# Two Molecules, Two Routes: How the Body Handles THC and CBD Differently

> **Author:** Benjamin Caplan, MD (ABFM Board Certified, MA Lic. #240562, NPI: 1962722637)
> **Publisher:** CED Clinic (https://cedclinic.com)
> **Canonical URL:** https://cedclinic.com/thc-and-cbd-metabolism-pathways-compared/
> **Published:** 2026-09-04T22:54:13-04:00 | **Last Modified / Clinically Audited:** 2026-09-28T10:39:42-04:00
> **Clinical Summary:** THC and CBD metabolism share liver enzymes but produce different products and act on different targets. What human evidence supports, and what it does not.

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CED Clinical Relevance #74Strong Clinical RelevancePatients and clinicians routinely treat THC and CBD as two versions of one drug. They share a liver and very little else, and the differences determine which interactions matter and which claims can be trusted.

THC and CBD are close structural relatives that the body treats as different problems. They are oxidized by overlapping but distinct enzymes, they produce metabolites with different properties, and their molecular targets barely overlap at all. Much of what circulates about their mechanisms comes from cell culture at concentrations no patient reaches.

Clinical Insight | CED Clinic

THC is oxidized principally by CYP2C9, with a contribution from CYP3A4, to 11-hydroxy-THC, which is itself psychoactive, then further oxidized to the inactive acid 11-nor-9-carboxy-THC. CBD takes a different route: human liver microsome studies identify CYP3A4 and CYP2C19 as the dominant enzymes, producing a family of monohydroxylated products rather than one principal active metabolite.

The receptor picture diverges even more sharply. THC is a partial agonist at CB1 and CB2 receptors. CBD has low direct affinity for either, and a comprehensive systematic review of its molecular pharmacology concluded it is very unlikely to exert its effects in neurological disease through the endocannabinoid system at all.

Cannabinoid PharmacologyTHC MetabolismCBD MetabolismDrug InteractionsCannabis Science
AudienceClinicians, pharmacists, and patients using cannabinoid therapyPrimary TopicComparative metabolism and molecular targets of THC and CBDSource[Read the full source](https://doi.org/10.1016/j.lfs.2011.05.018)
Why This Matters

Product marketing and a good deal of clinical shorthand treat THC and CBD as interchangeable ingredients on a label. The metabolism says otherwise: they load different enzymes, carry different interaction risks, and generate different downstream chemistry.

The mechanism literature for CBD in particular is enormous and mostly in vitro. Separating the handful of findings with plausible human relevance from the many that occur only at concentrations no oral dose produces is the difference between informed practice and citation theater.

Same Organ, Different Enzymes

The THC pathway was mapped first and is the simpler of the two. Work by Wall and colleagues, published in *Clinical Pharmacology and Therapeutics* in 1983, described microsomal hydroxylation converting THC to 11-hydroxy-THC, which the authors called both a key intermediate and a potent psychoactive metabolite in its own right. Liver alcohol dehydrogenase enzymes then oxidize it further to 11-nor-9-carboxy-THC, and from there the final products are that acid and related, more polar acids.

The CBD pathway is broader and messier. Jiang and colleagues, in *Life Sciences* in 2011, incubated CBD with pooled human liver microsomes and identified eight monohydroxylated metabolites. Four of them predominated: 6-alpha-hydroxy, 6-beta-hydroxy, 7-hydroxy, and 4-double-prime-hydroxy CBD. Of 14 recombinant human cytochrome P450 enzymes tested, seven metabolized CBD: CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5.

Correlation and inhibition experiments narrowed that to two principal contributors. CYP3A4 was chiefly responsible for forming 6-beta-hydroxy and 4-double-prime-hydroxy CBD, and CYP2C19 predominantly catalyzed 7-hydroxylation, the step that produces 7-hydroxy-CBD. THC’s pathway runs mainly through CYP2C9; CBD’s runs mainly through CYP3A4 and CYP2C19. They share a liver, not a route.

