Hypertensive Emergency Secondary to Combining Psilocybin Mushrooms, Extended Release Dextroamphetamine-Amphetamine, and Tranylcypromine

ABSTRACT

Data on medication interactions with psychedelics are limited. Here we present what may be the first published report of a hypertensive emergency following the combination of psilocybin mushrooms with a monoamine oxidase inhibitor (MAOI). A 42-year-old man with treatment-resistant major depressive disorder took 1 g of Psilocybe cubensis mushrooms, while prescribed tranylcypromine, extended-release dextroamphetamine-amphetamine, and other medications. Approximately half an hour later, he developed severe hypertension with chest pain, palpitations, and headache. Upon hospital presentation, the electrocardiogram demonstrated ST-elevation. The patient was diagnosed with a myocardial infarction and treated with lorazepam, nitroglycerin, and aspirin. He subsequently underwent emergency cardiac catheterization, which revealed no significant cardiac abnormalities. Following overnight hospitalization, he was discharged home with no lasting physical sequelae. Though data are few, past studies suggest that classic serotonergic psychedelics (5HT-2A receptor agonists) such as dimethyltryptamine (DMT), lysergic acid (LSD), and synthetic psilocybin should not produce hypertensive emergency when combined with MAOIs. We suspect phenylethylamine, found in Psilocybe cubensis and other species of psilocybin mushrooms, interacted with tranylcypromine and dextroamphetamine-amphetamine to produce this hypertensive emergency. Patients prescribed MAOIs should be warned of the potential for hypertensive emergency when consuming psilocybin mushrooms, particularly when also prescribed norepinephrine releasers such as dextroamphetamine-amphetamine.

KEYWORDS:

• Psilocybin
• psychedelic
• MAOI
• tranylcypromine

Introduction

Psychedelic use in the United States (US) is growing amid relaxed legal restrictions on psychedelic possession in multiple jurisdictions and prominent media coverage of clinical trials investigating potential therapeutic effects of these drugs (National Institute on Drug Abuse 2022). Although there is accumulating evidence for the efficacy of psychedelic-assisted therapy in the treatment of posttraumatic stress disorder, depression, and other psychiatric conditions, psychedelics have not been approved by the US Food and Drug Administration for treatment of any condition (Reiff et al. 2020). Still, patients may seek to self-treat mental health conditions with psychedelics. A 2023 study found that lysergic acid diethylamide (LSD) use in the US has increased disproportionately in recent years among people with depression, suggesting self-medication may be an important driver of growing psychedelic use (Walsh et al. 2023). As a result, psychiatrists may increasingly encounter adverse events related to patients combining psychedelics with psychiatric medications. For example, recent observational research indicates lithium may pose a seizure risk in combination with psychedelics (Nayak et al. 2021). Unfortunately, due to the Schedule 1 legal status of psychedelics in the US, psychiatrists have limited information on psychedelic-related medication interactions to guide harm reduction interventions.

Here we report the case of a patient prescribed tranylcypromine and extended-release dextroamphetamine-amphetamine who experienced a hypertensive emergency and ST-elevation myocardial infarction soon after consuming Psilocybe cubensis mushrooms.

Case report

The patient was a 42-year-old man with attention-deficit/hyperactivity disorder, borderline personality disorder, generalized anxiety disorder, treatment resistant major depressive disorder, traumatic brain injury, obstructive sleep apnea, hyperlipidemia, gastroesophageal reflux disease, hypogonadism, chronic pain, obesity, essential tremor, and type II diabetes. He reported rare alcohol and marijuana use with no history of substance use disorder. He provided written informed consent for publication of this report.

