Psychedelic Medicine Interactions: How to Analyze Conflicts for Purposes of Safety

Dr. Trina Nguyen | BSc Pharmacy, PharmD | dharmacisttrina@gmail.com

*This information is for educational purposes only. Please consult with your health care team for personalized medical advice*

There is a growing body of evidence demonstrating efficacy for the use of psychedelics for PTSD, anxiety, depression, etc. Haphazardly, many who would benefit from these alternative remedies are concurrently prescribed pharmaceuticals that are listed in the literature, as contraindicated.

Gauging the risk of potential drug interactions can be a challenge. There is no formal reporting body to gather data (as there are for pharmaceuticals), and when an interaction is reported, there are multiple confounding factors such as set and setting (a significant factor for a favourable outcome), as well as unfortunate biases in the literature that lead readers to assume harm where it may not be substantiated by evidence.

The current standard of care takes a conservative approach with a full wash-out period of psychoactive medications. However, based on what we know of pharmacokinetics and pharmacodynamics, some medications may be taken concurrently, or, the window of effective wash-out can be shorter.

In the real world, many are adamant in going ahead with self-experimentation, and a facilitated set and setting is preferred over unsupervised. Being a facilitator, our first priority is safety. This document is to offer guidance on how to navigate when a client is taking concurrent chronic medications and would like to work with you.

Included below is a chart of pharmacodynamic interactions with psychoactive agents, which cross-references types of pharmaceutical medications with a selection of psychedelics. Beyond that is a description of practical and conservative approaches to pharmaceutical wash-out, including specific examples of SSRIs and MAOIs. Lastly, a chart of pharmacokinetic interactions illustrates additional considerations when combining pharmaceutical medications and psychedelic medicines.

The growing excitement around the effectiveness of these medicines to treat persistent mental health issues must be tempered by an understanding of pharmacological interactions with pharmaceutical medications currently being prescribed to a large portion of the population. Thankfully, with medicinal contraindication analysis, we can know whether there is legitimate basis for concern and appropriate measures to be taken even in the cases where a contraindication is present. This practice will allow for the partnership between participant and practitioner to pursue a transformative experience while also ensuring set, setting, and safety.

Most Common Interaction — Muted Response

The most common interaction you as a guide will face will be an SSRI with psychedelics. Contrary to popular belief, which is that harm will result in the form of serotonin syndrome, studies have shown that when SSRIs are combined with MDMA, psilocybin or LSD, these antidepressants have consistently been shown to mute the response to the psychedelic¹-⁵. This interaction will be a challenge to the guide to provide a consistent experience. Below are two approaches that may be taken once informed consent has been given:

Flexible Approach

The flexible approach is to discuss with your client their compliance history to identify if they’ve missed doses in the past and if they experienced any significant withdrawal symptoms. If withdrawal symptoms are manageable, discuss holding the medication, which will reduce the binding competition between medication and psychedelic. One of the mechanisms of muted effect is that the SSRI binds more strongly to the receptor and does not allow the psychedelic to elicit its effect. If possible, the hold window should be at least one of the medications’ half-lives (refer to table 2). Pausing the medication for additional half-lives further decreases competition with the psychedelic, in theory increasing the chance of efficacy for the psychedelic, though this should be balanced against the effects of not taking the medication.

Example: Paroxetine (Paxil) half-life is 21 hours. If paroxetine is held for 21 hours, there will be 50% less of the medication available to block the psychedelic. A potential course of action is to ask the patient to hold the day’s dose before the journey as well as the morning dose the day of the journey (at least 21 hours). Paroxetine may be taken once the psychedelic effect has worn away.

Conservative Approach

If a conservative approach of a taper and wash-out period is more comfortable, the sitter should work with the client’s health care professional. For reference, described below is the protocol designed and employed by MAPS for their trials. In the trial, the investigators tapered off the participant’s prescription product as per an individualized plan, then held for at least five times the prescription drugs’ half-life, then lastly held an additional one week to monitor in case of discontinuation side effects.

Example: bupropion’s (Wellbutrin) half-life is 21 hours. Because of the serious risk of combining bupropion with ayahuasca, fully clearing the bupropion from the participant’s system ensures safety. Following the MAPS protocol, a tapering schedule is applied that was devised with the client’s health care professional, then a wash-out period of 5 days (equal to 5 half-lives) followed by 7 days for monitoring. Bupropion may be restarted once the ayahuasca has fully cleared from the body.

Potential Serious Interaction — Serotonin Syndrome

Also known as serotonin toxicity, serotonin syndrome results from excess serotonin in the brain synapses from two drugs that are serotonergically active. Serotonin syndrome symptoms may range from mild, non-specific adverse events such as confusion, agitation or restlessness, headache, nausea, vomiting, sweating and shivering, to more concerning events such as tremor, loss of muscle coordination or twitching, rapid heart rate and can be potentially fatal e.g. interaction SSRIs and ayahuasca.

Potential Serious Interaction — Pharmacokinetic Interactions

In addition to pharmacodynamic interactions, there are also pharmacokinetic interactions. The liver uses enzymes, known as the CYP450 system to metabolize and breakdown compounds in the blood. When we take psychedelics, pharmaceuticals, herbals, and even food, oftentimes we are activating this system to safely clear the chemicals from our bodies.

The most common pharmacokinetic interaction is when there is competition between a psychedelic and another molecule with the same enzyme, less breakdown leads to an increase of the psychedelic in the blood which may intensify the subjective effects, as well as prolong the effect, potentially leading to an accidental overdose.

