Review of delta‐8‐tetrahydrocannabinol (Δ⁸‐THC): Comparative pharmacology with Δ⁹‐THC

Abstract

The use of the intoxicating cannabinoid delta-8-tetrahydrocannabinol (Δ 8 -THC) has grown rapidly over the last several years. There have been dozens of Δ 8 -THC studies dating back over many decades, yet no review articles have comprehensively covered these findings. In this review, we summarize the pharmacological studies of Δ 8 -THC, including receptor binding, cell signalling, in vivo cannabimimetic activity, clinical activity and pharmacokinetics. We give special focus to studies that directly compared Δ 8 -THC to its more commonly studied isomer, Δ 9 -THC. Overall, the pharmacokinetics and pharmacodynamics of Δ 8 -THC and Δ 9 -THC are very similar. Δ 8 -THC is a partial agonist of the cannabinoid CB 1 receptor and has cannabimimetic activity in both animals and humans. The reduced potency of Δ 8 -THC in clinical studies compared with Δ 9 -THC can be explained by weaker cannabinoid CB 1 receptor affinity, although there are other plausible mechanisms that may contribute. We highlight the gaps in our knowledge of Δ 8 -THC pharmacology where further studies are needed, particularly in humans.delta-8-THC, pharmacodynamics, pharmacokinetics, Δ 8 -THC | INTRODUCTIONDelta-8-tetrahydrocannabinol (Δ 8 -THC) is a cannabinoid that is a double bond isomer of the more well-known Δ 9 -THC (Figure 1). Δ 8 -THC was first derived from the cyclization of cannabidiol (CBD) and it was discovered to be highly psychoactive in human studies (Adams, 1942).By 1966, it was realized that Δ 8 -THC was present in only negligible amounts in cannabis and cannabis-derived products, such as hash (Hively et al., 1966). Δ 9 -THC was determined to be the compound, almost entirely, responsible for the intoxicating properties of cannabis, including alterations in mood, perception and cognition. Subsequent research focused much more on Δ 9 -THC, but the effects of Δ 8 -THC continued to be characterized throughout the following decades. One reason for this is the better thermodynamic stability of Δ 8 -THC relative to Δ 9 -THC (Hanuš et al., 2016). Note that early studies referred to Δ 8 -THC as Δ 6 or Δ 1(6) and Δ 9 -THC as Δ 1 . This review will follow the modern ring numbering system even when the original publication used the old numbering.There is currently debate about the regulatory status of Δ 8 -THC in the United States (e.g. Koski, 2021). The Agriculture Improvement Act of 2018 (informally called the 'Farm Bill') removed hemp and hemp products containing less than 0.3% Δ 9 -THC from the legal definition of marijuana in the Federal Controlled Substances Act (Agriculture Improvement Act of 2018, 2018). Importantly for Δ 8 -THC, hemp was defined as including 'all derivatives, extracts, cannabinoids, isomers, acids, salts and salts of isomers'. Because Δ 8 -THC is both an isomer of CBD and a derivative of CBD when obtained from the cyclization Abbreviations: C max , maximal concentration; CYP, cytochrome P450; P-gp, P-glycoprotein; Tmax, time to maximal concentration; Δ 8 -THC, delta-8-tetrahydrocannabinol.

Delta-8-THC association with psychosis: A case report with literature review

“…CB 1 receptors are also implicated in pain and sensory perception, emotional regulation, attention and concentration, memory, and mood ( 26 ). Δ 8 -THC may have a similar effect on the CB 2 receptor as Δ 9 -THC, but fewer data exist ( 11 ). CB 2 receptors are thought to play a role in the inflammatory response ( 27 ).…”

“…Cannabinoid receptors are G-protein coupled receptors of the endocannabinoid system, in which the CB 1 receptor has been shown to propagate the psychotropic effects of 9 -THC (23). From the research available comparing 8 -THC to 9 -THC, it appears that 8 -THC acts at both the cannabinoid CB 1 and CB 2 receptors, like 9 -THC (24), but with a weaker affinity at the CB 1 receptor (11,25). CB 1 receptors are also implicated in pain and sensory perception, emotional regulation, attention and concentration, memory, and mood (26).…”

“…Some studies suggest that oral ingestion of 8 -THC or 9 -THC may be more potent than other routes of administration (29,30) due to the metabolite 11-OH-THC produced from first-pass metabolism. 11-OH-THC has been shown in rat models to have a higher binding affinity for CB 1 receptors, which are associated with the perceived high (11,31).…”

“…Delta-8-THC is an isomer of delta-9-THC, synthetically formed by the cyclization of CBD to move the double bond from the 9th position to the 8th position within the cyclohexane ring (11), as shown in Figure 1. This changes the molecule to an officially non-controlled substance because it is no longer structurally 9 -THC, despite being a psychoactive substance of the same molecular weight.…”

The Origin and Biomedical Relevance of Cannabigerol

“…Phytocannabinoids are a group of 21-carbon terpenophenolic compounds [ 19 ]. To date, more than 120 phytocannabinoids have been isolated from cannabis, including two compounds, (−)-trans-Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and (−)-trans-Δ 8 -tetrahydrocannabinol (Δ 8 -THC), which produce the characteristic psychotropic effect by binding to cannabinoid receptors [ 20 ]. Another group, containing 16 of the phytocannabinoids, are cannabigerol and its derivatives [ 21 ].…”