What Genotype Data Show, and Where They Stop

For THC there is a clean human demonstration that the enzyme identification has consequences. Sachse-Seeboth and colleagues, in *Clinical Pharmacology and Therapeutics* in 2009, gave oral THC to 43 healthy volunteers genotyped for CYP2C9. People carrying two copies of the reduced-function CYP2C9*3 allele had a median THC area under the curve three times higher than people with two normal-function copies, and a 70 percent lower area under the curve for 11-nor-9-carboxy-THC. The CYP2C9*2 allele made no measurable difference.

Those numbers behave exactly as the enzymology predicts and are the best available evidence that individual variation in cannabinoid response has a partly genetic basis.

No comparable controlled study exists for CBD. A 2025 retrospective chart review in the *Journal of Cannabis Research* examined 71 patients who used oral cannabis and had undergone pharmacogenomic testing, finding atypical CYP2C19 variants in 37 of them and CYP3A4 variants in 6. The authors stated plainly that the absence of published clinical outcomes in this field made it difficult to estimate the clinical significance of what they found. That is the correct level of confidence to carry.

Receptor Targets Barely Overlap

Pertwee’s review in the *British Journal of Pharmacology* in 2008 laid out the comparison directly. THC behaves as a partial agonist at both CB1 and CB2 receptors, and its effects are strongly shaped by how many receptors are expressed, how efficiently they signal, and how much endogenous cannabinoid is already being released. That is classical receptor pharmacology and it explains a good deal of the variability patients report.

CBD behaves nothing like that. In the same review, CBD displayed unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in cells and tissues expressing those receptors, which is a different relationship than simply binding weakly. Its low direct affinity combined with meaningful functional antagonism has driven a great deal of subsequent work on allosteric and indirect mechanisms.

The most rigorous attempt to sort out CBD’s targets is the systematic review by Ibeas Bih and colleagues in *Neurotherapeutics* in 2015. They searched the literature for original reports of CBD’s molecular pharmacology and appraised each proposed target for validity. More than 65 discrete molecular targets had been reported. After excluding those demonstrated only at concentrations difficult to reach in vivo, and those asserted through experimental designs showing correlation rather than causation, a relatively limited number remained plausible, and the survivors clustered around regulation of and response to intracellular calcium, including voltage-dependent anion channel 1, GPR55, and CaV3 channels.

Where the In Vitro Literature Outruns the Human Data

The 65-target problem is worth stating plainly, because it is the single most common source of confident but unsupportable claims about CBD. A compound tested at high micromolar concentrations against a panel of receptors will hit many of them. That does not mean a patient taking an oral dose reaches those concentrations at those targets.

The Ibeas Bih review made this its central methodological point. Some CBD effects at proposed targets manifest only at high concentrations that may be difficult to achieve in vivo, particularly given CBD’s relatively poor bioavailability. Several targets were asserted through designs demonstrating only correlation with a given target rather than causal proof. And when the plausible targets were then evaluated for whether they were relevant to the neurological diseases in question, some had little or no established link to those conditions.

The bioavailability point is not a technicality. A systematic review by Millar and colleagues in *Frontiers in Pharmacology* in 2018 retrieved 792 articles and found only 24 reporting human pharmacokinetic parameters for CBD. Reported half-life ranged from 1.4 to 10.9 hours after oromucosal spray, 2 to 5 days after chronic oral dosing, 24 hours after intravenous administration, and 31 hours after smoking. Bioavailability following smoking was 31 percent, and no study had attempted to establish absolute oral bioavailability in humans despite intravenous formulations being available. That is a thin foundation under a very large mechanistic literature.

The Interaction That Has Actually Been Measured

Amid a great deal of in vitro speculation, one CBD interaction has been documented in patients with clear numbers. Geffrey and colleagues, in *Epilepsia* in 2015, reported on 13 children with refractory epilepsy taking clobazam who were given CBD under an expanded access protocol. Clobazam levels rose by a mean of 60 percent with a standard deviation of 80, and levels of the active metabolite norclobazam rose by a mean of 500 percent with a standard deviation of 300, at four weeks.

