When psychedelics meet prescribed drugs

As you know, I like to read nonfiction. I should, however, be reading more fiction as doing so has been shown to increase cognitive abilities.1 Nevertheless, my favourite mindfulness advocate recommended that I should read “Trippy, The Peril and Promise of Medicinal Psychedelics” by Ernesto Londono. I was hoping this book would focus more on therapeutics; instead it was a well-written collection of psychedelic experiences from various people. So, I just saved you $40. (You’re welcome.) Naturally, reading the book piqued my interest in this emerging therapeutic medical practice. And as a pharmacist, the first thing I thought about was drug interactions. And off I went—so this blog will discuss the drug interactions with psychedelics. When someone mentions psychedelics, they are usually referring to the classic psychedelics that are primarily agonists (or partial agonists) on brain serotonin 5-hydroxytryptamine (5-HT) 2A receptors. These include LSD (lysergic acid diethylamide), psilocybin (mushrooms), Ayahuasca (DMT) and mescaline (Peyote).2 These are different from the non-classical psychedelics like MDMA (3,4-Methylenedioxymethamphetamine) and ketamine. A recent survey suggests that 2% of Canadian adults reported hallucinogen/psychedelic use in 2019,3 and it is believed that this number has increased since then. The demographics of users are not what I expected. In one survey, the mean age was 38 years and 56% female.4 This survey also did note that the most common uses were for fun, self-exploration and personal growth. However there is more recent interest in the therapeutic use for psychedelics, such as LSD in the treatment of alcoholism,5 MDMA as a treatment option for PTSD6 and psilocybin to help treat depression.7 There is actually quite a bit of data about drug interactions and psychedelics8 both from small clinical studies and case reports. While the depth of information is interesting, it is beyond the scope of this web article. But I shall generalize the primary interactions I’ve found below. If you wish to learn more detail I suggest reading Drug-drug interactions involving classic psychedelics: A systematic review.8 The rather troubling thing about these interactions is that reporting was not consistent. One free general public drug interaction website reported drug interactions with LSD but not psilocybin. Ironically, the opposite was reported by Lexi-interact. This inconsistency of information might give the general public the idea that these psychedelics might not affect their prescription medications. Psychedelic/Rx interactions in generalGenerally, there are two types of drug interactions: pharmacokinetic and pharmacodynamic. There is sparse data on the pharmacokinetic interactions with psychedelics and prescription medications. It is known that LSD is metabolized by several CYP450 enzymes in possibly other hallucinogenic LSD metabolites.9 Psilocybin is metabolized by hepatic phase II glucuronidation (conjugation) through UGT 1A10 and UGT 1A9 enzymes.10 It must be metabolized into its active form of psilocin in the acidic environment of the stomach. But this metabolism can also occur by alkaline phosphatase in the intestine. This is why therapeutically psilocybin is given on an empty stomach.Now we come to the interactions with MAO inhibitors. MAOI have been shown to attenuate or block the effects of LSD.8 DMT in Ayahuasca is rapidly metabolized by MAOI, which is why vine Banisteriopsis caapi is used in the Ayahuasca brew. The vine contains β-carbolines, which have MAOI properties11.There was little data to suggest that these above pharmacokinetic interactions led to clinically significant therapeutic concerns. However, it was suggested that if medications that influence CYP450 (ie. fluoxetine) were started or stopped, this might alter expectations of future hallucinogenic experiences based on prior experiences. Most practitioners know to thoroughly evaluate potential drug interactions when MAOIs are involved, as demonstrated by a case report of hypertensive crisis when combining Psilocybin mushrooms, tranylcypromine and dextroamphetamine-amphetamine12. The above-mentioned systematic review article of psychedelic and prescription use found that prescription medications tended to subjectively reduce the expected effects of psychedelics.8 This finding was consistent with all medications that had 5-HT2a or 1a or D2 receptor antagonism (risperidone, trazodone, buspirone, SSRIs etc). This led authors to caution that if these medications were changed or removed prior to subsequent psychedelic use it might lead to an unexpected therapeutic response. One older study found that high-dose niacin use delayed onset of LSD and prevented perceptual changes.13 TCAs (desipramine, imipramine and clomipramine) were shown to increase the psychological effects of LSD. Lithium has been shown to potentiate and cause an earlier onset of LSD effects. There is also some information regarding drug-drug interactions with MDMA. This information is primarily provided by the U.S. department of Veterans Affairs, as MDMA has promising potential in the treatment of PTSD. One article stated that MDMA did not have significant interactions with adrenergic agents (carvedilol, pindolol, clonidine and doxazosin).14 The beta-blockers reduced the MDMA-induced increases in heart rate. As with other psychedelics, SSRI/SNRIs tended to attenuate the effects of MDMA. But epidemiological or post-marketing surveillance of recreational ecstasy (MDMA) from