Δ⁹-Tetrahydrocannabinol (THC)

Cannabis sativa is a widely used psycotropic plant that contains more than 100 phytocannabinoids. The principal psychoactive component is Δ⁹-Tetrahydrocannabinol (THC), which functions as a partial agonist at cannabinoid CB₁ and CB₂ receptors. Approved therapeuticformulations include dronabinol for chemotherapy-induced nausea and HIV/AIDS-related anorexia and nabiximols for multiple sclerosis-associated spasticity and neuropathic pain. Use in other chronic pain syndromes remains off-label and under investigation. Recreational use is widespread typically in the form of smoking buds from the cannabis plant or ingested in the form of edibles.

After oral administration (e.g., as dronabinol or in the form of edibles), Δ⁹-THC bioavailability is approximately 6–20 % owing to first-pass hepatic metabolism. Administration via inhalation (e.g., smoking buds from the cannabis plant) yields 10–35 % bioavailability, with onset within 2–10 minutes, peak effects at 15–30 minutes, and duration of 2–4 hours. Oral onset occurs at 30–90 minutes, peaks at 2–3 hours, and effects may last up to 6 hours.

Phase I metabolism is initiated primarily by CYP2C9 (fm ≈ 70 %) Yabut et al., 2024, with lesser contributions from CYP2C19 and CYP3A4. Δ⁹-THC is oxidized to 11-hydroxy-THC (active) and then to 11-nor-9-carboxy-THC (inactive). Minor metabolites such as 8β-hydroxy-THC and epoxy-THC isomers are formed by CYP3A4. Phase II glucuronidation of 11-hydroxy-THC and THC-COOH by UGT1A1, UGT1A3, UGT1A9 and UGT1A10 facilitates renal and biliary elimination. Excretion is predominantly fecal (65–80 %) and to a lesser degree urinary (20–35 %).

Interindividual variability in pharmacokinetics is partly explained by CYP2C9 polymorphisms. CYP2C9*2 and *3 alleles reduce enzyme activity, leading to elevated and prolonged concentrations of Δ⁹-THC and 11-hydroxy-THC with increased risk of adverse effects. Variants in CYP2C19, CYP3A4 and UGT enzymes may further modulate clearance but require further characterization.

Several genes influence the pharmacokinetics and pharmacodynamics of THC. These include enzymes responsible for phase I and phase II metabolism, an endocannabinoid–hydrolyzing hydrolase, and proteins that modulate dopaminergic signalling. Genetic variants in these genes may alter enzyme activity or expression and thereby modify systemic exposure and central nervous system response to THC.

CYP2C9

CYP2C9 is a hepatic cytochrome P450 monooxygenase that catalyses the initial oxidation of Δ⁹-THC to 11-hydroxy-THC (active) and subsequently to 11-nor-9-carboxy-THC (inactive). It accounts for approximately 70 percent of Δ⁹-THC phase I clearance. Expression of CYP2C9is highest in liver with some expression in the intestinal mucosa.

As the major metabolic enzyme for THC, CYP2C9 is a key determinant of systemic exposure. It is therefore expected that genetic variation in CYP2C9 known to alter enzymatic activity will impact the pharmacokinetics of THC. Functional alleles *2 (rs1799853) and *3 (rs1057910) reduce CYP2C9 intrinsic clearance by 30–70%. Carriers of these alleles exhibit 1.5–3-fold higher area under the curve for Δ⁹-THC and 11-OH-THC, prolonged half life, and extended psychoactive effects Benak et al., 2024. Reduced clearance may magnify drug-drug interaction risk with CYP2C9 inhibitors such as fluconazole Rao et al., 2024.

FAAH

Fatty acid amide hydrolase (FAAH) is a membrane-associated serine hydrolase expressed in brain, liver and other tissues. It degrades endogenous cannabinoids such as anandamide and 2-arachidonoylglycerol. By controlling the steady-state concentration of these endocannabinoids at synapses, FAAH alters basal CB₁ receptor occupancy and thus may modulate the pharmacodynamic response to exogenous Δ⁹-THC.

The hypomorphic C385A variant (rs324420) decreases FAAH enzyme activity, elevating baseline anandamide and 2-arachidonoylglycerol levels. C385A carriers report greater subjective reward, higher craving, and increased vulnerability to cannabis use disorder Altun et al., 2023.

AKT1

AKT1 is a ubiquitously expressed serine/threonine kinase activated downstream of dopamine D₂ receptor engagement and growth factor signalling. In neurons of the ventral tegmental area and nucleus accumbens, AKT1 participates in regulation of synaptic plasticity and cell survival pathways. THC-induced CB₁ activation indirectly modulates AKT1 phosphorylation status and thus alters downstream gene transcription and neuroplastic responses.

The AKT1 variant rs2494732 influences dopamine signalling downstream of D₂ receptor activation. Heavy cannabis users homozygous for the C allele have 2–3-fold higher odds of psychotic disorder, especially if use begins in adolescence Carvalho & Vieira-Coelho, 2022. C-allele carriers also exhibit greater acute psychotomimetic sensitivity after Δ⁹-THC exposure Di Forti et al., 2012.

