- Cannabis plants don’t produce THC on their own; rather they create cannabinoids in acid form.
- To turn THCA into psychoactive THC, it must first be heated (for example, by vaping or smoking).
- THCA shows great promise in the treatment of epilepsy.
- A higher dose of THCA combined with THC is sometimes effective for seizures, pain, and arthritis.
- Scientists have shown that low doses of THCA prevent nausea in rats.
Cannabis doesn’t actually produce THC or CBD. The plant produces all cannabinoids in an acid form. Instead of making THC and CBD directly, it synthesizes tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) from their cannabigerolic acid (CBGA) precursor.
THCA is not psychoactive—it does not activate CB1 cannabinoid receptors in the brain. In order to make psychoactive THC from THCA, one needs to heat it. This can be done by smoking or vaporizing raw flower, baking edibles, or heating cannabis in a process known as decarboxylation. When smoking cannabis, it is estimated that more than 95% of the THCA is converted to THC. If so, a cannabis smoker might inhale the small amount of remaining THCA, which could also impart a therapeutic effect.
According to several doctors, THCA shows great promise in the treatment of epilepsy. Preclinical research indicates that THCA may be anti-inflammatory and may reduce nausea. One of the most significant features of THCA is its apparent ability to work at very low doses. The therapeutic potential of THCA is all the more noteworthy given that this compound is more readily available than THC or CBD because of the ubiquity of the raw marijuana plant.
Clinical use of THCA
Clinical experience is the best place to start. Dr. Dustin Sulak and Dr. Bonni Goldstein have both reported on the use of THCA in the treatment of patients. In a recent publication, Sulak, Goldstein, and Dr. Russel Saneto describe four case reports of patients using THCA along with other treatments (conventional antiepileptic drugs as well as cannabis). Among these patients, small doses—around 0.1-1 mg/kg/day THCA1—were used, corresponding to 0.01 to 0.1% of the patient’s body weight in THCA. For a child weighing 50 pounds, this entails between 2-23 milligrams of THCA in a day.
By contrast, studies with Epidiolex, a pure (99.5 percent) CBD sublingual spray, start at a dose of 5 mg/kg/day and usually increase to 25 mg/kg/day. The aforementioned doses of THCA are 10-100 times lower.2
THCA is typically administered along with other components of cannabis in a tincture via an under-the-tongue dropper or spray. Sulak’s article indicates that higher doses of THCA did not generally improve the response, with one patient getting worse after increasing the dose of THCA. Sulak also found that specific terpenes along with THCA in a given cannabis strain can contribute significantly to the antiepileptic effect. (Linalool, in this case, was necessary for the antiepileptic effect.)
Dr. Goldstein told Project CBD that daily consumption of 10-20 mg of THCA was effective in reducing pain in some of her patients with arthritis and irritable bowel syndrome. For one patient with Alzheimer’s disease, THCA improved cognitive symptoms and allowed the patient to reduce the use of other drugs.
Dr. Sulak also spoke with Project CBD, saying that a higher dose of 2 mg/kg of THCA combined with THC is sometimes effective for seizures, pain, and arthritis. For neurological issues, about 1 mg of THCA and THC used 2-3 times a day has helped some of his adult patients. In one teenager, a very low dose of THCA prevented severe refractory migraines.
Anecdotal reports from other sources indicate that a 10:1 CBD:THCA ratio can be effective for some epileptic children when a high CBD/low THC cannabis oil preparation does not deliver satisfactory results. One seven-year-old patient, weighing 42 pounds, has been seizure free for the past two-and-a-half years since he’s been on a dosage regimen of 50 mg/day of CBD and 10 mg/day of THCA.
THCA in the lab
Thus far, preclinical research into THCA has been very confusing. Erin Rock and other scientists at the University of Guelph in Ontario have demonstrated that low doses of THCA—about 10-100 times lower than the requisite dose of THC—prevent nausea in rats. In addition, they found that THCA synergizes with CBDA, which is also a potent antiemetic compound. It is possible that the anti-nausea effect of smoking cannabis is partly attributable to the small amount of THCA that remains when cannabis is burned.
Curiously, THCA’s effect in the Guelph study was prevented by blocking the CB1 cannabinoid receptor. This is surprising, given that THCA isn’t known to bind to CB1 and doesn’t cause psychoactive effects like THC does when the latter binds to CB1. Yet Rock et. al. did not observe any effects from THCA that they could attribute to central CB1 activity. A possible explanation for this finding is that Rimonabant, the experimental drug they used to block the CB1 receptor, may have inhibited THCA’s effects through a different channel or receptor, such as GPR55 (which is activated by Rimonabant). When asked by Project CBD, Dr. Rock indicated that they are uncertain as to how THCA prevents nausea, and that it may very well be an off-target or peripheral effect.
A study by Rosenthaler and a group of Austrian scientists surmised that THCA has a greater binding affinity to the CB1 receptor than THC does. It may be that this study was flawed (their data also suggested—likely incorrectly3—that CBN, a breakdown product of THC, binds to CB1 more potently than does THC). But it also might be the case that THCA acts primarily on peripheral CB1 receptors outside the brain and central nervous system. The main difference between THCA and THC could be related to how these compounds are distributed throughout the body. Another explanation might derive from an inconsistency between two molecular isoforms of THCA—THCA-A and THCA-B—which could give rise to different results (see sidebar).