Side effects occurred in 10 of the 13 children and were relieved by reducing the clobazam dose. Nine of 13 had a greater than 50 percent reduction in seizures, and clobazam doses were reduced in 10 of the 13 over the course of treatment. The authors’ conclusion was operational: monitoring of clobazam and norclobazam levels is necessary when the two drugs are used together.

Phase II metabolism adds a second interaction layer. Nasrin and colleagues, in *Drug Metabolism and Disposition* in 2021, found that CBD inhibited several UDP-glucuronosyltransferase enzymes with binding-corrected IC50 values as low as 0.12 micromolar against UGT1A9, and that THC and cannabinol also strongly inhibited UGT1A9 and UGT2B7. Those are laboratory measurements rather than patient outcomes, and they point in the same direction as the clobazam data: CBD is a more consequential perpetrator of interactions than THC.

Neurotransmitter and Hormone Claims Deserve Scrutiny

Popular summaries of cannabinoid biochemistry tend to include a tidy table of neurotransmitter and hormone effects: THC raises dopamine, CBD modulates serotonin, THC suppresses testosterone, CBD acts on estrogen receptors. The underlying evidence is far less tidy.

Take dopamine, the best studied of these. Bloomfield and colleagues reviewed the evidence in *Nature* in 2016 and described conflicting evidence from human and animal studies, complicated by the complexity of cannabinoid and dopamine interactions. Their summary was that acute THC administration causes increased dopamine release and neuron activity while long-term use is associated with blunting of the dopamine system. That is a time-dependent, bidirectional picture, not a simple arrow.

For hormonal effects the situation is worse. The claims that circulate generally trace to small human studies from the 1970s or to animal and cell work, and have not been replicated in modern controlled human designs. This article does not reproduce them. A table that assigns a direction and a dose threshold to each hormone receptor implies a level of knowledge the literature does not contain.

Evidence SnapshotTHC Phase ICYP2C9 with CYP3A4 contribution oxidizes THC to active 11-hydroxy-THC; alcohol dehydrogenase then forms 11-nor-9-carboxy-THC (Wall 1983, *Clin Pharmacol Ther* 34:352-363, PMID 6309462)CBD Phase IEight monohydroxylated metabolites formed in human liver microsomes; CYP3A4 and CYP2C19 the major isoforms; 7-hydroxylation predominantly CYP2C19Anchor StudyJiang R, et al. *Life Sci* 2011;89(5-6):165-170. PMID 21704641Enzyme Breadth7 of 14 recombinant human CYP enzymes metabolized CBD: CYP1A1, 1A2, 2C9, 2C19, 2D6, 3A4, 3A5THC PharmacogeneticsCYP2C9*3/*3 homozygotes showed threefold higher THC AUC and 70 percent lower THCCOOH AUC, n=43 (Sachse-Seeboth 2009, *Clin Pharmacol Ther* 85:273-276, PMID 19005461)Receptor BehaviorTHC is a CB1 and CB2 partial agonist; CBD shows high potency as an antagonist of CB1 and CB2 agonists in expressing tissues (Pertwee 2008, *Br J Pharmacol* 153:199-215, PMID 17828291)CBD Target CountMore than 65 discrete molecular targets reported; most excluded as implausible after appraisal (Ibeas Bih 2015, *Neurotherapeutics* 12:699-730, PMID 26264914)CBD Pharmacokinetics24 of 792 screened articles reported human parameters; half-life 1.4 to 10.9 hours oromucosal, 2 to 5 days chronic oral; smoked bioavailability 31 percent; absolute oral bioavailability never established (Millar 2018, *Front Pharmacol* 9:1365, PMID 30534073)Measured Human InteractionCBD raised clobazam levels 60 percent and norclobazam 500 percent in 13 children at 4 weeks (Geffrey 2015, *Epilepsia* 56:1246-1251, PMID 26114620)Phase II InhibitionCBD inhibited UGT1A9 with binding-corrected IC50 of 0.12 micromolar (Nasrin 2021, *Drug Metab Dispos* 49:1081-1089, PMID 34493601)PMID / DOI21704641 / 10.1016/j.lfs.2011.05.018
How Strong Is This Evidence?

