Δ-8-Tetrahydrocannabinol

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Contents

Δ-8-Tetrahydrocannabinol
Delta-8-THC Structure.svg
D8-THC.png
Names
IUPAC name
6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol
Other names
  • Δ8-THC
  • Δ-8-THC
  • Δ8-THC
  • δ-8-THC
  • (−)-trans-Δ8-tetrahydrocannabinol
  • (−)-trans-Δ8-tetrahydrocannabinol
  • Δ6-THC
  • Δ-6-THC
  • Δ6-THC
  • Δ1(6)-THC
  • (−)-trans-Δ6-tetrahydrocannabinol
  • (−)-trans-Δ6-tetrahydrocannabinol
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.165.076 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C21H30O2/c1-5-6-7-8-15-12-18(22)20-16-11-14(2)9-10-17(16)21(3,4)23-19(20)13-15/h9,12-13,16-17,22H,5-8,10-11H2,1-4H3
    Key: HCAWPGARWVBULJ-UHFFFAOYSA-N
  • CCCCCC1=CC(=C2C3CC(=CCC3C(OC2=C1)(C)C)C)O
Properties
C21H30O2
Molar mass 314.5 g/mol
Density 1.0±0.1 g/cm3
Boiling point 383.5±42.0 °C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Δ-8-tetrahydrocannabinol (delta-8-THC, [a] Δ8-THC) is a possibly psychoactive cannabinoid found in the cannabis plant. [1] It is an isomer of delta-9-tetrahydrocannabinol (delta-9-THC, Δ9-THC), the compound commonly known as 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. [2]

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 partially synthesized from industrial hemp 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, [3] 11% of US twelfth graders have used ∆8-THC over the past 12 months.

Effects

∆8-THC is moderately less potent than Δ9-THC. [4] [5] This means that while its effects are similar to that of Δ9-THC, 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. [6] The same study reported that the median lethal dose of ∆8-THC in rats was comparable to that of ∆9-THC. [6] Both isomers of THC have been found to cause a transient increase in blood pressure in rats, [7] although the effects of cannabinoids on the cardiovascular system are complex. [8] 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. [9] [10]

Production

∆8-THC is typically synthesized from cannabidiol extracted from hemp, [11] as the natural quantities of ∆8-THC found in hemp are low. This is called semisynthesis or partial synthesis. The reaction often yields a mixture that contains other cannabinoids and unknown reaction by-products. As a result, most products sold as ∆8-THC are not actually pure ∆8-THC. [11] Little is known about the identity and the health effects of the impurities. [11] Some manufacturers of ∆8-THC may use household chemicals in the synthesis process, potentially introducing harmful contaminants. [12] In that sense, ∆8-THC can be called a "semisynthetic phytocannabinoid" or semisynthetic endocannabinoid, as it is obtained by (partial) chemical synthesis. It is not to be confused with the term synthetic cannabinoid, however.

Safety

As of 2022, the safety profile, including risks of psychosis and addiction after regular, long-term ∆8-THC use was unknown. [13]

As of 2022, there have been at least 104 adverse event reports made regarding ∆8-THC, [12] and at least two deaths associated with ∆8-THC products. [14] US national poison control centers received 2,362 exposure cases of delta-8 THC products between 1 January 2021, and 28 February 2022; 58% of these exposures involved adults, and 70% thought they required medical care. [12]

Pharmacology

Mechanism of action

The pharmacodynamic profile of ∆8-THC is similar to that of ∆9-THC. [4] [5] 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. [15] [16] [17]

Pharmacokinetics

The pharmacokinetic profile of ∆8-THC is also similar to that of ∆9-THC. [4] [5] 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). [18] [19] 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). [19] [20] 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), [19] [20] which is then excreted in the urine. [21] [22]

Physical and chemical properties

∆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. [4] 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.

[?] -THC has a double bond (a) between the carbon atoms labeled 8 and 9. Delta-8-THC.jpg
∆ -THC has a double bond (a) between the carbon atoms labeled 8 and 9.
[?] -THC has a double bond (a) between the carbon atoms labeled 9 and 10. Delta-9-THC.jpg
∆ -THC has a double bond (a) between the carbon atoms labeled 9 and 10.