Referencing the above table, the enzyme CYP2D6 is responsible for the breakdown of MDMA, ibogaine, and 5-MEO-DMT. Inhibition of CYP2D6 will result in increased levels of the aforementioned psychedelics in the blood. Examples of strong pharmaceutical inhibitors of CYP2D6 include paroxetine, bupropion, quinidine, cinacalcet, fluoxetine, and terbinafine. LSD inhibition is not a concern as it is broken down by multiple enzymes.

Study 1: MDMA with fluoxetine

MDMA in combination with fluoxetine (strong 2D6 inhibitor) leads to less breakdown of the MDMA, therefore, an extended duration of effect¹⁷.

Important note: If fluoxetine is taken chronically, the competing pharmacodynamic interaction overrides the pharmacokinetic effect and therefore results in a muted response¹.

see pharmacodynamic interactions table (table 1) for guidance

Study 2: Ibogaine with paroxetine

A study combining paroxetine (strong CYP2D6 inhibitor) with ibogaine demonstrated ibogaine-noribogaine exposure increased by approximately 2-fold¹⁹.

Unfortunately, assessing pharmacokinetic interactions is complicated and many factors come in to play such as the psychedelics’ method of consumption, if the metabolite is active or inactive, as well as the interplay between substrates, inducers and inhibitors.

Providing clear understanding of pharmacokinetic interactions is beyond this scope of this educational, however, as demonstrated by the examples above, it is important to identify if there is competition in the metabolism of the psychedelic, but there are additional factors that must be considered before changing therapy. If you want to perform the most rigorous analysis, you may cross-reference enzymes metabolized by your client’s current medications to the enzymes impacted by the psychedelic they are considering taking. Whenever there is a conflict, it is important to consider the potentially amplifying effects and provide informed consent to any potential participants whose medications may be contraindicated.

References

1. Bronson, Kit. “The Interactions between Hallucinogens and Antidepressants” Erowid.org, 3 October 1994, Erowid.org/chemicals/maois/maois_info4.shtml
2. Malcolm BJ. Antidepressants and 3,4-methylenedioxymethamphetamine (MDMA): Blunted Experiences & Mechanisms of Drug Interaction. Poster presented at the Los Angeles Psychedelic Science Symposium 2018: June 22nd; Los Angeles CA
3. Farre, M., et al., Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther, 2007. 323(3): p. 954–62.
4. Stein, D.J. and J. Rink, Effects of “Ecstasy” blocked by serotonin reuptake inhibitors. J Clin Psychiatry, 1999. 60(7): p. 485.
5. Hysek, C.M., et al., Duloxetine inhibits effects of MDMA (“ecstasy”) in vitro and in humans in a randomized placebo-controlled laboratory study. PLoS One, 2012. 7(5): p. E36476.
6. Erowid. “Erowid Experience Vaults.” Erowid.org. 19 December 2019 <https://www.erowid.org/experiences/exp.cgi?S1=0&S2=-1&C1=3&Str=>.
7. Schmid, Y., et al., Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects. J Pharmacol Exp Ther, 2015. 353(1): p. 102–11.
8. Vuori E, Henry J Ojanpera I, Nieminen R, Savolainen T, Wahlsten P et al. Death following ingestion of MDMA (ecstasy) and moclobemide. Addiction 2003;98(3):365–8.
9. Kaskey G. Possible interaction between an MAOI and ecstasy. Am J of Psychiatry 1992;149:411–2.
10. Bonson KR, Murphy DL. “Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium”. Behav Brain Res. 1996 Dec; 73(1–2):229–33.
11. Brush DE, Bird SB, Boyer EW. “Monoamine oxidase inhibitor poisoning resulting from Internet misinformation on illicit substances.’’ J Toxicol Clin Toxicol. 2004 Jun;42(2):191–5.
12. Shen, H. W., Jiang, X. L., Winter, J. C., & Yu, A. (2010). Psychedelic 5-methoxy-N,N-dimethyltryptamine: Metabolism, pharmacokinetics, drug interactions, and pharmacological actions. Current Drug Metabolism, 11(8), 659–66.
13. Fisher D, Ungerleider J. “Grand mal seizures following ingestion of LSD.” Calif Med. 1967 Mar; 106(3): 210–11.
14. Brown M. “Interactions Between LSD and Antidepressants”. Erowid.org. Oct 16 2003. Erowid.org/chemicals/lsd/lsd_health3.shtml
15. Erowid. “Interactions Between MAOIs, SSRIs, and Recreational Drugs.” Erowid.org. 14 January 2020. Erowid.org/chemicals/maois/maois_info8.shtml
16. RXList. “Wellbutrin” RXList.com. 14 January 2020. Rxlist.com/wellbutrin-drug.htm#side_effects
17. Gilman, K., Monoamine oxidase inhibitors: A review concerning dietary tyramine and drug interactions. PsychoTropical Commentaries, 2017. 1(1): p. 105
18. Upreti, Vijay V., and Natalie D. Eddington. “Fluoxetine pretreatment effects pharmacokinetics of 3,4‐methylenedioxymethamphetamine (MDMA, ECSTASY ) in rat.” Journal of Pharmaceutical Science 97.4 (2008): 1593–1605.
19. Glue P, WInter H. “Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers”. The Journal of Clinical Pharmacology. 2015;55(6):680–8