@colleenyoung 1) CBD affects liver enzymes (CYP450)

From the FDA summary of Epidiolex (prescription CBD):

From a pharmacology review:

> “CBD interacts with cytochrome P450 enzymes… including CYPs … 2D6 … and antagonizes CYP3A4.”

From a clinical study abstract:

> “CBD … is reported to inhibit the drug-metabolizing proteins … CYP3A4/5, … CYP2D6, … The relevance of CBD-drug interactions is largely unknown.”

2) Tramadol metabolism is affected by CYP inhibitors:

From tramadol’s FDA drug interaction information.

3) Sedation/additive CNS effects observed in drug interaction guides:

From a clinician drug interaction resource.

4) Quality context on CBD drug interaction potential.

From the government’s CBD ingredient-drug interaction guidance.

Below are verbatim excerpts from FDA-approved prescribing information (actual label PDFs) for both tramadol and Epidiolex (prescription CBD) that relate to drug interactions and metabolism. I’ve included page/section references as they appear in the official labels.

📄 1) Tramadol (Tramadol Hydrochloride) — FDA Label Quotes

Metabolism and CYP450 Interaction

> “In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1.”

This is from the “ULTRAM (tramadol hydrochloride) Tablets Full Prescribing Information” — it’s part of the formal drug interaction section of the label.

Effect of CYP2D6 & CYP3A4 Inhibitors on Tramadol:

> “Follow patients receiving ULTRAM and any CYP2D6 inhibitor for the risk of serious adverse events including seizures and serotonin syndrome… The concomitant use of ULTRAM with cytochrome P450 3A4 inhibitors … may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression.”

This is from an FDA label version that specifically describes clinical consequences of enzyme inhibition, including seizures and serotonin syndrome — the same risks tramadol warns about in its interaction section.

Summary of Tramadol Interaction Risk:

> “Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite M1.”

This quote is from a consolidated prescribing information reference and reinforces that drug metabolism pathways are clinically relevant.

📄 2) Epidiolex (Prescription Cannabidiol) — FDA Label Quotes

CBD as a CYP Substrate and Potential Inhibitor

> “Cannabidiol is a substrate for cytochrome p450 (CYP) enzymes CYP3A4 and CYP2C19. Cannabidiol has the potential to inhibit CYP2C8, CYP2C9, and CYP2C19 at clinically relevant concentrations. Cannabidiol may induce or inhibit CYP1A2 and CYP2B6 at clinically relevant concentrations.”

This is from the official Epidiolex label (FDA PDF) under the drug interaction section (usually section 7 of the label).

CBD Inhibition of UGT Enzymes:

> “Cannabidiol inhibits uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes UGT1A9 and UGT2B7…”

UGT enzymes are another set of liver enzymes that contribute to metabolism of many drugs — this shows CBD can affect multiple pathways.

In Vivo Interaction Example:

> “Coadministration with clobazam in healthy volunteers … increased the clobazam active metabolite, N-desmethylclobazam, Cmax and AUC by approximately 3-fold.”

This is the most clinically documented interaction noted in the Epidiolex label, showing how CBD can alter drug levels — in this case with clobazam — via enzyme effects.

What This Means (Directly From the Labels):

Tramadol’s label clearly states that:

Drugs that inhibit CYP2D6 or CYP3A4 can change tramadol levels and may increase risk of seizures, serotonin syndrome, and respiratory depression.

Epidiolex’s label clearly states that:

CBD is metabolized by CYP3A4 and CYP2C19 and can inhibit several CYP enzymes (CYP2C8, CYP2C9, CYP2C19, and possibly others like CYP1A2 and CYP2B6).

It also inhibits UGT1A9 and UGT2B7, which metabolize other drugs.

Taken together, the official FDA labels support the mechanistic basis for a potential drug interaction between CBD and drugs metabolized by the same enzymes — like tramadol — though labels don’t specifically test CBD with tramadol. However, because tramadol’s metabolism and CBD’s enzyme interactions involve overlapping enzyme pathways, they could theoretically alter each other’s metabolism.

@colleenyoung Early today I sent you a thorough, detailed, and comprehensive document covering a topic broadly and deeply, going beyond a simple summary to include wide-ranging data, deep analysis, and multiple perspectives, emphasizing depth of insight rather than just length, following steps like research, outlining, drafting, and revision. I saw where you were active a few times on the forum. I assume you read my response. Any thoughts or response on my reply? Please advise.