THC and CBD May Increase Methylphenidate Levels Through a Shared Liver Enzyme | Research

The takeaway

Pharmacokinetic modeling predicted that THC from smoking cannabis could increase methylphenidate (Ritalin) blood levels by 34%, while prescription CBD doses could increase it by up to 94%, through inhibition of the CES1 liver enzyme.

Prescribers of ADHD medications; pharmacologists; patients taking methylphenidate who also use cannabis or CBD.

Predicted 34% MPH increase from THC, up to 55% from multiple CBD doses

What the researchers found

Both THC and CBD reversibly inhibited the CES1 enzyme that metabolizes methylphenidate. Static models predicted THC from a cannabis cigarette could increase MPH exposure by 34%. Multiple daily CBD doses (10 mg/kg twice daily) could increase MPH exposure by up to 55% and peak concentration by 45%.

Why it matters

Many people with ADHD use cannabis, and CBD is increasingly being explored for ADHD symptoms. If cannabinoids increase methylphenidate blood levels, this could lead to unexpected side effects or altered medication efficacy in a large patient population.

The numbers in context

THC unbound Ki: 0.031 mcM. CBD unbound Ki: 0.091 mcM. Static model: 34% MPH increase from smoked THC, 94% increase from prescription CBD. PBPK model: up to 55% AUC and 45% Cmax increase with multiple CBD doses. Single CBD doses showed no significant interaction.

How the study worked

In vitro inhibition studies using human liver S9 fractions to measure THC and CBD inhibition of CES1-mediated methylphenidate hydrolysis. Results were incorporated into static and physiologically-based pharmacokinetic (PBPK) models to predict clinical interaction significance.

What this study cannot tell us

Predictions are based on in vitro data and mathematical modeling, not clinical studies in humans. Actual interactions could be larger or smaller depending on individual variation, food effects, and other concurrent medications. The models assume specific cannabinoid exposure levels.

How to read the evidence

Preliminary: in vitro and modeling study that has not been confirmed in human clinical trials.

When this study was published

Published in 2022.

The bigger picture

This is the first study to identify CES1 as a mechanism for cannabinoid-methylphenidate interactions. Given overlapping use of these substances (especially in adolescents and young adults), even mild pharmacokinetic interactions could have clinical relevance at the population level.

Questions still open

Would a clinical pharmacokinetic study confirm the predicted interaction magnitudes? Should ADHD patients on methylphenidate be cautioned about cannabis use? Is CES1 inhibition also relevant for other ester-containing medications?

Common questions

Can cannabis affect ADHD medication?

This modeling study predicted that THC from cannabis smoking could increase methylphenidate blood levels by about 34%, and high-dose prescription CBD by more than 50%. These predictions have not been confirmed in human studies but suggest a potential interaction worth monitoring.

Is it safe to take CBD with Ritalin?

This study predicts a mild interaction, especially with repeated high-dose CBD. Single doses of CBD are unlikely to cause significant changes. Until human studies confirm these predictions, patients should inform their prescribers about any CBD or cannabis use.

Read the original research

Prediction of Carboxylesterase 1-mediated In Vivo Drug Interaction between Methylphenidate and Cannabinoids using Static and Physiologically Based Pharmacokinetic Models.

Drug metabolism and disposition: the biological fate of chemicals, 50(7), 968-979

View on PubMed ↗Publisher’s paper ↗

Citation

Qian, Yuli; Markowitz, John S. (2022). Prediction of Carboxylesterase 1-mediated In Vivo Drug Interaction between Methylphenidate and Cannabinoids using Static and Physiologically Based Pharmacokinetic Models.. Drug metabolism and disposition: the biological fate of chemicals, 50(7), 968-979. https://doi.org/10.1124/dmd.121.000823