Ketamine Does Not Mimic or Block the Subjective Effects of THC or Morphine in Rats | Research

The takeaway

Rats trained to recognize THC or morphine did not perceive ketamine as producing similar effects, though combining ketamine with THC caused pronounced sedation.

Researchers studying drug interactions and clinicians managing patients who use both ketamine and cannabis.

Zero ketamine isoforms substituted for THC or morphine

What the researchers found

In drug discrimination tests, no form of ketamine (R-, S-, or racemic) substituted for the subjective effects of either morphine or THC. Ketamine also did not block the discriminative effects of either drug. However, all ketamine forms suppressed response rates when combined with THC, suggesting a sedative interaction.

Why it matters

Ketamine is increasingly used alongside opioids and cannabinoids in both clinical pain management and recreational settings. This study suggests ketamine does not produce cannabis-like or opioid-like subjective effects, but the sedative interaction with cannabinoids warrants attention.

The numbers in context

Ketamine tested at 5, 10, and 30 mg/kg in R-, S-, and racemic forms. Fentanyl (0.1 mg/kg) fully substituted for morphine. Rimonabant (0.32-3.2 mg/kg) partially blocked THC. No ketamine isoform achieved full substitution or blockade for either drug.

How the study worked

Rats were trained in a two-lever drug discrimination paradigm to distinguish morphine (6.4 mg/kg) or THC (3 mg/kg) from vehicle. Ketamine isoforms were then tested at 5, 10, and 30 mg/kg as substitutes for or blockers of the training drugs. Standard positive controls (fentanyl for morphine, rimonabant for THC) confirmed the assay was working.

What this study cannot tell us

Drug discrimination in rats measures subjective-like effects but cannot perfectly predict human experience. The doses used may not cover all clinically relevant scenarios. The sedation interaction was measured indirectly through response rate suppression.

How to read the evidence

Well-designed animal drug discrimination study with appropriate positive controls, but results may not directly translate to human subjective experience.

When this study was published

Published in 2025.

The bigger picture

As ketamine therapy expands for depression and chronic pain, and cannabis use increases broadly, understanding how these drugs interact becomes increasingly important for clinical safety and for understanding polydrug use patterns.

Questions still open

What drives the pronounced sedation when ketamine and THC are combined? Could this interaction be clinically relevant for patients receiving both compounds?

Common questions

What is a drug discrimination study?

Animals are trained to press one lever when given a specific drug and another when given placebo. Researchers then test whether other drugs produce similar enough effects that the animal "mistakes" them for the training drug.

Is it dangerous to combine ketamine and cannabis?

This study found the combination caused pronounced sedation in rats. While it does not prove danger in humans, the interaction suggests caution is warranted when using both substances together.

Read the original research

Effects of ketamine enantiomers on morphine and THC subjective effects in rats.

Journal of psychopharmacology (Oxford, England), 2698811251406839

View on PubMed ↗Publisher’s paper ↗

Citation

Malikowska-Racia, Natalia; Golebiowska, Joanna; Starowicz, Katarzyna; Zajdel, Pawel; Bisaga, Adam; Popik, Piotr. (2025). Effects of ketamine enantiomers on morphine and THC subjective effects in rats.. Journal of psychopharmacology (Oxford, England), 2698811251406839. https://doi.org/10.1177/02698811251406839