The patient’s first use of psilocybin consisted of 3 g of dried mushrooms (species unknown) given to him by a close friend, which he took with the intention of improving his depression. At that time, he was taking phenelzine 45 mg twice daily and nortriptyline 100 mg nightly, atorvastatin 80 mg daily, fenofibrate 160 mg daily, glipizide 10 mg twice daily, liraglutide 0.6 mg subcutaneously daily, metformin 500 mg twice daily, omeprazole 40 mg daily, propranolol 20 mg three times daily, valproate extended release 2000 mg nightly, zolpidem 10 mg nightly, and elemental lithium 20 mg twice daily (over the counter). He did not inform his psychiatrist about his plans to use psilocybin mushrooms. Notably, he experienced no psychoactive effects from these mushrooms, though his friend had reported psychedelic experiences when taking other mushrooms from the same batch. Despite the lack of psychoactive effects, the patient described the next 3 or 4 days as the “best [he has] ever had” mental health wise. His family noticed this as well, and a colleague at work, whom the patient had known for several months, commented that during this short period it was the first time he had seen the patient laugh. Memories of this positive mood experience would lead the patient to try psilocybin mushrooms again approximately 2 months later.

Two weeks prior to his second episode of psilocybin mushroom use, the patient was started on tranylcypromine 10 mg twice daily for depression following a two-day washout period from phenelzine 45 mg twice daily. Nortriptyline 50 mg daily/100 mg nightly was also stopped at that time. Tranylcypromine was titrated up to 20 mg twice daily over 2 weeks and was well tolerated, though the patient’s depression was largely unchanged. Three days prior to the second episode of psilocybin mushroom use, extended-release dextroamphetamine-amphetamine 20 mg daily was initiated. The patient later reported that he had searched online for information about the safety of combining psilocybin mushrooms with tranylcypromine but could not find any. Again, he did not inform his psychiatrist of his plans to use psilocybin mushrooms. He was aware of the higher risk of hypertensive emergency with tranylcypromine compared to phenelzine (Blackwell et al. 1967; Brown, Taniguchi, and Yip 1989), so he took what he thought was a cautious approach, consuming only 1 g of dried “Golden Teacher” mushrooms (Psilocybe cubensis) he had grown himself. He estimated these mushrooms were approximately 3-months old at consumption. One week prior to using the mushrooms (and 4 days before he started the extended-release dextroamphetamine-amphetamine), the patient’s blood pressure was 122/82 mmHg.

On the day of the incident, the patient took his morning medications and consumed the mushrooms in the early afternoon. He denied eating any foods known to have risk for elevated tyramine content that day. At that time, he had approximately 1 year of experience maintaining monoamine oxidase inhibitor (MAOI) dietary restrictions (in addition to previously being prescribed phenelzine, he had also been prescribed selegiline), and he had never had an MAOI-related hypertensive episode. Within half an hour of ingesting the mushrooms, he began experiencing 10/10 (10 being most severe) intense chest pain radiating to the jaw, palpitations, and severe headache. Using his automated blood pressure cuff, the patient obtained a blood pressure reading of 200/160 mmHg. After several minutes, his blood pressure cuff could no longer register a reading. Soon after, he asked his wife to drive him to the hospital. Along the way they were stopped by a police officer due to speeding. After being informed of the situation, the officer radioed a nearby ambulance. Upon arrival, paramedics manually obtained a blood pressure in the “230s/100s” according to emergency department documentation. It is unclear whether paramedics administered any medications.

The patient arrived at the emergency department approximately 1 hour after symptom onset. Upon arrival, he reported chest pain, abdominal pain, nausea, and headache. He was diaphoretic and appeared to be in distress. Vital signs were as follows: temperature of 96.6 F, heart rate 56 bpm, respiration of 22 per minute, SpO2 99%, and blood pressure of 220/140 mmHg. Electrocardiogram (ECG) showed “ST elevation in aVR with lateral leads depression.” Serum troponin was normal at 0.02 ng/mL. Hypertensive emergency and acute coronary syndrome were diagnosed, and the patient was treated with lorazepam, nitroglycerin, and 324 mg aspirin (routes of administration not specified in records). Poison control recommended administration of benzodiazepines, treatment of the patient’s medical emergency, and continued monitoring. After three doses of nitroglycerin and 2 mg lorazepam, the patient’s blood pressure dropped to “130s/70s” and chest pain severity improved to 4–5/10. Repeat ECG approximately 1 hour post-arrival demonstrated sinus bradycardia, QT prolongation, and AVR elevation with lateral depressions, so an ST-elevation myocardial infarction (STEMI) was diagnosed.

