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The physiological relevance and effects of probable in vivo transformation of CBD to delta9-THC in humans

In a recent review published in Cannabis and Cannabinoid Research, researchers reviewed studies on the probable conversion of orally administered cannabidiol (CBD) to delta9-tetrahydrocannabinol (delta9-THC or THC) in humans.

Study: A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans. Image Credit: Yarygin/Shutterstock

In vitro studies with simulated gastric fluid (SGF) indicated that oral CBD could probably convert to THC in humans. The safety and implications of such a conversion need evaluation for further use of CBDs.

About the review

In the present review, researchers discussed the physiological relevance and effects of probable in vivo transformation of CBD to delta9-THC in humans.

CBD and delta9-THC are structurally similar; however, their properties substantially differ. CBD does not bind effectively to CBD1 receptors and, therefore, lacks psychotomimetic properties and cannabis-like intoxicating effects. CBD has been considered a negative modulator and reduces the binding interactions of agonists like delta9-THC, nabilone, and anandamide.

CBD is partially stable in solution and requires <8°C storage temperatures and protection from light. In an acidic environment, CBDs can be isomerized or converted to delta9-THC. CBDs used for therapeutics are either derived from plants, i.e., (-) trans CBD (>99.5% pure CBD, for e.g. BSPG, United Kingdom) or can be synthetic.

The marketed products are reported to be 98% to 99% pure. Herbal CBD byproducts are (-) CBDs since plants make only a single isomere and the synthetic CBD impurities arise from the remnant materials and products generated during synthesis. Trace amounts of delta9-THC in less-purified CBD products cannot be excluded but are unlikely to be of any concern.

Simulated gastric fluid in vitro was found to not reflect in the in vivo environment

A previous in vitro study used SGF containing 99% pure synthetic CBD, 0.2% methanol, and 1% sodium dodecyl sulfate, with 1.0 pH, to assess the CBD to THC conversion. In the study, 85% of CBD after one hour and >98% of CBD after two hours were converted into delta8-THC and delta9-THC.

In another study, plant-derived CBD was incubated in artificial (simulated) gastric juice containing 2.0 mg/mL NaCl but lacking pepsin, with pH 1.2. Even after 20 hours, the rate of transformation of CBD into cannabinol, 8-OH-iso-HHC, 9alpha-hydroxy-hexahydro cannabinol [9a-OH-HHC], and delta9-THC were merely 1%, 10%, 1%, and 3% respectively.

The negligible transformation rates indicate that SGF composition profoundly impacts CBD degradation. Further, CBDs significantly bind to proteins, which further decreases their transformation rates. A previous study also mentioned that CBD undergoes extensive oxidation and hydroxylation in vivo, resulting in the formation of nearly 100 CBD metabolites.

The conventional SGF is of the United States Pharmacopeial Convention (USP), containing 7.0 mL hydrochloric acid (HCl), 2.0 g sodium chloride (NaCl), 3.2 g pepsin, and 1.0 L water at 1.2 pH. However, even the USP SGF does not significantly resemble the physiologic gastric secretion (1.5 to 3.5 pH), which contains proteins such as gastrin, pepsin, trypsin, gelatinase, gastric amylase, mucin and gastric lipase, and inorganic molecules like sodium, calcium, and potassium.

CBD conversion to delta9-THC in the stomach must show delta9-THC metabolites in urine and blood

Detection of delta9-THC and its metabolites in bodily fluids such as urine is an established forensic testing method. Even if 1% of oral CBD dose is soluble, CBD levels (comprising delta8-THC and delta9-THC) of 6.5 mg in half-hour and 13 mg in one hour and CBD would be detected, and CBD is also excreted as glucuronide in urine. Further, 11-hydroxy-D-tetrahydrocannabinol (11-OH-THC), the prime metabolite of delta9-THC, is the precursor of delta9-THC-COOH (or THC-COOH or 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid), an important forensic marker.

THC-COOH tests can sensitively detect delta9-THC absorption. A CBD metabolite, 7-hydroxy-CBD (or 7-OH-CBD) and 7 is formed rapidly and gets oxidized to CBD7-oic acid, which can be detected in urine and plasma. Additionally, free CBD is excreted in the feces in large amounts. After a daily dose of oral 600 mg CBD, 33 metabolites of CBD in urine and many non-oxidized cannabinoids have been detected.

In a study, delta9-THC administration in its effective therapeutic dose (6.5 mg to 13 mg daily) produced positive results for the presence of THC-COOH and 11-OH-THC in urine and plasma. In contrast, 0.6 mg of THC daily produced negative THC-COOH results on analyzing urine samples of healthy individuals. In previous in vivo experiments, 2% delta8-THC and 0.7% delta9-THC were detected, and the glucuronide molecules were absent in urine. Likewise, THC metabolites were absent in urine or plasma after oral CBD (400mg and 800mg) administration with intravenous (i.v.) fentanyl in a double-blinded clinical trial, indicating that cyclization occurred after excretion.

CBD to THC transformation would cause THC side effects

Studies have indicated that CBD is not toxic (in doses <1500mg/day). Its chronic use does not induce catalepsy and appetite changes and does not affect physiological parameters such as blood pressure, body temperature, and heart rate. In addition, gastrointestinal transit time and psychological functions are not affected. However, after oral doses of CBD, documented side effects include lethargy, somnolence, fatigue, and poor motor and cognitive functions. Further, a study stated that 15 mg THC could cause sedation, whereas 15mg CBD can cause alertness.

In a recent study, two children received 90% CBD and three to four percent D9-THC (6.0 and 12.5 mg/kg/day doses, respectively) with standard antiepileptic therapy. They developed THC intoxication signs within four months. After administering 200 to 300 mg/day of 99.6% pure CBD (BSPG), the signs resolved completely. Follow-up after about a year showed seizure remission and progressive improvement of other symptoms, which could hardly be explained if CBD converted to THC.

In a double-blinded, crossover, randomized controlled trial, healthy males received either 10 mg oral THC or 600 mg oral CBD or a placebo. Relative to both placebo and CBD, THC administration was associated with dysphoria, anxiety, psychotic symptoms, tachycardia, and sedation at two hours. On the contrary, no clinical differences between CBD and placebo were noted.

To conclude, based on the reviewed studies, in vivo conversion of orally administered CBD to delta9-THC and/or other cannabinoids in humans is not likely and occurs in artificial environments.

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