The enzyme identification is strong on both sides. Recombinant enzyme panels combined with isoform-selective inhibitors, blocking antibodies, and correlation analysis across individual human liver microsome preparations is the accepted method, and independent laboratories agree on the principal assignments.

The human pharmacokinetic base is much thinner for CBD than for THC. A systematic review found only 24 human pharmacokinetic reports and noted discrepancies among them, and absolute oral bioavailability has never been measured in people.

The mechanistic target literature for CBD is the weakest tier despite being the largest in volume. When it was systematically appraised, most of the more than 65 reported targets did not survive scrutiny for concentration plausibility or causal design.

Where This Paper Deserves Skepticism

Human liver microsomes are a preparation, not a liver. They lack transporters, competing endogenous substrates, and the concentration gradients of an intact organ, and they tend to overstate how cleanly one isoform dominates a reaction.

The clobazam interaction data came from 13 children in an expanded access program, not a controlled trial, and the standard deviations were larger than the means in one case. The direction of the effect is convincing; the magnitude in any individual patient is not predictable from these numbers.

Comparisons of CBD potency across studies are hazardous because cannabinoids bind nonspecifically to proteins and plasticware. Work that does not correct for that binding reports weaker inhibition than the same chemistry shows when it is corrected, and much of the older literature did not correct.

What This Paper Does Not Show

This literature does not establish a clinical mechanism of action for CBD. It identifies candidate targets and eliminates many of them, which is a narrowing exercise, not an answer.

It does not show that THC and CBD have opposing hormonal effects, or that either has a defined dose threshold for effects on estrogen, testosterone, adrenaline, or acetylcholine signaling. Those claims appear in popular summaries without a supporting body of controlled human evidence, and they are omitted here for that reason.

It does not tell you what a given ratio of THC to CBD in a product will do in a given patient. Metabolic pathway maps describe chemistry, not clinical response.

It does not establish that CYP genotyping improves cannabinoid dosing. The THC association with CYP2C9*3 is real and no trial has tested whether acting on it changes outcomes.

How This Fits With the Broader Clinical Conversation

The practical consequence of two distinct routes is that THC and CBD carry different interaction profiles. CBD’s reliance on CYP3A4 and CYP2C19, combined with its inhibitory potency at several phase I and phase II enzymes, makes it the more consequential of the two in a complex medication list, which is the opposite of the intuition many patients bring in.

There is also a lesson about how mechanism literature should be read. CBD accumulated more than 65 proposed molecular targets in roughly two decades, most of which did not survive systematic appraisal. A compound with a plausible story at every target has, in practice, no established story at any of them. The narrowing work matters more than the accumulation.

Dr. Caplan’s Take

The most common misconception I correct in clinic is that CBD is the harmless one. On the metabolism, it is the opposite. THC has one main enzyme and a reasonably predictable arc. CBD loads CYP3A4 and CYP2C19, inhibits several enzymes at concentrations that matter, and has a documented interaction with clobazam large enough that dose reduction is routinely required.

That does not make CBD dangerous. It makes it a drug, which is how it should have been treated from the beginning. When a patient on a substantial medication list tells me they started high-dose CBD, that is a medication reconciliation conversation, not a wellness one.

On the receptor side I try to keep patients away from mechanism stories entirely. Nobody knows how CBD produces the effects it produces, and a confident explanation involving serotonin or the endocannabinoid system is not something I can support. What I can do is watch the response and the interactions, which is what practice actually consists of.

Clinical Bottom Line

THC and CBD share a liver but not a pathway. THC is oxidized principally by CYP2C9 to the active metabolite 11-hydroxy-THC and then to an inactive acid, with a threefold exposure difference between CYP2C9 genotypes. CBD is oxidized principally by CYP3A4 and CYP2C19 into a family of hydroxylated products, and it inhibits several enzymes potently enough to have produced a documented clinical interaction with clobazam. On targets, THC is a CB1 and CB2 partial agonist while CBD is not meaningfully acting through those receptors, and most of the many alternative targets proposed for it do not survive systematic appraisal.