The patient was transferred to the critical care unit and underwent emergency cardiac catheterization with no complications. This demonstrated angiographically normal coronary arteries, hyperdynamic left ventricle with ejection fraction 65%, and end diastolic pressure of 12 mm Hg. There was no aortic dissection. He was given hydralazine (unknown dose) and monitored overnight. His vital signs and physical examination were unremarkable the following morning, and he was discharged home in a stable condition. He was continued on his home medications, with aspirin 81 mg daily added, and advised not to take psilocybin mushrooms again.

No toxicology testing for psilocybin was undertaken, and the patient did not present with any mushrooms available for laboratory inspection. Notably, the patient once again reported no psychedelic effects during this episode of mushroom use. However, after discharge, he gave the remainder of his mushrooms to a friend who reported having psychedelic experiences after consuming them.

The patient remained on tranylcypromine and extended-release dextroamphetamine-amphetamine for 4 months afterward, during which the dose of tranylcypromine was eventually increased to a total of 90 mg daily. He tolerated this combination well, with his blood pressures during this period ranging from 127 to 130 systolic and 76 to 88 diastolic. The extended-release dextroamphetamine-amphetamine was then switched to lisdexamfetamine 30 mg daily. The patient continued lisdexamfetamine 30 mg daily and tranylcypromine up to a total of 120 mg daily for approximately 1 year before tranylcypromine was stopped due to limited efficacy. During this period, the patient remained normotensive and experienced no hypertensive emergencies.

Discussion

This may be the first reported case of an adverse psilocybin mushroom and MAOI interaction. Posts on online forums indicate that co-ingestion of psilocybin mushrooms with Syrian Rue (Peganum harmala) seeds and Banisteriopsis caapi (which contain reversible MAOIs such as harmine, harmaline, and tetrahydroharmine) to potentiate psilocybin’s psychoactive effects is somewhat common (curious guy 2020; Nafiz 2020). Combining psilocybin mushrooms and Banisteriopsis caapi is often termed “psilohuasca,” in reference to Banisteriopsis caapi’s more common combination with dimethyltryptamine (DMT) to produce ayahuasca. Intriguingly, at least some psilocybin mushrooms contain small amounts of reversible β-Carboline MAOIs (Blei et al. 2020). However, these trace amounts appear unlikely to potentiate psilocybin’s effects.

Some online posts report no adverse effects when combining psilocybin mushrooms with irreversible MAOIs such as tranylcypromine and phenelzine taken longterm (b9941, 2020; Bigmealplantime 2021). Like our patient, most of these people reported decreased or complete suppression of psilocybin’s psychoactive effects. Suppression of psychedelic effects secondary to repeated administration of MAOIs has been reported with lysergic acid (LSD), even when the MAOI was discontinued for 2-weeks prior to LSD administration (Bonson and Murphy 1996; Grof and Dytrych 1965; Resnick, Krus, and Raskin 1964). DMT’s psychoactive effects were largely attenuated in a study consisting of 4 days of iproniazid pre-treatment followed by a two-day washout pre-DMT administration (Sai-Halasz 1963). This diminution of psychedelic effects from repeated MAOI administration, in contrast to potentiation with single doses, might result from downregulation of 5HT-2A receptors following chronic MAOI exposure (Bonson and Murphy 1996). Notably, despite no subjective effects, our patient reported short-lived antidepressant effects following his use of mushrooms while on phenelzine, similar to a recent report describing persistent antidepressant effects despite no subjective effects after psilocybin administration in a study participant taking trazodone, a potent 5-HT2A receptor antagonist (Rosenblat et al. 2023).