the US FDA Adverse Event reporting system provides a stark contrast,15 finding that there were greater odds of mortality with concurrent use of MDMA and bupropion, citalopram, sertraline, venlafaxine and olanzapine. The highest risk of death from concurrent use was metoclopramide (11 out of 11 reports). It was thought that this was due to metoclopramide proarrhythmic effects, since MDMA is a CYP2D6 inhibitor and metoclopramide is a CYP2D6 substrate. The authors of both of the above-mentioned reports noted that these adverse reactions might not be applicable to a more controlled therapeutic setting. Admittedly, this is a very brief look at the potential drug-drug interactions between prescription medications and psychedelics. What my research clearly found was the demonstrated lack of consistency in the available information on this emerging subject. Practitioners and users might do a quick drug interaction check and not see any listed interactions and think these drugs are safe to use together. This is another instance where the pharmacist is ideally suitable to provide greater context to questions about their use. The references provided should give pharmacists a starting point for providing detail information on safety and potential therapeutic implications. It should also be noted that patients who have undergone psychedelic therapy self-reported reduced use of both prescription and non-prescription medications.16The author would like to thank Philippe Lucas, PhD for his expertise and contributions towards the preparation of this articleReferences: Wimmer L, Currie G, Friend S, Wittwer J, Ferguson HJ. Cognitive effects and correlates of reading fiction: Two preregistered multilevel meta-analyses. J Exp Psychol Gen. 2024 Jun;153(6):1464-1488. doi: 10.1037/xge0001583. Epub 2024 Apr 11. PMID: 38602788.Nichols DE. Psychedelics. Pharmacol Rev. 2016 Apr;68(2):264-355. doi: 10.1124/pr.115.011478. Erratum in: Pharmacol Rev. 2016 Apr;68(2):356. doi: 10.1124/pr.114.011478err. PMID: 26841800; PMCID: PMC4813425.Glynos NG, Kruger DJ, Kolbman N, Boehnke K, Lucas P. The Relationship Between Naturalistic Psychedelic Use and Clinical Care in Canada. J Psychoactive Drugs. 2023 Nov-Dec;55(5):660-671. doi: 10.1080/02791072.2023.2242353. Epub 2023 Jul 29. PMID: 37516904.Stephanie Lake and Philippe Lucas, The Canadian Psychedelic Survey: Characteristics, Patterns of Use, and Access in a Large Sample of People Who Use Psychedelic Drugs. Psychedelic Medicine, Vol 1 (2). Published Online: 14 June 2023. https://doi.org/10.1089/psymed.2023.0002Krebs TS, Johansen PØ. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol. 2012 Jul;26(7):994-1002. doi: 10.1177/0269881112439253. Epub 2012 Mar 8. PMID: 22406913.van der Kolk BA, Wang JB, Yehuda R, Bedrosian L, Coker AR, Harrison C, Mithoefer M, Yazar-Klosinki B, Emerson A, Doblin R. Effects of MDMA-assisted therapy for PTSD on self-experience. PLoS One. 2024 Jan 10;19(1):e0295926. doi: 10.1371/journal.pone.0295926. PMID: 38198456; PMCID: PMC10781106.Sloshower J, Zeifman RJ, Guss J, Krause R, Safi-Aghdam H, Pathania S, Pittman B, D'Souza DC. Psychological flexibility as a mechanism of change in psilocybin-assisted therapy for major depression: results from an exploratory placebo-controlled trial. Sci Rep. 2024 Apr 17;14(1):8833. doi: 10.1038/s41598-024-58318-x. PMID: 38632313; PMCID: PMC11024097.Halman A, Kong G, Sarris J, Perkins D. Drug-drug interactions involving classic psychedelics: A systematic review. J Psychopharmacol. 2024 Jan;38(1):3-18. doi: 10.1177/02698811231211219. Epub 2023 Nov 20. PMID: 37982394; PMCID: PMC10851641.Luethi D, Hoener MC, Krähenbühl S, Liechti ME, Duthaler U. Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use. Biochem Pharmacol. 2019 Jun;164:129-138. doi: 10.1016/j.bcp.2019.04.013. Epub 2019 Apr 11. PMID: 30981875.MacCallum CA, Lo LA, Pistawka CA, Deol JK. Therapeutic use of psilocybin: Practical considerations for dosing and administration. Front Psychiatry. 2022 Dec 1;13:1040217. doi: 10.3389/fpsyt.2022.1040217. PMID: 36532184; PMCID: PMC9751063.Rossi GN, Guerra LTL, Baker GB, Dursun SM, Saiz JCB, Hallak JEC, Dos Santos RG. Molecular Pathways of the Therapeutic Effects of Ayahuasca, a Botanical Psychedelic and Potential Rapid-Acting Antidepressant. Biomolecules. 2022 Nov 2;12(11):1618. doi: 10.3390/biom12111618. PMID: 36358968; PMCID: PMC9687782.Barnett BS, Koons CJ, Van den Eynde V, Gillman PK, Bodkin JA. Hypertensive Emergency Secondary to Combining Psilocybin Mushrooms, Extended Release Dextroamphetamine-Amphetamine, and Tranylcypromine. J Psychoactive Drugs. 2024 Jun 21:1-7. doi: 10.1080/02791072.2024.2368617. Epub ahead of print. PMID: 38903003.Agnew N, Hoffer A. Nicotinic acid modified lysergic acid diethylamide psychosis. J Ment Sci. 1955 Jan;101(422):12-27. doi: 10.1192/bjp.101.422.12. PMID: 14368207.Sarparast A, Thomas K, Malcolm B, Stauffer CS. Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review. Psychopharmacology (Berl). 2022 Jun;239(6):1945-1976. doi: 10.1007/s00213-022-06083-y. Epub 2022 Mar 7. PMID: 35253070; PMCID: PMC9177763.Cohen, I.V., Makunts, T., Abagyan, R. et al. Concomitant drugs associated with increased mortality for MDMA users reported in a drug safety surveillance database. Sci Rep 11, 5997 (2021). Glynos NG, Aday JS, Kruger D, Boehnke KF, Lake S, Lucas P. Psychedelic substitution: altered substance use patterns following psychedelic use in a global survey. Front Psychiatry. 2024 Feb 22;15:1349565. doi: 10.3389/fpsyt.2024.1349565. PMID: 38455520; PMCID: PMC10917882.