Article contributed by Dr. Erika Beerbower, PharmD

Psychedelic Drug Information Pharmacist

Dietary supplement use is more common than ever, with 57.6% of adults in the United States taking at least one supplement in 2017-2018 and supplement use is reported to increase with age [1].

Supplements may appear safer than prescription medications because they come from a natural source or are available without a prescription and the vast majority are unlikely to substantially change the benefits or risks of psychedelic use. However, some supplements may carry risks of drug interaction, particularly those that work to augment serotonin neurotransmission or raise monoamine neurotransmitters like serotonin, norepinephrine, and dopamine.

This post will discuss five supplements with serotonergic effects including St. John’s Wort, serotonin precursors (L-tryptophan/5-hydroxytryptophan), lithium orotate, methylene blue, and SAMe. We’ll focus on potential risks when combined with psychedelics as well as management strategies for safety.

St. John’s Wort

What is St. John’s Wort?

St. John’s Wort (Hypericum perforatum) containing hyperforin is a serotonergic herb that is effective for helping manage depressive symptoms, although notorious for potential drug interactions. These drug interactions could have several mechanisms due to both the actions of the herb in the Central Nervous System as well as its effects on metabolic liver enzymes.

What mechanisms of St. John’s Wort creates drug interactions with psychedelics?

Pharmacodynamics – Drug Interactions with Mechanism

While its exact mechanism is unclear it appears to potentiate the effects of monoamine neurotransmitters including serotonin, although may also have effects on norepinephrine or dopamine. For example, serotonin, dopamine and norepinephrine reuptake inhibition, affinity for several receptors including 5HT and GABA, effects on interleukin-6, as well as weak MAO-I inhibition have been described [2].

The potentiation of serotonin’s activity by St. John’s Wort may pose risks of intensified serotonergic side effects or even toxicity such as serotonin syndrome if combined with psychedelics. These risks are likely dose and agent dependent.

Classic psychedelics such as psilocybin, LSD, or DMT may not carry risks of severe toxicity due to their inability to significantly raise serotonin levels. If continuing St. John’s wort with psilocybin, LSD, or DMT, stopping the supplement on day of a psychedelic journey can be considered to provide the body a small break and decrease any potential overlapping side effects such as nausea and headache.26

However, serotonin releasing agents such as MDMA or MAOI containing psychedelics like ayahuasca may carry higher risks in combination. The half-life of hypericin and hyperforin is about 18 hours [3] and 5 days should be long enough to clear St. John’s wort from the body and avoid pharmacodynamic interactions prior to psychedelic use; however, depending on the intentions of the participant, the dosage, and the indication for use, a gradual taper can be considered. St. John’s wort can be restarted 24 hours (48 hours for MAOI) after the psychedelic journey.  

Pharmacokinetics – Drug Interactions with Metabolism

 St. John’s wort induces serval cytochrome P450 metabolic enzymes, including CYP3A4, CYP2C9 and CYP2C19, and the efflux transporter P-glycoprotein [4].  This means it can stimulate the liver to increase the number of enzymes available for metabolism which decreases concentrations of other drugs that are metabolized via those enzymes. This creates risks of subtherapeutic effects of interacting drugs due to increasing their metabolism. The amount of hyperforin contained in St. John’s Wort appears to play a role. For example, low doses of St. John’s wort (hyperforin content) below 1 mg [5] or 4 mg [6] daily are not subject to pharmacokinetic interactions described.

Concomitant use of St. John’s wort and oral ketamine decreased ketamine exposure by 58% and peak concentrations by 66% in one study[7]; the proposed mechanism is through St. John’s wort-mediated induction of CYP3A4, which is responsible for the metabolism of ketamine. Non-oral routes of ketamine administration are less likely to be significantly impacted by pharmacokinetic interactions [8]. LSD also likely utilizes CYP3A4 for metabolism [9] meaning decreased LSD exposure or a shortened duration of the experience with concomitant use of St. John’s wort is possible. This would likely be more significant if LSD was used orally.

How long should I avoid St. John’s Wort with Psychedelics?

Since metabolic enzyme induction is a genetic event involving upregulation of liver enzymes, it can take longer than the time of elimination for St. John’s Wort after discontinuation for metabolism to normalize. For example, enzyme induction by St. John’s wort has been reported to last anywhere from 1 week [10] to 3 weeks or longer [11]; therefore, an extended washout period prior to psychedelic use is necessary to avoid pharmacokinetic interactions. 2

What are the risks of mixing St. John’s Wort with Psychedelics?

Concomitant use of St. John’s wort with serotonin increasing psychedelics could result in symptoms of serotonin excess or serotonin syndrome (ranging from anxiety to pressured speech, eye movements, and tremor, and in more rare cases hyperthermia, hemodynamic instability, muscle rigidity, and delirium). 9 Possible serotonin syndrome has been reported with St. John’s wort when used in combination with other serotonin increasing agents such as SSRIs [12] and the serotonin agonist buspirone [13] in a few case reports2 however, one of these reports has been refuted [14] and others involved additional serotonergic or catecholamine increasing drugs. A true risk of serotonin syndrome with a single drug or supplement in combination with a psychedelic usually involves MAOI inhibition [15]; concomitant use of St. John’s wort should be avoided with MAOI-containing psychedelics such as ayahuasca. St. John’s wort in combination with ketamine may decrease the effects or shorten the duration of the experience; therefore, stopping St. John’s wort in advance may be advisable.

