Tetrahydrocannabinolic acid

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Tetrahydrocannabinolic acid
Tetrahydrocannabinolicacid.svg
Tetrahydrocannabinolic acid molecule ball.png
Clinical data
Other names2-Carboxy-THC; THCA, 2-COOH-THC
ATC code
  • none
Identifiers
  • (6aR,10aR)-1-Hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxylic acid
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.216.805 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H30O4
Molar mass 358.478 g·mol−1
3D model (JSmol)
  • CCCCCC1=CC2=C([C@@H]3C=C(CC[C@H]3C(O2)(C)C)C)C(=C1C(=O)O)O

Tetrahydrocannabinolic acid (THCA, 2-COOH-THC; conjugate base tetrahydrocannabinolate) is a precursor of tetrahydrocannabinol (THC), an active component of cannabis. [1]

Contents

THCA is found in variable quantities in fresh, undried cannabis, but is progressively decarboxylated to THC with drying, and especially under intense heating such as when cannabis is smoked or cooked into cannabis edibles. [1]

Uses

THCA is rarely directly used, but its presence is commonly analyzed when cannabis or hemp-based products are screened for THC; some countries require that it be measured in such screens. [2] [3] : 32 

THCA in its isolated form is available for purchase in select medical and recreational cannabis dispensaries in the form of a white crystalline powder. It can be smoked or vaporized in typical smoking devices, such as a bong or dab rig (device used for vaporizing hash oil). These methods convert the THCA to THC and so are used for their psychoactive effects. THCA is also sometimes encapsulated and taken as a supplement for a variety of illnesses, although there are currently no established medical applications. [4]

Pharmacological effects

Conversion of THCA to THC in vivo appears to be very limited, giving it only very slight efficacy as a prodrug for THC. [1] In receptor binding assays it is promiscuous; [5] there are papers showing it being an inhibitor of PC-PLC, COX-1, COX-2, TRPM8, TRPV1, FAAH, NAAA, MGL, and DGLα, and an inhibitor of anandamide transport, as well as an agonist of TRPA1 and TRPV2. [1] Many THCA reagents used in biochemistry experiments are contaminated with THC due to THCA's instability. [5]

A study found THCA and unheated Cannabis sativa extracts exert immuno-modulating effect, not mediated by the cannabinoid CB1 and CB2 receptor coupled pathways like THC. THCA was able to inhibit the tumor necrosis factor alpha (TNFα) levels in U937 macrophages and peripheral blood macrophages, an inhibition that persisted over a longer period of time, whereas after prolonged exposure time THC and heated extract tend to induce the TNFα level. THCA and THC show distinct effects on phosphatidylcholine specific phospholipase C (PC-PLC) activity, as THCA and unheated extracts inhibit the PC-PLC activity in a dose-dependent manner, but THC only induced PC-PLC activity at high concentrations, suggest THCA and THC exert their immuno-modulating effects via different metabolic pathways. [6]

The anti-inflammatory activity of C. sativa extracts was studied on three lines of epithelial cells and on colon tissue in a model of inflammatory bowel diseases (IBDs), where C. sativa flowers were extracted with ethanol, found the anti-inflammatory activity of Cannabis extracts derives from THCA present in fraction 7 (F7) of the extract. However, all fractions of C. sativa at a certain combination of concentrations show a significant increased cytotoxic activity and suppress COX-2 and MMP9 gene expression in both cell culture and colon tissue, suggest the anti-inflammatory activity of Cannabis extracts on colon epithelial cells derives from a fraction of the extract that contains THCA, and is mediated, at least partially, via GPR55 receptor. The cytotoxic activity of the C. sativa extract was increased by combining all fractions at a certain combination of concentrations and was partially affected by CB2 receptor antagonist that increased cell proliferation. It is suggested that in a nonpsychoactive treatment for IBD, THCA should be used rather than CBD. [7]

THCA binds to and activates PPARγ with higher potency than its decarboxylated products. [8]

THCA shows a similar metabolism to THC in humans, producing 11-OH-THCA and 11-nor-9-carboxy-THCA. [9] Although the decarboxylation of THCA to THC was assumed to be complete, which means that no THCA should be detectable in urine and blood serum of cannabis consumers, it is found in the urine and blood serum samples collected from police controls of drivers, suspected for driving under the influence of drugs (DUID). THCA was detected in the urine and blood serum samples of several cannabis consumers in concentrations of up to 10.8 ng/mL in urine and 14.8 ng/mL in serum. The concentration of THCA was below the THC concentration in most serum samples, resulting in molar ratios of THCA/THC of approximately 5.0–18.6%. Where a short elapsed time between the last intake and blood sampling was assumed, the molar ratio was 18.6% in the serum. [10]