What a Careful Reader Should Take Away

Carry forward the enzyme assignments and the interaction implications, because those are well supported and directly actionable. Carry forward the finding that CBD’s mechanism remains genuinely unresolved. Leave behind any tidy table matching cannabinoids to hormones and neurotransmitters with assigned directions and dose thresholds, because that table describes a level of knowledge that the human literature does not support.

Evidence Interpretation Guide

Table of Contents

- [How to read mechanism literature without mistaking volume for evidence](#How_to_read_mechanism_literature_without_mistaking_volume_for_evidence)
- [THC and CBD Metabolism, Seen From Eight Angles](#THC_and_CBD_Metabolism_Seen_From_Eight_Angles)[CBD is the one more likely to affect your other medications](#CBD_is_the_one_more_likely_to_affect_your_other_medications)
- [Screen the medication list before high-dose CBD](#Screen_the_medication_list_before_high-dose_CBD)
- [Sixty-five targets is not a mechanism](#Sixty-five_targets_is_not_a_mechanism)
- [The human CBD pharmacokinetic base is thin](#The_human_CBD_pharmacokinetic_base_is_thin)
- [THC was mapped first, and more cleanly](#THC_was_mapped_first_and_more_cleanly)
- [What changes in a visit](#What_changes_in_a_visit)
- [What should be studied next](#What_should_be_studied_next)
- [Labeling treats two different drugs as one category](#Labeling_treats_two_different_drugs_as_one_category)
- [Frequently Asked Questions](#Frequently_Asked_Questions)[Related](#Related)

## How to read mechanism literature without mistaking volume for evidence

The Research QuestionWhich human enzymes metabolize THC and CBD, what do they produce, and which of the many proposed molecular targets for each compound survive scrutiny?The Patient QuestionAre THC and CBD basically the same thing with different effects, and which one is more likely to interfere with my medications?The Bottom LineThe enzyme mapping and the clobazam interaction are established. The receptor pharmacology of THC is established. The mechanism of CBD is not, and the size of its target literature is a symptom of that rather than evidence against it.
CED Perspective Lens

## THC and CBD Metabolism, Seen From Eight Angles

Two cannabinoids, two pathways, read through the lenses that matter in practice.

Lens OverviewTHC runs mainly through CYP2C9 to an active metabolite, CBD runs mainly through CYP3A4 and CYP2C19 to a family of hydroxylated products, and their molecular targets scarcely overlap.

#### CBD is the one more likely to affect your other medications

Most people arrive assuming THC is the risky compound and CBD is the gentle one. On drug interactions, the evidence points the other way. CBD is processed by two enzymes that also handle a long list of common prescriptions, and it slows several enzymes down.

The clearest example is a study in children taking both CBD and the seizure medicine clobazam, where levels of clobazam’s active metabolite rose roughly fivefold and most children needed a dose reduction.

Lens takeawayTell your prescriber about CBD by product and dose, particularly if you take several medications.

#### Screen the medication list before high-dose CBD

CYP3A4 and CYP2C19 substrates deserve a look before a patient starts a meaningful daily CBD dose, and clobazam specifically warrants level monitoring. CBD also inhibits several UDP-glucuronosyltransferases potently in vitro, which extends the concern to phase II substrates such as morphine.

For THC the more relevant variable is CYP2C9 function, whether genetic or from a co-administered inhibitor, because that determines how much parent drug survives first pass.

Lens takeawayCBD is a phase I and phase II perpetrator; THC is mostly a CYP2C9 victim.

#### Sixty-five targets is not a mechanism

When a systematic review of CBD’s molecular pharmacology found more than 65 reported targets, the sensible reading is not that CBD does 65 things. It is that high-concentration screening against many assays produces many hits, and that the field had not been disciplined about concentration plausibility or causal design.

After appraisal, a limited number remained credible, and they clustered around intracellular calcium handling rather than the endocannabinoid system.

Lens takeawayBreadth of reported targets is a warning sign about method, not a measure of pharmacological richness.

#### The human CBD pharmacokinetic base is thin

A systematic search retrieved 792 articles and found only 24 with human pharmacokinetic parameters, with discrepancies among them. Absolute oral bioavailability of CBD has never been measured in humans despite intravenous formulations existing.

