Psychedelics and the Serotonergic Toxidrome – Part I: Defining the spectrum of toxicity

Author: Amelia B Furbish, PharmD, PhD Candidate

Editors: Michael Haichin, PharmD;  Mary Leonard Hornick, MS, PhD; Sa’ed Al-Olimat, PharmD; Regina Moore, PharmD

I. Pathogenesis

Serotonin (5-HT) syndrome, more appropriately referred to as serotonin toxicity, is a state of increased central and peripheral serotonergic activity thought to be caused by excess stimulation of serotonin receptors (predominantly 5-HT2A). This toxic state is characterized by excessive neuromuscular excitation associated with profound muscle contraction leading to hyperthermia. If left untreated, excessive muscle contraction and hyperthermia can result in severe life-threatening side effects including rhabdomyolysis, metabolic acidosis, renal failure, seizure, coma, and death. In addition, patients with serotonin toxicity may present with autonomic instability, most commonly presenting as hypertension and tachycardia, although significant fluctuations in heart rate and blood pressure may occur [1]. 

Serotonin is synthesized from the amino acid tryptophan and packaged into pre-synaptic vesicles by vesicular monoamine transporter 2 (VMAT2). Once released into the synapse, serotonin can be transported back into the presynaptic nerve terminal by serotonin reuptake transporters (SERT) or degraded by monoamine oxidase enzymes (MAO). Serotonergic neurotransmission can be altered through a variety of mechanisms. Serotonin precursors such as tryptophan and 5-hydroxytryptophan (5-HTP) can increase serotonin synthesis in serotonergic neurons. Monoamine oxidase inhibitors (MAOIs) and vesicular monoamine transport (VMAT2) inhibitors can increase intracellular pre-synaptic serotonin levels, and medications interacting with serotonin transporters can increase serotonin levels within the synapse. In addition, some drugs may act as agonists at postsynaptic serotonin receptors, thus increasing serotonergic neurotransmission (Figure 1) [1, 2]. 

Figure 1. Overview of serotonergic neurotransmission and including the key biologic targets of serotonergic drugs. Abbreviations: Serotonin (5-HT), 5-Hydroxytyptophan (5-HTP), Vesicular monoamine transporter 2 (VMAT2), Monoamine oxidase (MAO), Serotonin reuptake transporter (SERT), Serotonin receptors 1 and 2A (5-HT1A, 5-HT2A). Figure created with

The mechanism of action for medications associated with serotonin syndrome can be grouped into five major categories including (1) medications that inhibit serotonin reuptake, (2) medications that increase serotonin synthesis, (3) medications that inhibit serotonin metabolism, (4) medications that increase serotonin release, and (5) medications that activate postsynaptic serotonin receptors. Most commonly, serotonin syndrome is caused by concomitant use of medications that affect multiple pathways resulting in a significant increase in serotonergic neurotransmission. Despite the wide use of serotonergic medications in clinical practice, incidence of serotonin toxicity remains exceptionally low with the most common offending agents involving combination therapy of MAOIs along with other serotonergic drugs.  

Classic psychedelics such as N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and psilocybin act primarily as postsynaptic 5-HT2A agonists, the mechanism largely attributed to the psychedelic experience induced by these substances. However, the pharmacology of psychedelics is complex, and compounds within this class demonstrate affinity for a number of serotonergic, dopaminergic, and adrenergic receptors as well as the ability to differentially impact receptor signaling upon binding [3].

Incidence of serotonin toxicity associated with the use of classic psychedelics is exceptionally low, even with doses above those reported in clinical use [4, 5]. However, risk of serotonin toxicity may be increased in the setting of combination therapy, particularly with concomitant use of MAOIs, which are used to improve the oral bioavailability of DMT as part of the ayahuasca concoction (found in the Banisteriopsis caapi vine) or in the form of “pharmahuasca” [4]. In addition, while it has been suggested that risk of serotonin toxicity is low with all serotonin agonists [6], given the complexity of post-synaptic signaling and the ability of different agonists to preferentially activate distinct post-synaptic signaling cascades, risk of serotonin toxicity should be assessed independently by individual drug rather than by class. This is particularly well evidenced by contrasting the relatively benign risk associated with classic psychedelics and the multiple case reports and reported fatalities associated with certain novel psychoactive substances (i.e., NBOMes) [7-10], whose primary mechanism of action is agonism of 5-HT2A. As such, monotherapy with a psychedelic substance should not be used as rationale for ruling out life-threatening serotonin toxicity, especially in the setting of patients presenting to the emergency department following acute toxicity with an unknown psychedelic agent.