Chemistry

It has two isomers, THCA-A, in which the carboxylic acid group is in the 1 position, between the hydroxy group and the carbon chain, and THCA-B, in which the carboxylic acid group is in the 3 position, following the carbon chain. [11] : 20  The crystal structures of both THCA-A (colourless prisms, orthorhombic P212121) and THCA-B (also colourless prisms, orthorhombic P212121) have been reported. [12] [13]

In the past THCA was thought to be formed in plants by cyclization of cannabidiolic acid but due to studies in the late 1990s it became apparent that its precursor is cannabigerolic acid, which goes through oxidocyclization through the actions of the enzyme THCA-synthase. [3] : 14 

It is unstable, and slowly decarboxylates into THC during storage, and the THC itself slowly degrades to CBN, which has potential immunosuppressive and anti-inflammatory activities. [1] When heated or burned, as when cannabis is smoked or included in baked goods, the decarboxylation is rapid but not complete; THCA is detectable in people who smoke or otherwise consume cannabis. [1]

THCA is not scheduled by the United Nations' Convention on Psychotropic Substances. [14]

United States

THCA is not scheduled at the federal level in the United States, [15] but it is possible that THCA could legally be considered an analog of THC and sales or possession could potentially be prosecuted under the Federal Analogue Act. [16] In practice, because THCA spontaneously decarboxylates to form THC, no real sample of purified THCA will be completely free of THC. Thus, any laboratory analysis of THCA using any technique involving significant heat will generate THC in the handling and analytical process. Further, both the Farm Bill and the USDA specify that analytical testing of samples for total THC must use "post-decarboxylation or other similarly reliable methods". [17] [18]

See also

Related Research Articles

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

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

Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carboxylation, the addition of CO2 to a compound. Enzymes that catalyze decarboxylations are called decarboxylases or, the more formal term, carboxy-lyases (EC number 4.1.1).

<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 113 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 cannabinoid 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">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">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 one of more than 120 identified cannabinoid compounds found in the plant genus Cannabis. Cannabigerol is the decarboxylated form of cannabigerolic acid, the parent molecule from which other cannabinoids are synthesized.

<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">11-Nor-9-carboxy-THC</span> Main secondary metabolite of THC

11-Nor-9-carboxy-Δ9-tetrahydrocannabinol, often referred to as 11-nor-9-carboxy-THC or THC-11-oic acid, is the main secondary metabolite of tetrahydrocannabinol (THC) which is formed in the body after cannabis is consumed.

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

Cannabichromene (CBC), also called cannabichrome, cannanbichromene, pentylcannabichromene or cannabinochromene, exhibits anti-inflammatory properties in vitro, which may, theoretically, contribute to cannabis analgesic effects. It is a phytocannabinoid, one of the hundreds of cannabinoids found in the Cannabis plant. It bears structural similarity to the other natural cannabinoids, including tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol (CBD), and cannabinol (CBN), among others. CBC and cannabinols are present in cannabis. It is not scheduled by the Convention on Psychotropic Substances.

<span class="mw-page-title-main">Cannabis consumption</span> Methods of marijuana administration

Cannabis consumption refers to the variety of ways cannabis is consumed, among which inhalation and ingestion are most common. All consumption methods involve heating the plant's THCA to decarboxylate it into THC, either at the time of consumption or during preparation. Salves and absorption through the skin (transdermal) are increasingly common in medical uses, both of CBD, THC, and other cannabinoids. Each method leads to subtly different psychoactive effects due to the THC and other chemicals being activated, and then consumed through different administration routes. It is generally considered that smoking, which includes combustion toxins, comes on quickly but lasts for a short period of time, while eating delays the onset of effect but the duration of effect is typically longer. In a 2007 ScienceDaily report of research conducted at the University of California–San Francisco, researchers reported that vaporizer users experience the same biological effect, but without the toxins associated with smoking. Δ9-THC is the primary component when inhaled, but when eaten the liver converts this to the more psychoactive 11-hydroxy-THC form.

