cast doubts and queried the relevance of cannabinoid molecule administration through the oral route. The low bioavailability of oral cannabinoid formulations is exemplified with studies administering tetrahydrocannabinol and the pharmacokinetic data generated. ¹² Hence alternative formulations for the administration of cannabis-based medicines that take advantage of nanomedicine technologies may improve plasma levels and efficacy.