Δ8-Tetrahydrocannabinol (delta-8-THC, Δ8-THC) is a psychoactive cannabinoid found in the Cannabis plant. It is an isomer of Δ9-tetrahydrocannabinol (delta-9-THC, Δ9-THC), with which it co-occurs in hemp; natural quantities of ∆8-THC found in hemp are low. Psychoactive effects are similar to that of Δ9-THC, with central effects occurring by binding to cannabinoid receptors found in various regions of the brain. Partial synthesis of ∆8-THC was published in 1941 by Roger Adams and colleagues at the University of Illinois. After the 2018 United States farm bill was signed, ∆8-THC products synthesized from industrial hemp by acid-catalyzed cyclization experienced a rise in popularity; THC products have been sold in licensed recreational cannabis and medical cannabis industries within the United States in California, Pennsylvania, and medicinally licensed in Michigan and Oregon. According to a March 2024 study, 11% of US twelfth graders in the study had used ∆8-THC over the past 12 months.
Effects ∆8-THC is moderately less potent than Δ9-THC. This means that while its effects are similar to that of Δ9-THC, as both are psychoactive cannabinoids, it would take more ∆8-THC to achieve a comparable level of effect. A 1973 study testing the effects of ∆8-THC in dogs and monkeys reported that a single oral dose of 9,000 milligrams per kilogram of body mass (mg/kg) was nonlethal in all dogs and monkeys studied. The same study reported that the median lethal dose of ∆8-THC in rats was comparable to that of ∆9-THC. Both isomers of THC have been found to cause a transient increase in blood pressure in rats, although the effects of cannabinoids on the cardiovascular system are complex. Animal studies indicate that ∆8-THC exerts many of its central effects by binding to cannabinoid receptors found in various regions of the brain, including the cerebral cortex, thalamus, basal ganglia, hippocampus, and cerebellum.
Adverse effects As of 2022, there had been at least 104 adverse event reports made for ∆8-THC, and at least two deaths associated with ∆8-THC products. US national poison control centers received 2,362 exposure cases of Δ8-THC products between 1 January 2021 and 28 February 2022; 58% of these exposures involved adults, and 70% thought they required medical care. As of 2022, the safety profile, including risks of psychosis and addiction after regular, long-term ∆8-THC use was unknown.
Pharmacology
Mechanism of action The pharmacodynamic profile of ∆8-THC is similar to that of ∆9-THC. It is a partial agonist of CB1 and CB2 cannabinoid receptors with about half the potency of ∆9-THC in most but not all measures of biological activity.
Pharmacokinetics The pharmacokinetic profile of ∆8-THC is also similar to that of ∆9-THC. Following ingestion in humans, hepatic cytochrome P450 enzymes including CYP2C9 and CYP3A4 first convert ∆8-THC into 11-hydroxy-Δ8-tetrahydrocannabinol (11-OH-Δ8-THC). Next, dehydrogenase enzymes convert 11-OH-Δ8-THC into 11-nor-Δ8-tetrahydrocannabinol-9-carboxylic acid (11-nor-Δ8-THC-9-COOH, also known as Δ8-THC-11-oic acid). Finally, Δ8-THC-11-oic acid undergoes glucuronidation by glucuronidase enzymes to form 11-nor-Δ8-tetrahydrocannabinol-9-carboxylic acid glucuronide (Δ8-THC-COOH-glu), which is then excreted in the urine.
Chemistry ∆8-THC is a tricyclic terpenoid. Although it has the same chemical formula as ∆9-THC, one of its carbon-carbon double bonds is located in a different position. In ∆8-THC, the double bond is between the eighth and ninth carbons in structure, while in Δ9-THC, the double bond is between the ninth and tenth carbons in structure.
This difference in structure increases the chemical stability of ∆8-THC relative to ∆9-THC, lengthening shelf life and allowing the compound to resist undergoing oxidation to cannabinol over time. Like other cannabinoids, ∆8-THC is very lipophilic (log P = 7.4). It is an extremely viscous, colorless oil at room temperature. While ∆8-THC is naturally found in plants of the Cannabis genus, this compound can also be produced in an industrial or laboratory setting by acid-catalyzed isomerization of cannabidiol (CBD). Solvents that may be used during this process include dichloromethane, toluene, and hexane. Various Brønsted or Lewis acids that may be used to facilitate this isomerization include tosylic acid, indium(III) triflate, trimethylsilyl trifluoromethanesulfonate, hydrochloric acid, and sulfuric acid. Because it is possible for chemical contaminants to be generated during the process of converting CBD to ∆8-THC, such as Δ10-THC, 9-OH-HHC and other side products, concern has been raised about the safety of untested or impure ∆8-THC products. The ongoing controversy regarding the legal status of ∆8-THC in the US is complicated by terminology. According to a 2019 literature review published in Clinical Toxicology, the term synthetic cannabinoid typically refers to a full agonist of CB1 and CB2 cannabinoid receptors. According to the review, the following is stated:
"The psychoactive (and probably the toxic) effects of synthetic cannabinoid receptor agonists are likely due to their action as full receptor agonists and their greater potency at CB1 receptors." However, ∆8-THC and ∆9-THC are partial agonists of cannabinoid receptors. They are less potent than many synthetic cannabinoids. It has not been definitively proven if full agonism is the reason for the greater incidence of adverse reactions to synthetic cannabinoids since ∆9-THC has been shown to act as a full CB1 receptor agonist on specific CB1 receptors located in the hippocampus section of the brain. Furthermore, the synthetic cannabinoid EG-018 acts as a partial agonist. The classical cannabinoid structure is that of a dibenzopyran structure. This group includes THC. THC interacts with a different spot inside the CB1 receptor than synthetic cannabinoids such as JWH-018. This may explain the differences in adverse reactions to synthetic cannabinoids.
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