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. [15] Like other cannabinoids, ∆8-THC is very lipophilic (log P = 7.4 [23] ). It is an extremely viscous, colorless oil at room temperature. [24]

While ∆8-THC is naturally found in plants of the Cannabis genus, [1] this compound can also be produced in an industrial or laboratory setting by acid-catalyzed isomerization of cannabidiol. [25] [26] [27] Solvents that may be used during this process include dichloromethane, toluene, and hexane. [27] 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. [27] 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. [28]

The ongoing controversy regarding the legal status of ∆8-THC in the U.S. is complicated by chemical nomenclature. 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. [29] 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. [16] They are less potent than many synthetic cannabinoids. [30] 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 agonist on specific CB1 receptors located in the hippocampus section of the brain. [31] Furthermore, the synthetic cannabinoid EG-018 acts as a partial agonist. [32] The classical cannabinoid structure is that of a dibenzopyran structure. This group includes THC. THC interacts with a different spot inside of the CB1 receptor than synthetic cannabinoid such JWH-018. This may explain the differences in adverse reactions to synthetic cannabinoids. [33]

History

The partial synthesis of ∆8-THC was published in 1941 by Roger Adams and colleagues at the University of Illinois. [34] In 1942, the same research group studied its physiological and psychoactive effects after oral dosing in human volunteers. [35] Total syntheses of ∆8-THC were achieved by 1965. [36] In 1966, the chemical structure of ∆8-THC isolated from cannabis was characterized using modern methods by Richard L. Hively, William A. Mosher, and Friedrich W. Hoffmann at the University of Delaware. [37] A stereospecific synthesis of ∆8-THC from olivetol and verbenol was reported by Raphael Mechoulam and colleagues at the Weizmann Institute of Science in 1967. [38] ∆8-THC was often referred to as "Delta-6-THC" (Δ6-THC) in early scientific literature, but this name is no longer conventional among most authors. [39]

United States

Federal law

In 1937, ∆9-THC was effectively made illegal with the passage of the Marihuana Tax Act, which made growing cannabis require a tax stamp. In 1970, the Marihuana Tax Act was superseded and replaced with the Controlled Substances Act (or CSA). [40] The CSA replaced "[a] patchwork of regulatory, revenue, and criminal measures" [41] relating to drug control with a "comprehensive regulatory regime". [42]

As of 2024, 24 states have legalized recreational marijuana, with others having reduced penalties. [43] Section 10113 of the Agriculture Improvement Act of 2018 (2018 Farm Bill), amended the Agricultural Marketing Act of 1946, and added a new subtitle G related to hemp. [44] Under section 297A of that subtitle, is the definition of hemp as used in federal law:

The term "hemp" means the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.

— Section 297A of the Agricultural Marketing Act of 1946 (7 U.S.C. 1639o)

In October 2020, the DEA Interim Final Rule [45] addressed synthetic cannabinoids. Some believed that this also applied to ∆8-THC products and other hemp derivatives addressed by the Farm Bill. [46]

Despite claims of legality by manufacturers, independent testing of products from retail has often revealed significant levels of ∆9-THC. Many of these levels are well above one legal threshold. [47] [48] [49] [50]

FDA

∆8-THC has not been evaluated or approved by the FDA for safe use in any context. [51] The FDA has taken action against businesses that have illegally marketed ∆8-THC for therapeutic use. [51] The FDA has also taken action against businesses that sold ∆8-THC in forms that closely resemble (typically non-psychoactive) food products such as chips or cookies. [51]

Individual states

While many jurisdictions have not arrested significant numbers of people for ∆8-THC, some people have been arrested and charged, leading to confusion as to its legal status in those states. [52] [53] [54] [55]

In 2021, one store owner in Menomonee Falls, Wisconsin was facing a sentence of up to 50 years for allegedly selling ∆8-THC products with illegal amounts of ∆9-THC. [56] Other raids and arrests have happened due to the ∆9-THC content of these products in North Carolina, and Texas, among other places. [57] [58] [59] In 2022, Catoosa County, Georgia Sheriff Sisk announced to prosecute stores distributing ∆8-THC with non-compliant ∆9-THC levels: "The products the sheriffs office has purchased and tested all contain significant levels of ∆9. [We have the] evidence needed to move forward with prosecution and seizures." [60] There are also issues related to incidental manufacture of ∆9 THC, as ∆9 is produced as an intermediate product in the process of acid catalyzed ring closure of cannabidiol. [61]

∆8-THC products have been sold in licensed, regulated recreational cannabis and medical cannabis industries within the United States including California and Pennsylvania's licensed, regulated medical cannabis system since 2020. Both Michigan and the state of Oregon have regulated Delta-8-THC products sold under their regulated cannabis system. [62]

Federal litigation

The first case before a United States courts of appeals relating to the legality of ∆8-THC was AK Futures v. Boyd St. Distro (2022), a patent lawsuit where the 9th Circuit found that ∆8-THC products qualified for patent protection. The legality of ∆8-THC was addressed briefly in dicta, where the court held the products subject of the litigation were lawful. [63]

The ruling of the 9th Circuit is only binding to the states within that circuit, and other federal courts have reached differing conclusions. At the federal district court level, the United States District Court for the Western District of Arkansas reached a similar conclusion to the 9th Circuit, [64] yet the United States District Court for the District of Wyoming found that ∆8-THC was not legal and the 2018 Farm Bill did not imply for preemption of state laws. [65]