<i>N</i>-Acylethanolamine Class of chemical compounds

An N-acylethanolamine (NAE) is a type of fatty acid amide where one of several types of acyl groups is linked to the nitrogen atom of ethanolamine, and highly metabolic formed by intake of essential fatty acids through diet by 20:4, n-6 and 22:6, n-3 fatty acids, and when the body is physically and psychologically active,. The endocannabinoid signaling system (ECS) is the major pathway by which NAEs exerts its physiological effects in animal cells with similarities in plants, and the metabolism of NAEs is an integral part of the ECS, a very ancient signaling system, being clearly present from the divergence of the protostomian/deuterostomian, and even further back in time, to the very beginning of bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmic membranes. Fatty acid metabolites with affinity for CB receptors are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA), by brown algae which diverged about 1500 MYA, by sponges, which diverged from eumetazoans about 930 MYA, and a lineages that predate the evolution of CB receptors, as CB1 – CB2 duplication event may have occurred prior to the lophotrochozoan-deuterostome divergence 590 MYA. Fatty acid amide hydrolase (FAAH) evolved relatively recently, either after the evolution of fish 400 MYA, or after the appearance of mammals 300 MYA, but after the appearance of vertebrates. Linking FAAH, vanilloid receptors (VR1) and anandamide implies a coupling among the remaining ‘‘older’’ parts of the endocannabinoid system, monoglyceride lipase (MGL), CB receptors, that evolved prior to the metazoan–bilaterian divergence, but were secondarily lost in the Ecdysozoa, and 2-Arachidonoylglycerol (2-AG).

<span class="mw-page-title-main">Dronabinol</span> Generic name of Δ9-THC in medicine

Dronabinol (INN), also known under the trade names Marinol and Syndros, is a generic name for the molecule of delta-9-tetrahydrocannabinol in the pharmaceutical context. It has indications as an appetite stimulant, antiemetic, and sleep apnea reliever and is approved by the FDA as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting only.

<span class="mw-page-title-main">Tetrahydrocannabinolic acid synthase</span> Enzyme

Tetrahydrocannabinolic acid (THCA) synthase is an enzyme responsible for catalyzing the formation of THCA from cannabigerolic acid (CBGA). THCA is the direct precursor of tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, which is produced from various strains of Cannabis sativa. Therefore, THCA synthase is considered to be a key enzyme controlling cannabis psychoactivity. Polymorphisms of THCA synthase result in varying levels of THC in Cannabis plants, resulting in "drug-type" and "fiber-type" C. sativa varieties.

The entourage effect is a hypothesis that cannabis compounds other than tetrahydrocannabinol (THC) act synergistically with it to modulate the overall psychoactive effects of the plant.

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

Tetrahydrocannabiphorol (THCP) is a potent phytocannabinoid, a CB1 and CB2 agonist which was known as a synthetic homologue of THC, but for the first time in 2019 was isolated as a natural product in trace amounts from Cannabis sativa. It is structurally similar to Δ9-THC, the main active component of cannabis, but with the pentyl side chain extended to heptyl. Since it has a longer side chain, its cannabinoid effects are "far higher than Δ9-THC itself." Tetrahydrocannabiphorol has a reported binding affinity of 1.2 nM at CB1, approximately 33 times that of Δ9-THC (40 nM at CB1).

<span class="mw-page-title-main">Δ-8-Tetrahydrocannabinol</span> Isomer of tetrahydrocannabinol

Δ-8-tetrahydrocannabinol is a psychoactive cannabinoid found in the Cannabis plant. It is an isomer of delta-9-tetrahydrocannabinol, the compound commonly known as THC, with which it co-occurs in hemp; natural quantities of ∆8-THC found in hemp are low.

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

Δ9-Tetrahydrocannabiorcol (Δ9-THCC, (C1)-Δ9-THC) is a phytocannabinoid found in Cannabis pollen. It is a homologue of THC and THCV with the alkyl side chain replaced by a smaller methyl group. Unlike THC and THCV, THCC has negligible affinity for the CB1 and CB2 cannabinoid receptors because of the smaller methyl group and does not have psychoactive effects as a result, but conversely it is significantly more potent than THC or THCV as an activator of the TRPA1 calcium channel which plays an important role in pain perception, and it has been shown to produce analgesic effects via activation of spinal TRPA1 channels. THCC was studied by Roger Adams as early as 1942.

Cannabinoids are compounds found in the cannabis plant or synthetic compounds that can interact with the endocannabinoid system. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (Delta-9-THC), the primary intoxicating compound in cannabis. Cannabidiol (CBD) is another major constituent of some cannabis plants. At least 113 distinct cannabinoids have been isolated from cannabis.