Any argument that a proposed CBD target is reachable in vivo has to rest on concentration data that mostly do not exist. That is a serious constraint on mechanistic reasoning.

Lens takeawayClaims about what CBD reaches in tissue rest on pharmacokinetics nobody has fully measured.

#### THC was mapped first, and more cleanly

The THC pathway was described in the 1970s and quantified in the early 1980s, with a single dominant active metabolite and a clear terminal acid. That simplicity made the pharmacology tractable early.

CBD’s metabolism was not characterized in human liver microsomes until 2011, and the answer was eight hydroxylated products rather than one. The later start and the greater complexity together explain much of the current imbalance in evidence quality.

Lens takeawayCBD’s pathway was mapped three decades later and turned out to be considerably messier.

#### What changes in a visit

Three habits follow. Record cannabinoid products by compound, dose, and route rather than as a single line reading cannabis. Ask specifically about CBD when reviewing a medication list, since patients often do not consider it a medication. Reconsider mechanism explanations offered to patients, because for CBD there is no defensible one to offer.

For THC, the useful individualized variable is response to a test dose, since genotype testing has not been shown to improve outcomes.

Lens takeawayDocument the compound and dose; skip the mechanism story you cannot support.

#### What should be studied next

The most consequential missing study is an absolute oral bioavailability determination for CBD in humans, because nearly every mechanistic argument about reachable concentrations depends on it and it has never been done.

The second is prospective testing of whether CYP genotype information changes cannabinoid dosing outcomes. The pharmacogenomic associations exist; the clinical utility has not been demonstrated.

Lens takeawayMeasure CBD’s oral bioavailability, then test whether genotype-guided dosing helps.

#### Labeling treats two different drugs as one category

Products are regulated and labeled largely by total cannabinoid content, which groups compounds with distinct enzyme dependencies and distinct interaction risks under one heading. A patient reading a label has no way to know that the CBD figure carries more interaction relevance than the THC figure.

Prescription cannabidiol carries interaction warnings in its labeling. The same molecule sold as a supplement generally carries none, which is a regulatory inconsistency rather than a pharmacological one.

Lens takeawayThe same molecule carries interaction warnings as a prescription and none as a supplement.
Related Reading at CED ClinicContinue exploring the evidence[Does CBD Change How Your Body Handles THC? A New Meta-Analysis](https://cedclinic.com/cbd-thc-pharmacokinetic-interaction-meta-analysis/)

What happens when both compounds are taken together and compete for the same enzymes.

[Read the meta-analysis](https://cedclinic.com/cbd-thc-pharmacokinetic-interaction-meta-analysis/)[Cannabis and Drug Interactions: Recent Studies](https://cedclinic.com/cannabis-and-drug-interactions-recent-studies/)

The broader interaction picture for patients on multiple medications.

[Review the interactions](https://cedclinic.com/cannabis-and-drug-interactions-recent-studies/)[Running CBD and the Ketogenic Diet Together](https://cedclinic.com/cbd-and-ketogenic-diet-for-epilepsy-combination-study/)

A clinical setting where CBD’s enzyme interactions and dosing genuinely change management.

[See the epilepsy data](https://cedclinic.com/cbd-and-ketogenic-diet-for-epilepsy-combination-study/)[The Last Step of THC Metabolism: Glucuronidation](https://cedclinic.com/thc-glucuronidation-metabolism-excretion/)

Where both pathways converge, and the phase II enzymes that CBD inhibits most potently.

[Follow the pathway out](https://cedclinic.com/thc-glucuronidation-metabolism-excretion/)[What the Liver Does to an Edible Before You Feel Anything](https://cedclinic.com/11-hydroxy-thc-edibles-first-pass-metabolism/)

The CYP2C9 step in detail, and why route changes the metabolite ratio so dramatically.