There are multiple other court decisions pertaining to the legality of Delta-8 THC. While AK Futures LLC vs Boyd Street Distro, LLC (2022) was one of the earliest decisions made in a federal court, stating "On the available record, the delta-8 THC in AK Futures’ e-cigarette liquid appears to fit comfortably within the statutory definition of “hemp.”". [66] United States vs. Rice, however, came to the opposite conclusion, "In short, Delta-8 remains a controlled substance. Although Delta-10 was not directly referenced in the DEA’s letter, there is no basis (in the record before the court) to believe that the DEA will treat Delta-10 in a different manner." [67] . United States vs. Plancarte also states, "There is no legal D9-THC threshold for synthetic derivatives of THC. A gray area is whether Delta-8 THC is legal; it probably is when it occurs naturally in hemp, but this is not clear." [68]

Economics

Common Delta-8 products range from bulk quantities of unrefined distillate to prepared cannabis edibles and atomizer cartridges. [69] [70] In the US, they are usually marketed as legal alternatives to their ∆9-THC counterparts. [71]

∆8-THC products partially synthesized from industrial hemp experienced a rise in popularity in the US following the passage of the 2018 Farm Bill. [72] This led to it being sold by a diverse range of retailers, including head shops, smoke shops, vape shops, dispensaries, gas stations, and convenience stores. [73] [74]

In March 2024, a study of self-reported prevalence of Δ8-THC use among US twelfth graders was published: Of those reporting Δ8-THC use, 35% had used it at least 10 times in the past 12 months. Consumption was lower in Western than Southern and in states, where Δ8-THC was regulated versus not regulated. [75]

Research

Although it is a minor constituent of cannabis, no large clinical studies have been conducted on delta-8-THC alone as of 2022. [76] One study (ongoing as of November 2023) is focused on determining the degree of pharmacologic and pharmacokinetic similarity between ∆8-THC and ∆9-THC. [77]

Related Research Articles

<span class="mw-page-title-main">Tetrahydrocannabinol</span> Psychoactive component of cannabis

Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. It is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term THC usually refers to the delta-9-THC isomer with chemical name (−)-trans-Δ9-tetrahydrocannabinol. It is a colorless oil.

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 100 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.

<span class="mw-page-title-main">Cannabinol</span> Naturally-occurring cannabinoid

Cannabinol (CBN) is a mildly psychoactive phytocannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors. This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS).

<span class="mw-page-title-main">Cannabidiol</span> Phytocannabinoid discovered in 1940

Cannabidiol (CBD) is a phytocannabinoid, one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. Medically, it is an anticonvulsant used to treat multiple forms of epilepsy. It was discovered in 1940 and, as of 2024 clinical research on CBD included studies related to the treatment of anxiety, addiction, psychosis, movement disorders, and pain, but there is insufficient high-quality evidence that CBD is effective for these conditions. CBD is sold as an herbal dietary supplement and promoted with yet unproven claims of particular therapeutic effects.

<span class="mw-page-title-main">Tetrahydrocannabivarin</span> Homologue of tetrahydrocannabinol

Tetrahydrocannabivarin is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of pentyl (5-carbon), making it non-psychoactive in lower doses. It has been shown to exhibit neuroprotective activity, appetite suppression, glycemic control and reduced side effects compared to THC, making it a potential treatment for management of obesity and diabetes. THCV was studied by Roger Adams as early as 1942.

<span class="mw-page-title-main">Parahexyl</span> Synthetic homologue of THC

Parahexyl, also known as synhexyl, is a synthetic homologue of tetrahydrocannabinol (THC) which was invented in 1941 during attempts to elucidate the structure of Δ9-THC, one of the active components of cannabis.

<span class="mw-page-title-main">THC-O-acetate</span> Acetate ester of tetrahydrocannabinol (THC)

THC-O-acetate is the acetate ester of THC. The term THC-O-acetate and its variations are commonly used for two types of the substance, dependent on which cannabinoid it is synthesized from. The difference between Δ8-THC and Δ9-THC is bond placement on the cyclohexene ring.

<span class="mw-page-title-main">11-Hydroxy-THC</span> Active metabolite of Δ9-THC

11-Hydroxy-Δ9-tetrahydrocannabinol, usually referred to as 11-hydroxy-THC is the main active metabolite of tetrahydrocannabinol (THC), which is formed in the body after Δ9-THC is consumed.

<span class="mw-page-title-main">Cannabigerol</span> Minor cannabinoid

Cannabigerol (CBG) is a non-psychoactive cannabinoid and minor constituent of cannabis. It is one of more than 120 identified cannabinoids found in the plant genus Cannabis. The compound is the decarboxylated form of cannabigerolic acid (CBGA), the parent molecule from which other cannabinoids are biosynthesized.