Take a deep dive into serotonin syndrome by reviewing our subject guide https://www.spiritpharmacist.com/blog/serotoninhealing

L-tryptophan and 5-hydroxytryptophan (5-HTP)

What are L-Tryptophan and 5-hydroxytryptohpane (5-HTP)?

L-tryptophan and 5-hydroxytrytophan (5-HTP) are supplements that act as precursors or building blocks for the neurotransmitter serotonin.

L-tryptophan is an essential amino acid which is converted via tryptophan hydroxylase to 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to serotonin (5-HT). The precursors are commonly used to ‘raise serotonin’ since they can readily cross the blood brain barrier while serotonin cannot. In persons with depleted serotonin levels or adequate levels of neurotransmitter precursors, dietary supplementation may help. However, most persons obtain adequate amounts from their diet, neurotransmitter synthesis is tightly regulated (raising precursor levels doesn’t increase serotonin synthesis unless the precursors are depleted at baseline), and the correlation between major depression and depleted peripheral tryptophan levels has not been strongly confirmed. For example, a systematic review of tryptophan and 5-HTP for depression showed a trend towards efficacy but was inconclusive [16]. 

What are the Risks of Mixing L-tryptophan or 5-HTP with Psychedelics?

Due to increased levels of serotonin, L-tryptophan and 5-HTP could increase the risk of serotonergic side effects or even serotonin toxicity with serotonin increasing psychedelics such as MDMA or ayahuasca. Since 5-HTP can cross the blood brain barrier without a transport molecule21 and it is a direct precursor to serotonin, it may result in a higher risk of serotonin syndrome compared with L-tryptophan supplementation. A search of literature did yield one case of serotonin syndrome that the authors attributed to 5HTP with an SSRI [17]; however, this case involved several supplements and at least 1 other suspect medication. Several cases of serotonin syndrome have been reported due to accidental 5-HTP overdose in dogs [18].

How Long should L-Tryptophan or 5-HTP be Avoided Prior to Psychedelic Use?

The half-life of 5-HTP has been reported to be approximately 6 hours [19]. Avoidance of L-tryptophan and 5-HTP for about 24 to 30 hours prior to serotonergic psychedelics and restarting the supplement 24 hours later will avoid the risk of serotonin syndrome [20].

How Could L-tryptophan or 5-HTP Support Recovery from MDMA Use?

Due to the serotonin releasing effects of MDMA and hypotheses that this mechanism contributes to ‘hangover’ like side effects of MDMA use, there is great interest in leveraging serotonin precursors to aid in recovery from its use. While we do not believe that to date there have been any studies in humans evaluating benefit of L-tryptophan or 5-HTP supplementation following MDMA in humans, some data exists in animals. In rodents, MDMA has been shown to deplete 5HT and inhibit tryptophan hydroxylase[21] [22], the rate limiting step in serotonin synthesis, and 5-HTP supplementation was shown to restore 5-HT depleted by MDMA in the brains of rats [23].

A common dosage for recovery after MDMA is L-tryptophan or 5-HTP  50 to 100mg daily for 5 to 7 days or 200 mg daily for 5 days starting 24 hours after MDMA. It is important to wait 24 hours after MDMA use, and to ensure further ingestion of MDMA will not occur concomitantly during the L-tryptophan or 5-HTP dosing period due to the risk of serotonin syndrome [24]. Higher doses of 5-HTP may increase the likelihood of nausea [21].

For a deeper dive on MDMA’s neurotoxic mechanisms check out this post https://www.spiritpharmacist.com/blog/is-mdma-neurotoxic

For a comprehensive discussion of supplements that may enhance recover from MDMA see this resource https://psychedelic.support/resources/supplements-to-reduce-side-effects-mdma/

Lithium Orotate

What is Lithium Orotate?

Lithium orotate is an over-the-counter version of the metallic element lithium, which is also available as a prescription medication used for the treatment of mania in bipolar disorder35 and depression. The dosing of lithium orotate (5 to 20 mg; equivalent to 27 to 107 mg lithium carbonate [25]) is much lower than prescription lithium carbonate (300 to 1200 mg daily [26]).

The mechanism of lithium carbonate for the treatment of mania is still relatively unknown; however, it may treat depression through effects on serotonin signaling [27]. Advocates of low-dose lithium cite possible neuroprotective effects that have been reported in areas where there is high lithium content in the food chain and water supply [28]. A survey study evaluating lithium supplements revealed reports of reduced anxiety and improved mood and cognition [29]. Some studies have suggested that the orotate salt acts as a “targeted delivery system” that transports lithium more effectively to the cell [30], enabling lower doses and fewer side effects [32].

What are the Risks of Mixing Lithium Orotate with Psychedelics?

