Tetrahydrocannabinolic acid (THCA, 2-COOH-THC;

conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...

tetrahydrocannabinolate) is a precursor of

tetrahydrocannabinol Tetrahydrocannabinol (THC) 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' ...

(THC), an active component of

cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: '' Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternative ...

. 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. THCA is often the majority constituent in cannabis resin concentrates, such as hashish and

hash oil Hash oil or cannabis oil, is an oleoresin obtained by the extraction of cannabis or hashish. It is a cannabis concentrate containing many of its resins and terpenes – in particular, tetrahydrocannabinol (THC), cannabidiol (CBD), and other ...

, when prepared from high-THC cannabis fresh plant material, frequently comprising between 50% and 90% by weight.

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. 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 A bong (also known as a water pipe) is a filtration device generally used for smoking cannabis, tobacco, or other herbal substances. In the bong shown in the photo, the gas flows from the lower port on the left to the upper port on the right. ...

or dab rig (device used for vaporizing

). These methods convert the THCA to THC and so are used for their psychoactive benefits. THCA is also sometimes encapsulated and taken as a supplement for a variety of illnesses, although there are currently no established medical applications.

Pharmacological effects

Conversion of THCA to

THC Tetrahydrocannabinol (THC) 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' ...

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' appears to be very limited, giving it only very slight efficacy as a prodrug for THC. In receptor binding assays it is

promiscuous Promiscuity is the practice of engaging in sexual activity frequently with different partners or being indiscriminate in the choice of sexual partners. The term can carry a moral judgment. A common example of behavior viewed as promiscuous by ma ...

; there are papers showing it being an inhibitor of PC-PLC,

COX-1 Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of two cyclooxygenases. ...

COX-2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...

TRPM8 Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the ''TRPM8'' gene. The TRPM8 channel is the primary molecular ...

TRPV1 The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the ''TRPV1'' gene. It was the first isolated member of th ...

, FAAH, NAAA, MGL, and DGLα, and an inhibitor of

anandamide Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid r ...

transport, as well as an agonist of

TRPA1 Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Wasabi Receptor, is a protein that in humans is encoded by the ''TRPA1'' (and in mice and rats by the ''Trpa1' ...

and

TRPV2 TRPV is a family of transient receptor potential cation channels (TRP channels) in animals. All TRPVs are highly calcium selective. TRP channels are a large group of ion channels consisting of six protein families, located mostly on the plasma ...

. Many THCA

reagents In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...

used in biochemistry experiments are contaminated with THC due to THCA's instability. A study found THCA and unheated ''

Cannabis sativa ''Cannabis sativa'' is an annual herbaceous flowering plant indigenous to Eastern Asia, but now of cosmopolitan distribution due to widespread cultivation. It has been cultivated throughout recorded history, used as a source of industrial fibe ...

extracts An extract is a substance made by extracting a part of a raw material, often by using a solvent such as ethanol, oil or water. Extracts may be sold as tinctures, absolutes or in powder form. The aromatic principles of many spices, nuts, ...

exert immuno-modulating effect, not mediated by the

cannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

CB1 and CB2 receptor coupled pathways like THC. THCA were able to inhibit the tumor necrosis factor alpha (

TNF-alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

) levels in U937 macrophages and peripheral

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...

macrophages, an inhibition that persisted over a longer period of time, whereas after prolonged exposure time THC and heated extract tend to induce the TNF-alpha level. THCA and THC show distinct effects on

phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybea ...

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 pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...

s. The

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

activity of ''C. sativa'' extracts was studied on three lines of

epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...

and on colon tissue in a model of inflammatory bowel diseases (IBDs), where ''C. sativa'' flowers were extracted with

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

, 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 Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extrace ...

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 G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the ''GPR55'' gene. GPR55, along with GPR119 and GPR18, have been implicated as novel cannabinoid receptors. History GPR55 was id ...

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. THCA binds to and activates

PPARγ Peroxisome proliferator- activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a tran ...

with higher potency than its decarboxylated products. THCA show a similar

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

as THC in humans, producing 11- OH-THCA and 11-nor-9-

carboxy In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

-THCA. Although the decarboxylation of THCA to THC was assumed to be complete, which means that no THCA should be detectable in

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

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.

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. The crystal structures of both THCA-A (colourless prisms, orthorhombic P2₁2₁2₁) and THCA-B (also colourless prisms, orthorhombic P2₁2₁2₁) have been reported. In the past THCA was thought to be formed in plants by

cyclization A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...

of cannabidiolic acid but due to studies in the late 1990s it became apparent that its precursor is

cannabigerolic acid Cannabigerolic acid (CBGA) is the acidic form of cannabigerol (CBG). It is a dihydroxybenzoic acid and olivetolic acid in which the hydrogen at position 3 is substituted by a geranyl group. It is a biosynthetic precursor to Delta-9-tetrahydrocann ...

, which goes through oxidocyclization through the actions of the enzyme THCA-synthase. It is unstable, and slowly decarboxylates into THC during storage, and the THC itself slowly degrades to CBN, found with potential

immunosuppressive Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...

and

activities. 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.

Legal status

THCA is not scheduled by the

United Nations The United Nations (UN) is an intergovernmental organization whose stated purposes are to maintain international peace and security, develop friendly relations among nations, achieve international cooperation, and be a centre for harmoniz ...

' Convention on Psychotropic Substances.Convention on Psychotropic Substances, 1971
/ref>

United States

THCA is not scheduled at the federal level in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...

, but it is possible that THCA could legally be considered an

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

of THC and sales or possession could potentially be prosecuted under the

Federal Analogue Act The Federal Analogue Act, , is a section of the United States Controlled Substances Act passed in 1986 which allows any chemical "substantially similar" to a controlled substance listed in Schedule I or II to be treated as if it were listed in ...

.Erowid Analog Law Vault : Federal Controlled Substance Analogue Act Summary
/ref> 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.

References