Cannabis laws in the U.S. are a masterclass in contradiction—both legal and chemical. At the federal level, cannabis remains a Schedule I drug—lumped in with heroin and LSD—despite being legal for medical or recreational use in the majority of states. This creates a surreal legal landscape where a substance can be both a felony and a booming industry, depending entirely on which side of a state line you're standing on—or which "jurisdiction" happens to judge you. Pure crazy.
Legal? Probably. Or not.
Hemp products [1] are legal, provided their concentration of THC (delta-9-tetrahydrocannabinol—the primary psychoactive chemical in marijuana) does not exceed 0.3% by dry weight [2].
That limit does not include non-psychoactive cannabis compounds like cannabidiol (CBD) or THCA.
But now Tennessee has taken it to the next level. The state legislature just passed a bill—HB 1376—that effectively bans THCA (tetrahydrocannabinolic acid), a non-psychoactive "chemical tagalong" found in virtually all raw cannabis. Unsurprisingly, the Tennessee hemp industry is outraged. By counting THCA in the 0.3% total THC threshold, the new law effectively bans many hemp products that were previously compliant. This makes it essentially impossible to sell any hemp products in the state because the amount of THCA itself often exceeds that of THC (Table 1).
Table 1. Relative amount of THC and THCA in various cannabis samples. From multiple sources. Don't take this too seriously. It's more illustrative than quantitative.
THCA is a Pro-drug of THC. Sort of.
A pro-drug is a chemically modified, pharmacologically inactive compound that is converted into an active drug within the body through metabolic or chemical processes once taken. Pro-drugs usually have a pharmacological advantage over the active species, for example, better absorption.
This is the reason that Valtrex (valacyclovir), an anti-herpes medication, is preferred to acyclovir, the active antiviral drug. Valacyclovir is not an active antiviral, but it converted in the gut and liver to acyclovir, the active species by enzymes in the gut and liver. The advantage is better absorption and less frequent dosing.
Figure 1. The enzymatic conversion of valacyclovir (Valtrex) to acyclovir
What is special about THCA?
To answer this we need to call on Steve and Irving, who have done plenty of ganja in their time. And continue to do so...
Steve (Left) and Irving were called upon to host a Dreaded Chemistry Lesson from Hell®, but the idiots were too wasted to do so.
Let's proceed without the stoners.
Why is THCA as issue at all?
The answer is that THCA is (technically) a pro-drug of THC, although not in the usual sense. When heated, THCA undergoes a decarboxylation, a well known reaction in organic chemistry. Why? You asked... (Figure 2)
Figure 2. Heating beta-ketobutyric acid causes it to lose CO2, giving acetone (loss of 1 carbon). How does this work? I'm not going to tell you. Live with it. The red shapes show the loss of CO2, which is replaced by hydrogen.
What on earth does this have to do with THCA forming THC? After all, THCA isn't a beta-keto acid, right?
Wrong.
Figure 3. The decarboxylation of THCA
Just to make your already-miserable life even more so, THCA exists in two forms in equilibrium, the phenol form and also the beta-keto acid form. The latter is susceptible to the same heat-promoted decarboxylation reaction shown in figure 2. Heating THCA (smoking) converts it to THC.
This is why it is accurate to call THCA a pro-drug of THC and why legislators want to ban it.
Of course, it's not that simple.
THCA is not a prodrug in the designed sense, but it does act exactly like one due to heat conversion. Why the hedging?
When we medicinal chemists make pro-drugs it is almost always to correct a problem with an early discovery lead, usually metabolism or oral absorption. Pro-drug implies (at least to us) an intentional modification of a problematic molecule to address a specific issue.
Does this make THCA a pro-drug of THC? Yes and no, depending on how you look at it. Confusing? Hopefully no more than this hideous article.
NOTES:
[1] Hemp products include CBD oil, THCA flowers, edibles, tinctures and vapes.
[2] This quantity is legal due to the the 2018 Farm Bill, which established that level (based on dry weight) of any part of the plant.
Josh Bloom
Director of Chemical and Pharmaceutical Science
Dr. Josh Bloom, the Director of Chemical and Pharmaceutical Science, comes from the world of drug discovery, where he did research for more than 20 years. He holds a Ph.D. in chemistry.