We are also aware of a clinical study investigating synthetic psilocybin with tranylcypromine pretreatment (we have had this translated from Czech to English) (Vojtĕchovský, Hort, and Safratová 1968). In that study, nine subjects with alcohol use disorder in remission received either 80 mg tranylcypromine or placebo 48 hours prior to consuming 20 mg of psilocybin in counterbalanced order. The authors concluded “short-term premedication with tranylcypromine potentiated psilocybin-induced peripheral manifestations (pressor reaction of blood pressure, mydriasis, and the occurrence of side reactions) and only antagonized the decrease in dynamogeny and mental alertness in the emotional sphere. However, the psychotropic and psychodysleptic effects of psilocybin were not significantly reduced by premedication. Some perceptual disorders were even potentiated.” Mydriasis peaked approximately 7.5 mm 2 hours post-psilocybin ingestion following tranylcypromine pretreatment and 6 mm 3 hours post-psilocybin ingestion after placebo pretreatment. Statistically significant differences were noted in pupil diameter between tranylcypromine and placebo pretreatment groups at 2 hours post-psilocybin administration [7.5 mm and 5.8 mm, respectively; p = .05] and 2.5 hours post-psilocybin administration [7.5 mm and 5.7 mm, respectively; p = .05], though not at other timepoints. Psilocybin-induced increases in systolic blood pressure were potentiated by tranylcypromine pre-treatment, though no data were reported. Increases in diastolic blood pressure during the first 4 hours post-psilocybin administration were modestly higher in the tranylcypromine pre-treatment group compared to placebo, though the difference was statistically significant for only one of eight measurements during that period. At hours five and six post-psilocybin administration, diastolic blood pressures for both pre-treatment conditions fell below baseline, with readings in the placebo group dropping lower than those in the tranylcypromine group. During the 10 measurements collected over 6 hours post-psilocybin administration, only two showed statistically significant differences between tranylcypromine and placebo pre-treatment groups [(+7 and −1 mmHg changes from baseline 10-min post-psilocybin administration, respectively, and −6 and −14 mmHg decreases from baseline 5 hours post-administration, respectively (p = .05 for both comparisons)]. The increase in diastolic blood pressure from baseline peaked at 1.5 hours post-psilocybin administration for both tranylcypromine and placebo groups (+12 mmHg versus +4 mm Hg, respectively; difference not statistically significant). Insomnia, dry mouth, and thirst were the only adverse events reported.

The aforementioned studies indicate that classic serotonergic psychedelics such as DMT (Sai-Halasz 1963), LSD (Grof and Dytrych 1965; Resnick, Krus, and Raskin 1964), and psilocybin (Vojtĕchovský, Hort, and Safratová 1968) are unlikely to produce hypertensive emergencies in combination with MAOIs. In fact, following pretreatment with 30 mg isocarboxazid daily after 2 or 5 weeks, “the objective psychological effects, the autonomic effects, and the neurologic responses to LSD-25 were also attenuated, and in some cases even reversed” (Resnick, Krus, and Raskin 1964). The observations from these studies are consistent with insignificant noradrenergic activity for DMT (Carbonaro and Gatch 2016) and LSD (Schmid et al. 2015), while noradrenergic activity of psilocybin has only been observed at extremely high doses (Stolk et al. 1974).

When applying the Naranjo Adverse Drug Reaction (ADR) Probability Scale (Naranjo et al. 1981), an instrument designed to assess causality for adverse drug reactions, we found an ADR score of 3 (indicating “possible” likelihood) for an interaction between tranylcypromine and Psilocybe cubensis mushrooms. We derived this score as follows: +2 points for appearance of the hypertensive emergency after the mushrooms were self-administered; +1 point for the hypertensive emergency improving when the mushrooms were discontinued; +1 point for confirmation of the hypertensive emergency by any objective evidence; and −1 point for a potential alternative cause of the hypertensive emergency (the combination of dextroamphetamine-amphetamine and tranylcypromine can produce hypertensive reactions).

