Toxicological properties of Δ⁹-tetrahydrocannabinol and cannabidiol

Abstract

Cannabis sativa L. contains more than 100 phytocannabinoids that can interact with cannabinoid receptors CB1 and CB2. None of the cannabinoid receptor ligands is entirely CB1- or CB2-specific. The effects of cannabinoids therefore differ not just because of different potency at cannabinoid receptors but also because they can interact with other non-CB1 and non-CB2 targets, such as TRPV1, GPR55, and GPR119. The most studied phytocannabinoid is Δ9-tetrahydrocannabinol (THC). THC is a partial agonist at both cannabinoid receptors, but its psychotomimetic effect is produced primarily via activation of the CB1 receptor, which is strongly expressed in the central nervous system, with the noteworthy exception of the brain stem. Although acute cognitive and other effects of THC are well known, the risk of irreversible neuropsychological effects of THC needs further research to elucidate the association. Unlike THC, phytocannabinoid cannabidiol (CBD) does not appear to have psychotomimetic effects but may interact with some of the effects of THC if taken concomitantly. CBD administered orally has recently undergone well-controlled clinical trials to assess its safety in the treatment of paediatric epilepsy syndromes. Their findings point to increased transaminase levels as a safety issue that calls for postmarketing surveillance for liver toxicity. The aim of this review is to summarise what is known about acute and chronic toxicological effects of both compounds and address the gaps in knowledge about the safety of exogenous cannabinoids that are still open.

Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature

“…In fact, CBD is described as “non-psychotropic” [ 45 ] or even “anti-psychotropic” [ 11 , 12 ] as it does not show effects comparable to Δ 9 -THC, neither in studies on animals as already reported by Mechoulam et al [ 46 ] in 1970 nor in humans as reviewed by Iseger et al [ 12 ]. However, a multitude of psychological and physiological effects (some examples are anti-inflammatory, antiemetic, antipsychotic, anticarcinogenic, anxiolytic and analgesic effects, effects on appetite, positive effects on multiple sclerosis and spinal cord, as well as on Gilles de la Tourette’s syndrome, epilepsy, glaucoma, diabetes, Parkinson disease and dystonia) were associated with CBD and reviewed in a number of articles [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. In agreement with the hypothesis by Compton et al [ 44 ], a physiological explanation for the different pharmacology was presented by Pertwee et al [ 47 ], when they reported on the unexpectedly high potency of CBD to act as the antagonist of CB1/CB2 receptors in cells or tissues expressing these receptors.…”

“…Thus, as such a history has not been demonstrated so far, CBD extracts are classified as Novel Food and are therefore not authorized in the EU. Besides Δ 9 -THC, the non-psychotropic cannabidiol (CBD, Figure 1c) gained increasing popularity due to a broad spectrum of health-promoting effects ascribed to it with several reviews on safety and efficacy available [7][8][9][10][11][12][13][14][15][16][17][18]. In recent years, this culminated in extensive consumer interest with heavily increasing numbers starting in 2018 (Figure 2).…”

Opportunities, Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19

“…In addition, careful examination of whether the influence of CBD on the immune system could exacerbate viral infection is required (reviews [ 64 , 65 ]). Indeed, viral, fungal infections and pneumonia infections are listed among the side effects of CBD [ 166 , 167 , 168 , 169 ]. Moreover, it has to be considered that CBD, which was found to have a pro-oxidative effect in one preclinical study ([ 83 ]; Table 1 ), might even aggravate the feared cytokine storm.…”

“…However, the authors of the latter two reviews postulated the need to conduct additional clinical trials. Indeed, various side effects of CBD have recently been described [ 166 , 167 , 168 , 169 ]. In addition to the increased risk of infection mentioned above, the increased tendency for respiratory depression and aspiration to occur, that is, symptoms also occurring in COVID-19, should be considered.…”

“…In addition, careful examination of whether the influence of CBD on the immune system could exacerbate viral infection is required (reviews [64,65]). Indeed, viral, fungal infections and pneumonia infections are listed among the side effects of CBD [166][167][168][169].…”