How does THCA work?
So how does THCA confer its effects? Through which biochemical channels does THCA act? The only receptor to which THCA is known to potently bind is TRPM8—the receptor that makes mint feel cold. THCA is a strong antagonist of TRPM8. But there is no research to indicate that inhibiting TRPM8 prevents nausea or reduces seizures, so this does not explain the clinically observed effects of THCA.
At higher concentrations, THCA also may activate TRPV4, a heat-sensing receptor, and TRPA1, a receptor that mediates the edginess of spices such as mustard and cinnamon.
THCA may also convey therapeutic effects by inhibiting the metabolic enzyme MAGL that breaks down the endogenous cannabinoid 2-AG; this would result in higher levels of 2-AG, which activates both CB1 and CB2 cannabinoid receptors throughout the brain and body.
In these preclinical tests, THCA was about 10 times more potent when used as a whole-plant extract rather than as an isolate.4 But this evidence is based on only a few studies performed in cell cultures, which does not necessarily translate to clinical experience.
Other data from preclinical work suggests that THCA may be an anti-inflammatory compound that protects against cancer, but this work is an unconvincing explanation of clinical reports. One study on THCA and breast cancer required a high concentration of THCA, about 1000 times more than the concentration in the blood of Dr. Sulak’s patients. Another study suggested that THCA was a much weaker antioxidant than THC or CBD and that THCA is only slightly neuroprotective at similarly high doses. Two studies on inflammation revealed that THCA does not inhibit COX-2, an inflammatory enzyme blocked by ibuprofen and aspirin, and high doses of THCA were required for an anti-inflammatory effect.
The fact that doctors and patients are reporting significant health-positive effects from THCA at very low concentrations underscores that there is much more to understand about THCA. The properties of THCA indicated by preclinical research may be relevant to cannabinoid medicine in the future, but they do not explain the remarkable results with low doses of THCA that patients are experiencing today.
Adrian Devitt-Lee is a Project CBD research associate and contributing writer. Research for this article was supported by CannaCraft, a California-based medical marijuana company.
Copyright, Project CBD. May not be reprinted without permission.
Learn More: Medical Marijuana for Seizures
1 The unit mg/kg – pronounced milligrams per kilogram – means milligrams of marijuana product per kilogram of the patient’s bodyweight. A 1 mg/kg/day dose for an adult who weighs 70 kg (154 lbs) is 70 mg per day.
2 The range of 10 to 100 may seem very large. But the dosage of different drugs is generally measured on the “log” scale. Log stands for the logarithm, a mathematical function which is the inverse of raising 10 to a power. (It is approximately one less than the number of digits in the number.) log(10) = 1 and log(100) = 2, so these two numbers are only one log-scale apart. The difference between a milligram and a gram is three log-scales.
3 In one method of determining how well a compound like CBN or THCA binds to CB1, scientists label a known CB1 agonist with a radioactive atom. They then measure how well CBN or THCA displaces the radioactive agonist from the CB1 receptor. Different agonists can give different results, and this does not necessarily translate to activity (a compound could bind to a receptor but block its activation). However the potency of CBN in this experiment was 10-100 times higher than the values summarized in Robert Pertwee’s Handbook of Cannabis.
4 A whole plant extract of THCA means that THCA was extracted from cannabis, producing a “crude” product with THCA as well as some terpenes, flavonoids, and plant fats. The isolate can then be made by purifying the crude extract so that it is almost only THCA (usually over 98% pure). An isolate can also be synthesized from scratch.
- De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011 Aug.
- Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 2006 Sep.
- Mechoulam R, Ben-Zvi Z, Yagnitinsky B, Shani A. A new tetrahydrocannabinolic acid. Tetrahedron Lett. 1969 Jun.
- Moldzio R, Pacher T, Krewenka C, Kranner B, Novak J, et al. Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine. 2012 Jun 15.
- Rock EM, Limebeer CL, Navaratnam R, Sticht MA, Bonner N, et al. A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping. Psychopharmacology. 2014 Aug.
- Rock EM, Kopstick RL, Limebeer CL, Parker LA. Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus. Br J Pharmacol. 2013 Oct.
- Rosenthaler S, Pöhn B, Kolmanz C, Huu CN, Krewenka C, et al. Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures. Neurotoxicol Teratol. 2014 Dec.
- Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, et al. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011.
- Sulak D, Saneto R, Goldstein B. The current status of artisanal cannabis for the treatment of epilepsy in the United States. Epilepsy Behav. 2017 Feb 18.
- Takeda S, Misawa K, Yamamoto I, Watanabe K. Cannabidiolic acid as a selective cyclooxygenase-2 inhibitory component in cannabis. Drug Metab Dispos. 2008 Sep.
- Verhoeckx KC, Korthout HA, van Meeteren-Kreikamp AP, Ehlert KA, Wang M, et al. Unheated Cannabis sativa extracts and its major compound THC-acid have potential immuno-modulating properties not mediated by CB1 and CB2 receptor coupled pathways. Int Immunopharmacol. 2006 Apr.
Scientific studies have established that synthetic, single-molecule CBD has a narrow therapeutic window and requires high doses for efficacy as compared to whole-plant, cannabis-derived CBD.
In this edition of Cannabis Conversations, Project CBD Director, Martin A. Lee, discusses the benefits of CBD, the “entourage effect” and the microbiome with Dr. Ethan Russo.