Considering reports of people safely combining psilocybin mushrooms and tranylcypromine, why did this adverse event occur? We hypothesize that it was precipitated by the cumulative pressor effects of non-psilocybin compounds in the mushrooms and extended-release dextroamphetamine-amphetamine in combination with tranylcypromine’s MAOI properties. The most likely candidate compound in psilocybin mushrooms is phenylethylamine (PEA), which exerts amphetamine-like effects, has peripheral sympathomimetic effects, and has been referred to as an endogenous amphetamine (Van den Eynde 2021). PEA has significant indirect sympathomimetic action via displacement of norepinephrine from adrenergic neurons (Paterson 1993; Pesce and Adler-Graschinsky 1983; Trendelenburg 1972). It has also recently been detected in Psilocybe cubensis via high-resolution mass spectrometry (Hernandez 2024), though detailed findings have not yet been published. PEA is also present in Psilocybe semilanceata, another species of psilocybin mushrooms (Beck et al. 1998). In that study, which involved analyses of Psilocybe semilanceata from four different locations, there was considerably more variation in PEA content (146-fold) than psilocybin content (3-fold). The mushrooms with the highest PEA level (146 ug/gram of wet mushrooms) were also associated with adverse reactions and hospitalization. Ten grams of wet psilocybin mushrooms is equivalent to approximately 1 g of dry mushrooms (United States Sentencing Commission 2018), so the mushrooms in that study with the highest PEA levels could have contained approximately 1.46 mg PEA/gram when dried.

PEA is endogenous in humans but is rapidly broken down by monoamine oxidase. It is primarily metabolized by the MAO-B isozyme, with a known point mutation being associated with considerably slower PEA degradation in some people (Pregeljc et al. 2018). PEA may also play a role in spontaneous hypertension rarely observed in some patients prescribed phenelzine or tranylcypromine (Van den Eynde 2021). While PEA is only about one-tenth as potent a pressor as tyramine (Rice, Eitenmiller, and Koehler 1976), MAOIs can elevate brain PEA levels up to 1000-fold in rats (Sabelli et al. 1978; Van den Eynde 2021). In addition to PEA, it should also be noted that at least some psilocybin mushroom species also contain numerous other alkaloids besides psilocybin such as baeocystin, norbaeocystin, and aeruginascin (Gotvaldová et al. 2022). Very little is known about these compounds, so they or other compounds could also exert important pressor effects when combined with MAOIs.

Regarding dextroamphetamine-amphetamine’s suspected contribution to this hypertensive emergency, amphetamines have noradrenergic potentiation properties like tyramine via norepinephrine-releasing action. Amphetamines are listed as contraindicated in tranylcypromine’s package insert (Concordia Pharmaceuticals 2018). However, case series support safely combining amphetamines and MAOIs when done cautiously (Israel 2015), though hypertension-related deaths from combining MAOIs with amphetamine (Zeck 1961) and dextroamphetamine (Lloyd and Walker 1965) have occurred. According to expert consensus, medium to high doses of amphetamines are absolutely contraindicated with MAOIs due to serotonin-releasing activity at these doses (Van den Eynde et al. 2022). Because they are monoamine releasers without significant serotonergic activity at low doses, the contraindication for combining low-dose amphetamines and MAOIs is considered relative. Of note, this patient did not experience further hypertensive episodes, despite continuing tranylcypromine and extended-release dextroamphetamine-amphetamine.

Importantly, our patients did not develop serotonin toxicity. Serotonin toxicity would be unlikely when combining classic psychedelics, low-dose dextroamphetamine-amphetamine, and MAOIs (Malcolm and Thomas 2022), since it typically occurs following serotonergic drug overdose or when drugs capable of increasing intrasynaptic serotonin are combined with an MAOI. Psilocybin, LSD, and other classic psychedelics are partial, selective agonists at 5-HT receptors and do not significantly raise extracellular serotonin. On the contrary, some non-classic psychedelics, such as 3,4-methylenedioxymethamphetamine (MDMA), act as potent serotonin releasers (Schenk and Highgate 2021), which can cause serotonin toxicity and death in combination with MAOIs (Pilgrim et al. 2012).