Prescription doses of lithium carbonate for refractory depression or bipolar conditions are often considered contraindicated with serotonergic psychedelics due to being associated with an increased risk of seizures and dysphoric experiences [31]. A retrospective questionnaire study reported intensified effects with concomitant use of lithium and LSD [32]. Lithium orotate is unlikely to carry the same risk due to the low dosage of the supplement; however, in an abundance of caution, avoid use to reduce any risks of seizures or serotonin toxicity.

How Long to Lithium Orotate Prior to Psychedelic Use?

To mitigate any risk associated with lithium orotate, avoid 48-72 hours prior to serotonergic psychedelics such as psilocybin, LSD, and DMT, and 72-120 hours prior to MAOI-containing psychedelics such as ayahuasca. It is safe to restart 24 to 48 hours following psychedelic use.

For a detailed overview of lithium with psychedelics check out this post https://www.spiritpharmacist.com/blog/lithium-and-psychedelics

Methylene Blue and Natural MAOIs

What is Methylene Blue?

Methylene blue was synthesized in 1876 as a textile dye and is now given intravenously as a diagnostic dye or to treat certain medical conditions [33]. Methylene blue has recently gained popularity when taken orally for a variety of conditions, including cognitive enhancement, chronic fatigue, or for anti-aging properties. It is a potent and reversible inhibitor of MAO-A (RIMA) [34] which is responsible for breakdown for neurotransmitters norepinephrine, serotonin, and dopamine. Naturally occurring MAO-A inhibitors include the antioxidant quercetin and harmala alkaloids. Aside from the MAOI component in ayahuasca, harmala alkaloids have been utilized alone or to “boost” other psychedelics such as psylocibin.

What are the Risks of Mixing Methylene Blue with Psychedelics?

Inhibition of MAO-A by methylene blue will prevent the breakdown of serotonin when taken concomitantly with serotonin releasing psychedelics, leading to an increased risk of serotonin toxicity or serotonin syndrome. In the last decade, there have been several case reports of IV administered methylene blue-induced serotonin toxicity with other medications such as SSRIs [35] and one case with oral administration of methylene blue with several other serotonergic medications [36].  Harmala alkaloids additionally inhibit the liver enzyme CYP2D6 [37], which is partly responsible for the metabolism of agents such as MDMA and 5-MeO-DMT; thus, concomitant use may lead to increased levels of these psychedelics in the body. A case of serotonin syndrome was reported with a harmala alkaloid in combination with fluoxetine and quetiapine [38].

How Long should Methylene Blue be Avoided Prior to Psychedelic Use?

Due the reversibility of MAOI inhibition and short half-life of methylene blue (around 6 hours33), long washout times are not necessary. Avoid methylene blue and natural MAOIs 24 to 48 hours prior to serotonin increasing psychedelics (eg, MDMA, 5-MeO-DMT). It is safe to restart after greater than 5 half-lives of the psychedelic used (eg, at least 30 hours for MDMA).

S-Adenosyl Methionine (SamE)

What is SamE?

SamE is a methyl donor for plasma phospholipids and a required cofactor for the synthesis of monoamine neurotransmitters including norepinephrine, dopamine, and serotonin. SamE has shown efficacy for the treatment for depression [39], presumably due to increases in production of these neurotransmitters. SamE has also been investigated as an adjunctive therapy in combination with antidepressants [40], with some studies showing improvement in depression scores when SamE was added to SNRIs or SSRIs in patients with treatment resistant depression,[41] [42] while others have shown little benefit [43].

What are the Risks of Mixing SamE with Psychedelics?

Concomitant use of SamE with serotonin increasing psychedelics could result in symptoms of serotonin excess. Although SamE has been given in combination with antidepressants in studies for depression, there is still a theoretical risk of serotonin syndrome, especially with multiple serotonergic agents. Although cases appear to be rare, a literature search did yield one case of serotonin syndrome with SamE in combination with clomipramine [44]. Additionally, higher doses of SamE can cause gastrointestinal side effects such as nausea.

How Long should SAMe be Avoided Prior to Psychedelic Use?

The half-life of SamE is about 100 minutes [45], so avoidance of SamE 24 hours before and after serotonin increasing psychedelics may be reasonable to negate any possible risk of serotonin toxicity. Additionally, this short break from SamE should prevent any potential overlapping side effects with psychedelics that can cause gastrointestinal side effects, such as nausea.

High Notes

Concomitant use of selected supplements and psychedelics can pose significant risks that could affect safety or efficacy. Supplements are unregulated and can contain different blends of herbal ingredients with differing quantities of active compounds, even within the same type of supplement. The mechanism of action of some supplements is still unknown and clinical research is lacking. Therefore, a conservative approach with breaks may help reduce risks of harm. It is important to take all supplements into consideration with psychedelic use. Participants with complex prescription and supplement combinations may require a consultation prior to a psychedelic journey.

Get full access to a comprehensive discussion of supplements, herbs, and Over the Counter (OTC) drugs with psychedelics here https://www.spiritpharmacist.com/offers/GF3pjBie/checkout

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