II. Distinguishing the toxidrome

Serotonin syndrome, more appropriately referred to as severe serotonergic toxicity, is characterized by hyperthermia, altered mental status, and increased muscular tone.  Serotonin toxicity may be distinguished from similar hyperthermic toxidromes primarily by the presence of clonus, or rhythmic involuntary muscle contractions, distinct from the rigidity seen in neuroleptic malignant syndrome and malignant hyperthermia, and absent in anticholinergic toxicity. However, it is important to note that in patients with severe serotonergic toxicity, excessive neuromuscular excitation may lead to extreme muscle contractions resembling rigidity, thus complicating diagnosis [1, 11, 12]. 
In addition to characteristic hyperreflexia and clonus, serotonin toxicity may be distinguished from anticholinergic toxicity, neuroleptic malignant syndrome, and malignant hyperthermia by the presence of hyperactive bowel sounds. Further distinguishing characteristics include mydriasis, which is absent in neuroleptic malignant syndrome and malignant hyperthermia, and sialorrhea, which is absent in anticholinergic toxicity (Table 1).

Several diagnostic criteria have been proposed for the identification of serotonin syndrome including the Sternbach Criteria [13], the Radomski Criteria [14], and the Hunter Criteria [15]. Of these proposed criteria, diagnosis based on the Hunter Criteria (Figure 2) is considered the recommended standard for clinical diagnosis, as these criteria were developed based on the largest patient data set and were able to predict serotonin toxicity with this highest level of sensitivity (84%) and specificity (97%) when compared to alternative diagnostic criteria. However, as serotonin syndrome is a clinical diagnosis and there are currently no confirmatory laboratory tests available, it is imperative for clinicians to consider differential diagnosis in the setting of suspected serotonin toxicity.

Figure 2. The Hunter criteria diagnostic decision tree for the diagnosis of serotonin toxicity. Adapted from Dunkley, et al. [15].

III. Pharmacologic management of serotonin toxicity

Treatment of serotonin toxicity consists primarily of supportive care, sedation, and appropriate management of excessive neuromuscular excitation (Figure 3), autonomic instability, and hyperthermia. Of note, appropriate management of severe symptoms resembling serotonin toxicity is imperative, regardless of whether diagnostic criteria are met [16].

Figure 3. Spectrum of neuromuscular excitation and corresponding clinical presentation.

Patients presenting with serotonin toxicity should receive appropriate supportive care including supplemental oxygen and IV fluids to maintain adequate oxygen saturation and fluid status. Benzodiazepines are the recommended treatment strategy for sedation and agitation. As there is no specific benzodiazepine that has shown superior efficacy, benzodiazepine selection should be based on severity of toxicity, clinical preference, desired duration of sedation, and available dosage forms. Benzodiazepines with available parenteral formulations (lorazepam, diazepam, and midazolam) represent an appropriate option for sedation in settings where oral administration is not feasible. Sedating drugs that exhibit anticholinergic properties including neuroleptics (e.g.haloperidol) and antihistamines should be avoided, as these drugs may exacerbate hyperthermia and reduce diaphoresis [16]. In addition, the use of physical restraints should be avoided, as this has been shown to result in worsening muscle contractions leading to severe hyperthermia and lactic acidosis [1]. This recommendation is supported by multiple case studies in which the use of physical restraints resulted in worsening hyperthermia and death [5, 12]. Although there is limited evidence regarding efficacy of use [17], the 5-HT2A antagonist cyproheptadine is recommended in cases of moderate to severe serotonin toxicity (Initial dose of 12 mg by mouth or crushed via nasogastric tube followed by 2 mg every two hours until clinical response is achieved) [1, 11, 18]. 