Associations with AKT1 and risk of psychosis have been identified in case-control studies though are not definitive. Individuals who carry the C allele may be at higher risk though there is disagreement in the literature about the degree of risk.

COMT

Catechol-O-methyltransferase (COMT) is a cytosolic enzyme that methylates catecholamines, including dopamine. Predominantly expressed in prefrontal cortex and liver, COMT regulates extracellular dopamine clearance. Following THC-induced dopamine release in mesolimbic pathways, COMT activity determines duration and magnitude of dopaminergic signalling and thereby shapes behavioural and psychotropic effects.

The Val158Met missense variant (rs4680) alters COMT activity threefold. Val/Val individuals may experience larger Δ⁹-THC-induced dopamine surges and earlier onset of psychotic-like symptoms induced by THC, although meta-analyses report inconsistent effect sizes Kennedy et al., 2018 Fischer et al., 2023. Similar to the AKT1 variant, the Val158Met variant has been associated with risk of psychosis in case-control studies though the evidence is not definitive.

Together these proteins constitute mechanistic nodes at which genetic variation can modulate Δ⁹-THC exposure, receptor engagement and downstream signalling. Current evidence supports a probabilistic rather than deterministic contribution of these variants. Effect sizes vary across cohorts, underscoring the need for replication in larger, ancestry-diverse populations.

CYP2C9 Dosing Guideline

Phenotype	Implication	Recommendation
Normal metaboliser (*1/*1)	Clearance within population reference; anticipated duration 4–6 h after inhalation.	Initiate usual dose.
Intermediate metaboliser (*1/*2 or *1/*3)	~30 % slower clearance – higher peak and area under curve.	Start at standard dose but titrate slowly; monitor for exaggerated psychotropic or cardiorespiratory effects.
Poor metaboliser (*2/*3 or *3/*3)	Marked accumulation; elimination half‑life may double.	Begin at ≤25 % of usual dose; consider low‑THC or balanced THC:CBD products.
Indeterminate	Unknown impact	Standard starting dose

FAAH Dosing Guideline

Phenotype	Implication	Recommendation
Normal function (C/C)	Baseline endocannabinoid tone; typical subjective response.	Usual dosing.
Decreased function (C/A or A/A)	Elevated anandamide levels may potentiate rewarding effects and impair extinction of drug‑seeking.	Consider 25 % dose reduction and reinforce harm‑reduction strategies.
Indeterminate	Unknown impact	Standard starting dose

AKT1 Dosing Guideline

Phenotype	Implication	Recommendation
T/T	Average psychotomimetic risk.	Usual dosing; routine psychological monitoring.
C/T	Approximately double risk of transient psychotic‑like symptoms with high‑dose THC.	Start low, go slow; avoid concentrates >15 % THC.
C/C	Highest observed risk; some studies report odds ratio >2 for first‑episode psychosis among heavy users.	Consider alternative therapy or THC ≤5 %; ensure informed consent regarding psychiatric risks.
Indeterminate	Unknown impact	Standard starting dose

COMT Dosing Guideline

Phenotype	Implication	Recommendation
Val/Val	Higher COMT activity – greater dopamine swing; cognitive impairment or paranoia more likely.	Begin at 50 % normal dose; monitor cognition and mood.
Val/Met	Intermediate activity; risk approximates population average.	Usual dosing.
Met/Met	Lower COMT activity – smaller dopamine surge; protective trend in some studies but not definitive.	Usual dosing.
Indeterminate	Unknown impact	Standard starting dose

• Rao JS et al. A study on CYP2C9 polymorphism in Puerto Rican Alzheimer’s patients and THC pharmacokinetics. Med Res Arch 2024. link
• Benak Y et al. CYP2C9, CYP3A and CYP2C19 metabolise Δ⁹‑THC. Biochem Pharmacol 2024. link
• Hovelson DH et al. Global distribution of functionally important CYP2C9 alleles. Hum Genomics 2023. link
• Altun B et al. CNR1, FAAH and MGLL gene variations and synthetic cannabinoid use disorder. Turk J Biochem 2023. link
• Genes journal. FAAH rs324420 polymorphism review. Genes 2023. link
• Di Forti M et al. AKT1 rs2494732 genotype and cannabis‑related psychosis. Biol Psychiatry 2012. link
• Carvalho C, Vieira‑Coelho M. Cannabis‑induced psychosis – role of genetic polymorphisms. Pharmacol Res 2022. link
• Nájera DJ et al. DRD2 and AKT1 interaction on psychosis risk in cannabis users. NPJ Schizophr 2015. PDF
• Fischer AS et al. Acute THC effects and COMT Val158Met modulation. Drug Alcohol Depend 2023. link
• Kennedy O et al. Interaction between cannabis use and COMT Val158Met – meta‑analysis. PLoS One 2018. link