References

  1. 1 2 3 4 5 6 Moreno-Sanz G (2016). "Can You Pass the Acid Test? Critical Review and Novel Therapeutic Perspectives of Δ9-Tetrahydrocannabinolic Acid A". Cannabis and Cannabinoid Research. 1 (1): 124–130. doi:10.1089/can.2016.0008. PMC   5549534 . PMID   28861488.
  2. ↑ Dussy FE, Hamberg C, Luginbühl M, Schwerzmann T, Briellmann TA (April 2005). "Isolation of Delta9-THCA-A from hemp and analytical aspects concerning the determination of Delta9-THC in cannabis products". Forensic Science International. 149 (1): 3–10. doi:10.1016/j.forsciint.2004.05.015. PMID   15734104.
  3. 1 2 United Nations Office on Drugs Crime (2009). Recommended methods for the identification and analysis of cannabis and cannabis products [electronic resource] : manual for use by national drug testing laboratories (PDF) (Rev. and updated. ed.). New York: United Nations. ISBN   978-92-1-148242-3. Archived from the original (PDF) on 29 August 2017.
  4. ↑ Hanna A (2018-01-26). "What Is THCA Crystalline?". High Times. Retrieved 2020-02-04.
  5. 1 2 McPartland JM, MacDonald C, Young M, Grant PS, Furkert DP, Glass M (2017). "Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two". Cannabis and Cannabinoid Research. 2 (1): 87–95. doi:10.1089/can.2016.0032. PMC   5510775 . PMID   28861508.
  6. ↑ Verhoeckx KC, Korthout HA, van Meeteren-Kreikamp AP, Ehlert KA, Wang M, van der Greef J, et al. (April 2006). "Unheated Cannabis sativa extracts and its major compound THC-acid have potential immuno-modulating properties not mediated by CB1 and CB2 receptor coupled pathways". International Immunopharmacology. 6 (4): 656–665. doi:10.1016/j.intimp.2005.10.002. PMID   16504929.
  7. ↑ Nallathambi R, Mazuz M, Ion A, Selvaraj G, Weininger S, Fridlender M, et al. (2017-07-01). "Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts". Cannabis and Cannabinoid Research. 2 (1): 167–182. doi:10.1089/can.2017.0027. PMC   5627671 . PMID   29082314.
  8. ↑ Nadal X, Del Río C, Casano S, Palomares B, Ferreiro-Vera C, Navarrete C, et al. (December 2017). "Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity". British Journal of Pharmacology. 174 (23): 4263–4276. doi:10.1111/bph.14019. PMC   5731255 . PMID   28853159.
  9. ↑ Huestis MA, Mazzoni I, Rabin O (November 2011). "Cannabis in sport: anti-doping perspective". Sports Medicine. 41 (11): 949–966. doi:10.2165/11591430-000000000-00000. PMC   3717337 . PMID   21985215.
  10. ↑ Jung J, Kempf J, Mahler H, Weinmann W (March 2007). "Detection of Delta9-tetrahydrocannabinolic acid A in human urine and blood serum by LC-MS/MS". Journal of Mass Spectrometry. 42 (3): 354–360. Bibcode:2007JMSp...42..354J. doi:10.1002/jms.1167. PMID   17219606.
  11. ↑ Brenneisen R (2007). "Chapter 2: Chemistry and Analysis of Phytocannabinoids and Other Cannabis Constituents". In ElSohly MA (ed.). Marijuana and the Cannabinoids. Totowa, NJ: Humana Press/Springer. pp. 17–49. ISBN   978-1-59259-947-9.
  12. ↑ Skell JM, Kahn M, Foxman BM (February 2021). "Δ9-Tetrahydrocannabinolic acid A, the precursor to Δ9-tetrahydrocannabinol (THC)". Acta Crystallographica Section C. 77 (Pt 2): 84–89. doi:10.1107/S2053229621000280. PMID   33536371. S2CID   231804940.
  13. ↑ Rosenqvist E, Ottersen T (1975). "The crystal and molecular structure of delta-9-tetrahydrocannabinolic acid b". Acta Chemica Scandinavica B. 29 (3): 379–384. doi: 10.3891/acta.chem.scand.29b-0379 . PMID   1138526.
  14. ↑ "Convention on Psychotropic Substances". 1971. Archived from the original on 2014-03-17. Retrieved 2015-09-21.
  15. ↑ "§1308.11 Schedule I." Archived from the original on 2009-08-27. Retrieved 2014-12-29.
  16. ↑ "Federal Controlled Substance Analogue Act Summary". Erowid Analog Law Vault.
  17. ↑ "7 CFR § 990.25 - Standards of performance for detecting total delta-9 tetrahydrocannabinol (THC) concentration levels". LII / Legal Information Institute. Retrieved 2023-07-05.
  18. ↑ "AGRICULTURE IMPROVEMENT ACT OF 2018" (PDF). Congress Public Law Library. Retrieved July 4, 2023.
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