Autonomic instability in patients with serotonergic toxicity most commonly manifests as hypertension and tachycardia, however large and rapid fluctuations in heart rate and blood pressure may occur. As such, the use of short acting antihypertensive agents such as nitroprusside and nicardipine [12,16] represent appropriate selections for pharmacologic management. Although alternative short acting antihypertensive agents have been suggested (e.g. esmolol), caution should be used in the setting of MDMA toxicity (or toxicity from another serotonin/dopamine releasing agent). The use of beta blockers in this setting remains controversial due to concerns for unopposed alpha-adrenergic activity and the potential risk of coronary artery vasospasm [19]. 

Management of hyperthermia is vital for prevention of life-threatening complications of serotonin toxicity including rhabdomyolysis, seizure, and coma. As hyperthermia associated with serotonin toxicity occurs due to  increased neuromuscular activity, antipyretic medications such as acetaminophen have no indication and management consists primarily of minimizing excessive muscle contractions. In addition, non-pharmacologic cooling measures are recommended. 

In patients presenting with hyperthermia above 41.1°C (105.98°F), sedation, paralysis, and intubation is recommended [1]. Of note, clinicians should exercise caution in the selection of medications used for rapid sequence intubation and sedation, as succinylcholine may worsen rhabdomyolysis and exacerbate hyperkalemia, and the use of fentanyl may worsen serotonergic toxicity [1]. 

IV. Spectrum of toxicity and symptomatic assessment

There is a broad spectrum of risk associated with the use of serotonergic drugs and a range of physiologic effects associated with their use. As the therapeutic use of serotonergic psychedelics and entactogens continues to increase in the clinical setting, conducting an adequate risk assessment, as well as gaining the ability to distinguish between serotonergic side effects and severe serotonergic toxicity, presents a unique challenge for clinicians, particularly as the occurrence of characteristic serotonergic effects may be more pronounced with the therapeutic use of psychedelics in comparison to more traditional serotonergic drugs such as SSRIs or triptans. As much of the symptomatology characteristic of the serotonergic toxidrome is used for distinguishing a causative agent to aid in management, it is important to draw a distinction between side-effects indicative of underlying changes in serotonergic activity and side-effects warranting advanced medical intervention (Figure 4).  

Figure 4. Symptomatic features associated with the use of MDMA and serotonergic psychedelics (LSD and psilocybin) in the clinical setting, and distinction between expected side-effects vs. symptoms requiring advanced intervention [20, 21].

Patients receiving treatment with serotonergic psychedelics may experience a wide variety of physiologic changes as well as adverse effects including altered mental status, anxiety, gastrointestinal distress, diaphoresis, mydriasis, increased neuromuscular tone, and changes in heart rate and blood pressure. Although these symptoms are consistent with increased serotonergic activity, they do not pose a substantial risk to the safety of the patient and generally resolve following treatment. 

Although the risk of severe serotonin toxicity is low with the use of classic serotonergic psychedelics (psilocybin, LSD, DMT), and there have been no reports of serotonin syndrome occurring with treatment in the clinical setting, reasonable monitoring parameters include assessment of vital signs (heart rate, blood pressure, temperature), mental status (agitation), and overall neuromuscular tone [20, 21]. 

V. Concluding thoughts

Risk of serotonin toxicity from the use of classic psychedelics is low, particularly in the clinical setting and at therapeutic doses. However, there is a broad spectrum of risk associated with the use of serotonergic drugs in combination with psychedelics, and certain novel psychedelic drugs (e.g. NBOMes) appear to hold an increased risk of serotonin toxicity when compared to classic psychedelics. Thus, as the therapeutic use of serotonergic psychedelics and entactogens continues to increase among both the general public and in the clinical setting, it is imperative for clinicians to gain familiarity with conducting an adequate risk assessment and distinguishing between generalized serotonergic side effects and severe serotonin toxicity. 

For further information on drug-drug interactions and a more comprehensive safety assessment for specific psychedelics, please see reference [4] (Malcolm & Thomas, 2022).  

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