Medical Marijuana and Other Cannabinoids _____________________________________________________
In the Netherlands, cannabis with the following THC and CBD concentrations are available [87]: • 22%, 14%, or 13.5% THC with <1% CBD • 6.3% THC/8% CBD • <1% THC/7.5% CBD In Canada, cannabis is available in potencies of [14]:
Analgesic mechanisms of THC include interaction with sero- tonergic 5-hydroxytryptamine (5-HT) systems. THC inhibits 5-HT release from platelet cells, increases cerebral production of 5-HT, and decreases synaptosomal uptake. These effects involve multiple trigeminovascular system mechanisms asso- ciated with migraine headache. Dopaminergic inhibition by THC may also contribute to analgesic benefits [31; 91]. The glutamatergic system is foundational in chronic neuro- pathic pain and is causal in the development of secondary and tertiary hyperalgesia, via NMDA mechanisms, that characterize conditions such as migraine and fibromyalgia [92]. Cannabi- noids inhibit pre-synaptic glutamate release, and THC reduces NMDA response by 30% to 40%. THC is also neuroprotective through antioxidant activity [93]. THC inhibits calcitonin gene-related peptide to reduce hyperalgesia, and preclinical studies show that THC blocks capsaicin-induced hyperalgesia at sub-psychoactive doses [94; 95]. THC stimulates beta-endorphin production, and this impor- tant opioid system interaction partially accounts for the repeated findings of the opioid sparing effects with cannabis in clinical trials and preventing development of opioid tolerance and withdrawal and the reinstatement of analgesia when a prior opioid dosage has worn off in other studies [96; 97; 98]. THC also produces extensive anti-inflammatory activity through mechanisms that include inhibition of PGE2 syn- thesis, suppression of platelet aggregation, and stimulation of lipoxygenase. Studies have confirmed that THC produces 20 times the anti-inflammatory potency of aspirin and twice the potency of hydrocortisone, but unlike NSAIDs, it has not demonstrated COX inhibition [31; 99]. 11-Hydroxy-THC 11-hydroxy-THC is the primary metabolic product of THC. It is four times more potent in producing psychoactive and immunosuppressive effects than the parent compound [68; 69]. Δ 8-THC Δ 8-THC is a Δ 9-THC isomer found in smaller amounts in the cannabis plant and has activity as a partial CB1 and CB2 agonist. In vitro assays have shown comparable efficacy and potency with Δ 9-THC, and preliminary clinical results sug- gest greater antiemetic potency with Δ 8-THC compared with Δ 9-THC [100; 101]. Δ 8-THC is psychoactive, but the effect is very weak and substantially overshadowed by THC due to its low concentration [8]. In 2022, the FDA issued a warning letter and consumer update regarding products containing Δ 8-THC [102]. These products contain concentrated amounts of Δ 8-THC, typically manufactured from CBD. At the levels found in these prod- ucts, the isomer induces significant psychoactive effects, and adverse effects have been reported, including hallucinations, vomiting, tremor, anxiety, dizziness, confusion, and loss of consciousness [102].
• 22% THC/<1% CBD • 17% THC/<1% CBD • 15% THC/5% CBD • 12.5% THC/<0.5% CBD • 9% THC/9.5% CBD • 4% THC/10% CBD • 0.7% THC/13% CBD
The cannabis used by the CMCR is of comparable pharmaceu- tical quality to the medical cannabis in the Netherlands and Canada [26]. In contrast, legal medicinal cannabis purchased from dispensaries in the United States lacks government- controlled standardization of cultivation, potency, and purity [88]. In the United States, cannabis grown for recreational or medical use has been bred to increase THC effects by increas- ingly reducing the CBD concentration. This also increases the side effect potential, and medical cannabis users may want to avoid this by seeking strains bred for higher CBD concentra- tion [89]. PHYTOCANNABINOIDS In contrast to pharmaceuticals that contain a single canna- binoid or a combination of two cannabinoids, the effects of inhaled cannabis are the result of pharmacologic activity from multiple agents. The psychoactive effects are largely the result of THC activity at the CB1 receptor. Therapeutic effects are influenced by THC and also by additional cannabinoids lack- ing psychoactive properties [8]. Δ -9-Tetrahydrocannabinol (THC) THC is present in the living Cannabis plant as a mixture of monocarboxylic acids, and heating to greater than 120°C decar- boxylates THC to promote biologic activity. THC decomposes from exposure to air, heat, or light, and oxidizes to cannabinol when exposed to acid [68; 69]. THC binds to CB1 and CB2 receptors as a partial agonist, with preferential binding at CB1. The mechanism of action, transmitter system interactivity, and demonstrated and theoretical therapeutic utility of THC are complex and vast, and the following summary is limited to the area of pain. Among natural cannabinoids, THC possesses the greatest psychoactive potency and also exhibits the greatest analgesic activity. Epidural (i.e., intrathecal, intraventricular) administra- tion of THC produces antinociception similar in magnitude to that of opioid analgesics [90].
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