<span class="mw-page-title-main">Tetrahydrocannabutol</span> Chemical compound

Δ9-Tetrahydrocannabutol is a phytocannabinoid found in cannabis that is a homologue of tetrahydrocannabinol (THC), the main active component of Cannabis. Structurally, they are only different by the pentyl side chain being replaced by a butyl side chain. THCB was studied by Roger Adams as early as 1942

<span class="mw-page-title-main">Tetrahydrocannabinolic acid</span> THC precursor

Tetrahydrocannabinolic acid is a precursor of tetrahydrocannabinol (THC), an active component of cannabis.

<span class="mw-page-title-main">8,9-Dihydrocannabidiol</span> Chemical compound

8,9-Dihydrocannabidiol is a synthetic cannabinoid that is closely related to cannabidiol (CBD) itself. that was first synthesized by Alexander R. Todd in 1940 derived from the catalytic hydrogenation of cannabidiol.

<span class="mw-page-title-main">Tetrahydrocannabiphorol</span> Cannabinoid agonist compound

Tetrahydrocannabiphorol (THCP) is a potent phytocannabinoid, a CB1 and CB2 receptor agonist which was known as a synthetic homologue of tetrahydrocannabinol (THC), but for the first time in 2019 was isolated as a natural product in trace amounts from Cannabis sativa.

<span class="mw-page-title-main">Δ-3-Tetrahydrocannabinol</span> Chemical compound

Δ-3-Tetrahydrocannabinol is a synthetic isomer of tetrahydrocannabinol (THC) developed during the original research in the 1940s to develop synthetic routes to the natural products Δ8-THC and Δ9-THC found in the cannabis. While the normal trans configuration of THC is in this case flattened by the double bond, it still has two enantiomers as the 9-methyl group can exist in an (R) or (S) conformation. The (S) enantiomer has similar effects to Δ9-THC though with several times lower potency, while the (R) enantiomer is many times less active or inactive, depending on the assay used. It has been identified as a component of vaping liquid products.

<span class="mw-page-title-main">Hexahydrocannabinol</span> Hydrogenated derivative of THC

Hexahydrocannabinol (HHC) is a hydrogenated derivative of tetrahydrocannabinol (THC). It is a naturally occurring phytocannabinoid that has rarely been identified as a trace component in Cannabis sativa, but can also be produced synthetically by firstly acid cyclization of cannabidiol and then hydrogenation of tetrahydrocannabinol. The synthesis and bioactivity of HHC was first reported in 1940 by Roger Adams.

<span class="mw-page-title-main">11-Hydroxy-Δ-8-THC</span> Metabolite of delta-8-THC

11-Hydroxy-Δ-8-tetrahydrocannabinol is an active metabolite of Δ8-THC, a psychoactive cannabinoid found in small amounts in cannabis. It is an isomer of 11-OH-Δ9-THC, and is produced via the same metabolic pathway. It was the first cannabinoid metabolite discovered in 1970.

<span class="mw-page-title-main">11-Hydroxyhexahydrocannabinol</span> Chemical compound

11-Hydroxyhexahydrocannabinol is an active metabolite of tetrahydrocannabinol (THC) and a metabolite of the trace cannabinoid hexahydrocannabinol (HHC).

<span class="mw-page-title-main">Tetrahydrocannabihexol</span> Chemical compound

Tetrahydrocannabihexol is a phytocannabinoid, the hexyl homologue of tetrahydrocannabinol (THC) which was first isolated from Cannabis plant material in 2020 along with the corresponding hexyl homologue of cannabidiol, though it had been known for several decades prior to this as an isomer of the synthetic cannabinoid parahexyl. Another isomer Δ8-THCH is also known as a synthetic cannabinoid under the code number JWH-124, though it is unclear whether this occurs naturally in Cannabis, but likely is due to Δ8-THC itself being a degraded form of Δ9-THC. THC-Hexyl can be synthesized from 4-hexylresorcinol and was studied by Roger Adams as early as 1942.

<span class="mw-page-title-main">JWH-138</span> Chemical compound

JWH-138 (THC-Octyl, Δ8-THC-C8) is a synthetic cannabinoid first synthesized by Roger Adams and studied heavily by John W. Huffman, with a Ki of 8.5nM at the CB1 cannabinoid receptor. THC-Octyl and its hydrogenated analog HHC-Octyl was synthesized and studied by Roger Adams as early as 1942.

Conversion of cannabidiol (CBD) to tetrahydrocannabinol (THC) can occur through a ring-closing reaction. This cyclization can be acid-catalyzed or brought about by heating.

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Notes

  1. ↑ Commonly called "delta-8 THC", or just "delta 8".
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