Does CBD affect the potency of LSD?

A microdose of psychedelic drugs, such as psilocybin mushrooms and even LSD, has become accepted as a clinical tool. Currently, however, the source of the full therapeutic reward has eluded scientific discovery. LSD possibly depends on its ability to unlock two signals to induce a mind-altering experience. So, what if there was a way to hijack a potent psychedelic drug like LSD in a way that eliminates the hallucinogenic experience while preserving its antidepressant benefits? The answer might lie in CBD, which can affect the potency of LSD.

Psychedelic signals

Our bodies are filled with tiny ports, called receptors. They accept neurotransmitters, such as serotonin, and drugs like opioids and LSD. Compounds rely on their physical shape to bind to a receptor. The classic metaphor says that a key (the drug) opens a lock (the receptor). The real world is, however, more complex than a simple philosophy. Some receptors have multiple openings and a drug must fit into the correct one to fully activate the receptor.

A limited number of entrances into serotonin receptors, for example, will grant certain drugs full access to their pharmacology. Psychedelic molecules induce a profound suite of effects when they reach deep inside a special target site known as the 5-HT2a receptor. There, the drug can bind with proteins that induce a mind-altering experience. Otherwise, a drug can sit partially inside an opening, which will narrow the outcome.

A loose fit does not mean the molecule is entirely neutral. 5-HT2a agonists can activate two different outcomes. We understand that the secondary signaling pathway potentially helps prime brain maps. (1) Whereas, the primary signal turns on drug-induced psychedelic states, according to theories presented in the literature. The idea is that you can hijack 5-HT2a receptors with CBD and keep the primary on-switch out of LSD’s reach, lowerings its potency. (2)

What is a modulator?

Correctly dosing psychedelics to ensure the outcome will deliver a sub-hallucinogenic experience comes with psychiatric risk. Scientists, inventors, and drug developers hope that one solution lies in a common ingredient found in cannabis. CBD (cannabidiol) interferes with the serotonin-2a receptor. The cannabinoid effectively sits inside the receptor in a position that prevents access to the primary signal. Larger agonists, therefore, exclusively activate the secondary signal in the presence of CBD.

The discovery comes from a study on rat neurons and human kidney cells by an international team of researchers. (2) LSD taken in combination with the cannabinoid appears to induce physiological effects without turning on the psychedelic experience. Co-administration of the two drugs can only activate one of the two signals, thus creating a non-intoxicating outcome — a pseudodelic.

Under the parameters of the study, the cannabinoid blocks the mind-altering effects of LSD at a cellular level. The results suggest that CBD negatively modulates the serotonin-2a receptor, although it does so selectively. The cannabinoid abolishes activity through both signals for drugs with a smaller molecular structure, such as psilocin and 5-MEO-DMT.

Psychedelia and therapy

Preclinical research does not always relate to real-world results. As an example, CBD produces a similar modulating effect on the cannabinoid 1 receptor in cellular assays. This implies it can stunt the intoxicating effects of THC, although the dose and consumption form are critical. (3) Large doses of oral CBD proved to increase the potency of THC in one Randomized Clinical Trial. This is largely due to the polypharmacy of the cannabinoid. (4) The interaction of CBD at cannabinoid receptors shows us how early preclinical results are not a guide for the real world.

CBD possesses a significant efficacy selectively towards the serotonin receptor known for provoking a large part of the experience induced by LSD. The cannabinoid clearly acts as a negative allosteric modulator of the 5-HT2a site. This implies that CBD might turn potent hallucinogenic compounds into pseudodelic therapies.

Unfortunately, though, the study could not replicate significant antidepressant effects. (2) While the results showed potential for CBD in future studies through its ability to block a signal induced by LSD. The team of Canadian and Italian scientists could not prove that co-administration with CBD will retain the therapeutic outcome reported after clinical psychedelic-assisted therapy. The paper concluded,

Our present results open the possibility that CBD antipsychotic effect is at least partly relying on its negative allosteric modulation of 5-HT2A, and we encourage further clinical investigation.

The science

Researchers scanned Human Embryonic Kidney cells after exposure to combinations of LSD and CBD. They also tested primary cortical neurons derived from rat specimens. Results published in Billard et al. reveal that lisuride is a Beta-Arrestin-biased agonist that does not produce hallucinogenesis. Other compounds analyzed in the study included, psilocin, serotonin, 5-MEO DMT, and 2-bromo-LSD (BRL). Like lisuride, the latter is also a non-psychedelic agonist of the 5-HT2a receptor with a bias for beta-arrestin. CBD stunted Gq signaling when given in combination with LSD or (2,5-dimethoxy-4-iodoamphetamine) DOI without affecting beta-arrestin recruitment. 

The study further used a special subset of Molecular Dynamics simulations to test CBD against the fatty acid, oleamide, a known positive allosteric modulator of the 5-HT2a receptor. Following co-administration with LSD, the cannabinoid lowered the production of DAG in HEK downstream of 5-HT2a modulation. Contrary to results on embryonic cells, CBD did not affect endocannabinoid synthesis in rat neurons simultaneously exposed to LSD.

Sources

1. Rudy LM, Godlewski MM. Molecular Pathways Potentially Involved in Hallucinatory Experiences During Sleep Paralysis: The Emerging Role of β-Arrestin-2. Int J Mol Sci. 2025;26(15):7233. Published 2025 Jul 26. doi:10.3390/ijms26157233

2. Billard E, Torbey A, Inserra A, et al.

   Pharmacological characterization of cannabidiol as a negative allosteric modulator of the 5-HT2A receptor. Cell Signal. 2025;127:111588. doi:10.1016/j.cellsig.2025.111588

3. Solowij N, Broyd S, Greenwood LM, et al. A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects. Eur Arch Psychiatry Clin Neurosci. 2019;269(1):17-35. doi:10.1007/s00406-019-00978-2

4. Zamarripa CA, Spindle TR, Surujunarain R, et al. Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial. JAMA Netw Open. 2023;6(2):e2254752. Published 2023 Feb 1. doi:10.1001/jamanetworkopen.2022.54752