After the identification of THC, several investigations on humans showed that, when THC was taken orally or intravenously it showed substantial potency similar to that reported by recreational cannabis users. At present, two analogues of THC that have been approved by the US Food and Drug Administration are available in the United States in capsules that may be prescribed for chemotherapy-induced nausea and vomiting: nabilone (Cesamet, Valeant Pharmaceuticals North America) and dronabinol (Marino', Solvay Pharmaceuticals). More recently, the cannabis-based medicine nabiximols (Sativex, GW Pharmaceuticals), which contains approximately equal amounts of THC and CBD and is administered as a sub-lingual spray, was first licensed as a medicine in Canada for relief of pain in adult patients suffering from multiple sclerosis (MS) or cancer and subsequently to reduce spasticity in MS .
Let’s get back to basics for a while. What are exactly cannabinoids?
Cannabinoids are the derivatives of the cannabis plant, the most potent bioactive component of which is tetrahydrocannabinol (THC). The most commonly used drugs containing cannabinoids are marijuana, hashish, and hashish oil. These compounds exert their effects via interaction with the cannabinoid receptors CB1 and CB2. Type 1 receptors (CB1) are localized mostly in the central nervous system and in the adipose tissue and many visceral organs, including most endocrine organs. Type 2 cannabinoid receptors (CB2) are positioned in the peripheral nervous system (peripheral nerve endings) and on the surface of the immune system cells. Recently, more and more attention has been paid to the role that endogenous ligands play for these receptors, as well as to the role of the receptors themselves. So far, endogenous cannabinoids have been confirmed to participate in the regulation of food intake and energy homeostasis of the body, and have a significant impact on the endocrine system, including the activity of the pituitary gland, adrenal cortex, thyroid gland, pancreas, and gonads. Interrelations between the endocannabinoid system and the activity of the endocrine system may be a therapeutic target for a number of drugs that have been proved effective in the treatment of infertility, obesity, diabetes, and even prevention of diseases associated with the cardiovascular system.
Tetrahydrocannabinolic acid A (THCA-A) reduces adiposity and prevents metabolic disease caused by diet-induced obesity.
Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored. Here we present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with Δ9-THCA-A confirmed its mode of action through PPARγ. Administration of Δ9-THCA-A in a mouse model of HFD-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation.
THCA also serves as an anti-emetic and anti-nausea agent in animal models, which suggests that it may have therapeutic potential. Tetrahydrocannabivarin (THCV), identified in the 1970s (Gill 1971; Merkus 1971), was initially described as sharing with A9-THC the ability to produce catalepsy in the mouse ring mobility test and as able to produce mild z9-THC-like effects in humans. These effects have been shown to be limited to very high doses, with low doses acting as an antagonist at the CB, receptor. Indeed, at low doses THCV suppresses food intake and reduces body weight, as does the CB1 receptor antagonist/inverse agonist rimonabant (a drug previously approved for weight control in humans). However, unlike rimonabant, THCV produces neither nausea nor anxiety, two side effects produced by inverse agonism of the CB, receptor that limit the usefulness of rimonabant as a drug. Therefore, THCV may be a useful drug for weight loss.
The primary non-psychoactive cannabinoid of cannabis (particularly in hemp) is cannabidiol (CBD), first isolated from Mexican marijuana by Roger Adams (1941) and from Indian Charas by Alexander Todd (1946). Mechoulam and Shvo (1963) later isolated CBD from Lebanese hashish and established its structure. Unlike THC, CBD lacks psychotropic activity; however, research from pre-clinical animal models suggests that it has therapeutic potential for management of inflammation, anxiety, emesis, nausea, inflammatory pain, and epilepsy.
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• PMID: 31706843 DOI: 10.1016/j.bcp.2019.113693
• Cannabinoids and the brain by Linda A. Parker