[See the first-pass step](https://cedclinic.com/11-hydroxy-thc-edibles-first-pass-metabolism/)

Join the Conversation

Have a question about how this applies to your situation? [Ask Dr. Caplan](https://benjamincaplan.com/ask-dr-caplan)

Want to discuss this topic with other patients and caregivers? [Join the forum discussion](https://cedclinic.com/interact/discussion-forums/forum/cannabis-industry/)

## Frequently Asked Questions

Are THC and CBD metabolized by the same enzymes?

They overlap but differ in emphasis. THC is oxidized principally by CYP2C9 with a contribution from CYP3A4. Human liver microsome studies show CBD metabolized by seven different cytochrome P450 enzymes, with CYP3A4 and CYP2C19 doing most of the work. The practical consequence is that the two compounds carry different drug interaction profiles rather than a shared one.

What is the main active metabolite of THC?

11-hydroxy-THC. Microsomal hydroxylation converts THC into it, and it is psychoactive in its own right rather than an inert breakdown product. Liver alcohol dehydrogenase enzymes then oxidize it further to 11-nor-9-carboxy-THC, which is inactive and is the compound that urine drug screens detect after laboratory hydrolysis of its glucuronide conjugate.

What does the body turn CBD into?

A family of hydroxylated products rather than a single principal metabolite. Incubation with pooled human liver microsomes produced eight monohydroxylated metabolites, four of which predominated. CYP3A4 mainly formed 6-beta-hydroxy and 4-double-prime-hydroxy CBD, while CYP2C19 predominantly catalyzed formation of 7-hydroxy-CBD. This multiplicity is one reason CBD pharmacokinetics have been harder to characterize than those of THC.

Does CBD act on cannabinoid receptors?

Not in the way THC does. THC is a partial agonist at CB1 and CB2. CBD has low direct affinity for both, though it shows surprisingly high potency as an antagonist of their agonists in tissues expressing them. A systematic review of CBD’s molecular pharmacology concluded that CBD is very unlikely to exert its effects in neurological disease through the endocannabinoid system.

How many molecular targets does CBD have?

More than 65 have been reported, which is closer to a methodological problem than a finding. A 2015 systematic review appraised each one and excluded those demonstrated only at concentrations difficult to reach in the body and those supported by correlation rather than causal evidence. The plausible survivors clustered around regulation of and response to intracellular calcium, including voltage-dependent anion channel 1 and GPR55.

Does CBD interact with prescription medications?

Yes, and one interaction is well documented. In 13 children with refractory epilepsy taking clobazam, adding CBD raised clobazam levels by a mean of 60 percent and levels of the active metabolite norclobazam by a mean of 500 percent at four weeks. Ten of the 13 required a clobazam dose reduction. Review the medication list before a patient begins a substantial daily CBD dose.

Does genetics change how someone responds to THC?

It can. In 43 healthy volunteers given oral THC, people carrying two copies of the reduced-function CYP2C9*3 variant showed a median THC exposure three times higher than people with two normal-function copies, along with 70 percent lower exposure to the carboxy metabolite and a trend toward greater sedation. Whether genotype testing improves dosing decisions has not been tested in a trial.

Does THC raise dopamine?

The picture is time dependent rather than simple. A 2016 review in Nature described conflicting human and animal evidence and summarized the pattern as acute THC administration increasing dopamine release and neuron activity, while long-term use is associated with blunting of the dopamine system. Claims that THC straightforwardly raises dopamine describe only the acute half of that finding.

 

### Related

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### Verification & Medical Governance

- **Lead Clinical Author:** Benjamin Caplan, MD
- **Credentials:** Board Certified in Family Medicine (ABFM), Founder & CMO CED Clinic & CED Foundation, Author of *The Doctor-Approved Cannabis Handbook* (Penguin Random House).
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- **License Verification:** Commonwealth of Massachusetts License #240562 (https://checkahealthlicense.mass.gov/).
- **NPI Registry:** 1962722637 (https://npiregistry.cms.hhs.gov/provider-view/1962722637).
- **Ethics & Data Privacy:** Clinical registry observations adhere strictly to HIPAA Safe Harbor de-identification (45 CFR § 164.514(b)) and criteria for secondary research exemption under 45 CFR § 46.104(d)(4).