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''. Alternatively ...

. THCA is found in variable quantities in fresh, undried cannabis, but is progressively

decarboxylated 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 t ...

to THC with drying, and especially under intense heating such as when cannabis is smoked or cooked into

cannabis edibles A cannabis edible, also known as a cannabis-infused food or simply an edible, is a food product (either homemade or produced commercially) that contains decarboxylated cannabinoids (cannabinoid acids converted to their orally bioactive form) f ...

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

hashish Hashish ( ar, حشيش, ()), also known as hash, "dry herb, hay" is a drug made by compressing and processing parts of the cannabis plant, typically focusing on flowering buds (female flowers) containing the most trichomes. European Monitorin ...

and hash oil, 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 hash oil). 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 ''

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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

for THC. In receptor binding assays it is promiscuous; there are papers showing it being an inhibitor of PC-PLC, COX-1, COX-2, TRPM8, TRPV1,

FAAH Fatty acid amide hydrolase or FAAH (, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993. In humans, it is encoded by the gene ''FAAH''.; Fun ...

, NAAA, MGL, and DGLα, and an inhibitor of anandamide 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 used in biochemistry experiments are contaminated with THC due to THCA's instability. A study found THCA and unheated '' Cannabis sativa''

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, h ...

exert immuno-modulating effect, not mediated by the cannabinoid CB1 and CB2 receptor coupled pathways like THC. THCA were able to inhibit the tumor necrosis factor alpha ( TNF-alpha) levels in U937

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s 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 c ...

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 specific

phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...

(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 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 intercellula ...

and on colon tissue in a model of

inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...

s (IBDs), where ''C. sativa'' flowers were

extracted ''Extracted'', also known as ''Extraction'' in the UK, is an independent 2012 American science fiction thriller directed and written by Nir Paniry. Sasha Roiz stars as a scientist whose consciousness becomes trapped in the mind of a convict (Dom ...

with

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

, 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 Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...

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 extracel ...

gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...

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 Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...

. It is suggested that in a nonpsychoactive treatment for IBD, THCA should be used rather than CBD. THCA binds to and activates PPARγ with higher potency than its

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 cell ...

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 excretion, excreted from the body through the urethra. Cel ...

and

blood serum Serum () is the fluid and solute component of blood which does not play a role in clotting. It may be defined as blood plasma without the clotting factors, or as blood with all cells and clotting factors removed. Serum includes all proteins not u ...

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 In crystallography, the orthorhombic crystal system is one of the 7 crystal systems. Orthorhombic lattices result from stretching a cubic lattice along two of its orthogonal pairs by two different factors, resulting in a rectangular prism with a r ...

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 of

cannabidiolic acid Cannabidiolic acid (CBDA), is a cannabinoid found in cannabis plants. It is most abundant in the glandular trichomes on the female seedless flowers or more accurately infructescence often colloquially referred to as buds. CBDA is the chemical precu ...

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-tetrahydroc ...

, 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 and anti-inflammatory 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 international security, security, develop friendly relations among nations, achieve international cooperation, and be ...

Convention on Psychotropic Substances The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as #Amphetamine-type stimulants, amphetamine-type stimulants, barbiturates, benzodiazepines, and Psychedelic drug, psychede ...

.Convention on Psychotropic Substances, 1971
/ref>

United States

THCA is not

scheduled A schedule or a timetable, as a basic time-management tool, consists of a list of times at which possible tasks, events, or actions are intended to take place, or of a sequence of events in the chronological order in which such things are i ...

at the

federal level Federal or foederal (archaic) may refer to: Politics General *Federal monarchy, a federation of monarchies *Federation, or ''Federal state'' (federal system), a type of government characterized by both a central (federal) government and states or ...

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 territorie ...

, 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 analo ...

of THC and sales or

possession Possession may refer to: Law * Dependent territory, an area of land over which another country exercises sovereignty, but which does not have the full right of participation in that country's governance * Drug possession, a crime * Ownership * ...

could potentially be prosecuted under the Federal Analogue Act.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