As to why our patient suffered a hypertensive emergency after combining psilocybin mushrooms with tranylcypromine but not with phenelzine, we suspect the lack of co-prescription of dextroamphetamine-amphetamine with the latter was the primary explanatory factor. However, there are other potential explanations. One is that the unknown species of psilocybin mushrooms taken initially may have contained lower PEA levels than Golden Teacher mushrooms. Additionally, the patient was taking nortriptyline with phenelzine. This may have protected against hypertensive emergency since nortriptyline and other tricyclic antidepressants may attenuate pressor effects of norepinephrine releasers such as PEA in patients taking MAOIs (Freyschuss, Sjöqvist, and Tuck 1970; Kline et al. 1981, 1982; Pare et al. 1982; White and Simpson 1984). Finally, tranylcypromine carries significantly greater hypertensive risk than phenelzine (Blackwell et al. 1967; Brown, Taniguchi, and Yip 1989).

Patients should be warned that combining tranylcypromine and dextroamphetamine-amphetamine with psilocybin mushrooms may precipitate hypertensive emergency. Given how little is known about the constituents of psilocybin mushrooms, it also worth emphasizing that these fungi could also contain serotonergic compounds besides psilocybin that might create a risk for potentially fatal serotonin toxicity in combination with MAOIs. From a harm reduction perspective, patients taking MAOIs should be informed that synthetic psilocybin, LSD, or DMT would appear to be physiologically safer alternatives than psilocybin mushrooms.

This case highlights safety challenges that psychiatrists may now be increasingly facing as patients augment psychiatric medications with psychedelics to self-treat their mental health conditions. Psychiatrists need to educate themselves about psychedelic interactions with psychiatric medications and continuing medical education programming should incorporate such information, which is one of the most desired psychedelic-related education topics for psychiatrists (Barnett et al. 2021). Due to limited research on psychedelics, our knowledge of their pharmacological interactions is meager, though it will grow as patients experience adverse events amid increasing use (Weleff et al. 2024). Unfortunately, most psychedelic users appear hesitant to disclose use to health-care providers (Glynos et al. 2022), so it behooves clinicians to proactively inform patients about the risks of combining psychedelics with psychiatric medications and encourage them to be open about psychedelic use.

Conclusion

This case suggests combining tranylcypromine, dextroamphetamine-amphetamine, and Psilocybe cubensis mushrooms can result in hypertensive emergency. A previous clinical trial reported no hypertensive emergencies following tranylcypromine pretreatment prior to synthetic psilocybin administration, while online reports indicate co-ingestion of psilocybin mushrooms with MAOIs, including tranylcypromine, has occurred without resulting in hypertensive emergencies. Therefore, we speculate that the cumulative pressor effects of extended-release dextroamphetamine-amphetamine and PEA, which exerts indirect sympathomimetic effects and has recently been identified in Psilocybe cubensis mushrooms, precipitated this tranylcypromine-associated hypertensive emergency.

Disclosure statement

Dr. Barnett serves on advisory boards for CB Therapeutics, Compass Pathways, and Livanova. He also holds stock options in CB Therapeutics. He receives monetary compensation for editorial work for DynaMed Plus (EBSCO Industries, Inc). He is a consultant for Janssen Pharmaceuticals. He receives research support from MindMed and Compass Pathways. In the last year he has received consulting fees from Cerebral, though this relationship is no longer active. Mr. Van den Eynde has received consulting fees from PsychoTropical Research, NeuraWell Therapeutics, Aristo Pharma GmbH, and a speaker’s fee from the Flemish Psychiatric Association (donated to a charitable trust for MAOI research). He has acquired a grant from Neon Healthcare for PsychoTropical Research and for the International MAOI Expert Group. He has stock options in NeuraWell Therapeutics. Dr. Gillman has equity interests in and is on the advisory board of NeuraWell Therapeutics, the company that has the patent for a modified form of tranylcypromine. He has received a speaker’s fee from the Flemish Psychiatric Association (donated to a charitable trust for MAOI research). Dr. Bodkin has received research support from Alkermes and Otsuka and has served as a consultant to both firms. Dr. Koons declares no potential conflicts of interest.