Psilocybin-induced takotsubo cardiomyopathy

Discussion

P. semilanceata is one of the most widely known psychedelic ‘magic mushrooms’ with its psychotropic effects largely caused by psilocybin and psilocin compounds. Both compounds act on partial agonists on serotonin receptors (5-Ht_1A and 5-Ht_2A) in the brain and induce a range of physical and psychological side effects.14 Physical effects range from: heart rate variations, nausea, tremors, hyper-reflexia and pupil dilation, whereas psychological side effects are heavily influenced by the individual’s environment and personality traits which can include ‘positive effects’ of euphoria, hallucinations and joy, and ‘negative effects’ including depression, paranoia and anxiety.15

The majority of intoxications resolve without the need for hospitalisation; however, emerging literature highlights isolated cases of severe health consequences after high mushroom dosages or persistent use. Several reports of nephrotoxic and cardiotoxic associations have been identified, such as development of kidney failure, Wolff-Parkinson-White syndrome, arrhythmias, myocardial infarction and TTC following ingestion in previously healthy individuals without strong cardiac risk factors.13 16 17 A case of a 17-year-old boy was reported, who developed chest pain and dyspnoea at rest, right bundle branch block, ST-segment elevation, raised troponin and creatine kinase concentrations following mushroom ingestion. Drug screening excluded other substances and no obstruction in coronary arteries was found. Characteristic TTC regional wall motion abnormality in apical segment of left ventricle and reduced ejection fraction with pericardial effusion signs were found on his imaging which resolved with anti-inflammatories consistent with a TTC diagnosis.13 Similarly, other mushroom variants such as Panaeolus subbalteatus and Conocybe zeylanica have also shown to exhibit cardiotoxic effects in reported cases, including development of sinus, atrial or ventricular arrhythmias, prolonged QT intervals and ST-segment elevation.18 Existing evidence therefore suggests a potential direct cardiac impairment reminiscent with TTC following mushroom ingestion.

The mechanisms of cardiovascular toxicity by psilocybin are complex involving catecholamine-like action. Active metabolites present in psilocybin are known to interact with dopaminergic, adrenergic and serotonergic receptors and pathways. While these three distinct pathways are often viewed in isolation as their cell bodies are localised to distinct nuclei, their projections to the forebrain create intersecting and reciprocal innervation to allow intricate and synchronised coordination of neuronal activity.19 This allows complex neurohormonal interactions which regulate basic cerebral functions. Therefore, it can be hypothesised that the psilocybin agonistic effect on 5-HT receptors may simultaneously activate adrenergic receptors in the adrenal medulla and stimulate catecholamine release which remains the most widely described pathophysiological theory of TTC aetiology.

Catecholamine role is reinforced by biopsy samples taken during acute phase TTC showing morphology changes consistent with catecholamine-induced cardiotoxic effects and vascular influences. During extreme emotional or physical stress, abnormally elevated plasma catecholamine and neuropeptide levels may induce a switch from stimulatory to cardioinhibitory (cardioprotective) secondary messengers within cardiomyocytes leading to negative ionotropy and resultant LV contractile dysfunction. This mechanism is referred to as ‘stimulus trafficking’ and may explain apical forms of TTC as LV apical myocardium contains highest density of beta-adrenoceptors most sensitive to circulating catecholamines, consistent with characteristic apical TTC cases.1 It does not however explain the mechanisms behind other forms of TTC observed. For this reason, the catecholamine hypothesis is the most widely accepted theory to date.20

It is believed that TTC is triggered more commonly by preceding emotional rather than physical triggers such as infection, haemorrhage or severe hypoxia, particularly in younger patients without significant underlying medical conditions. In the context of P. semilanceata, the psychedelic effect of psilocybin on the brain, for example, enhancing paranoia or hallucinations, may have induced an emotional trigger in the individual resulting in this TTC presentation. It is therefore challenging to distinguish the precise aetiology of TTC and its pathogenesis in cases involving psychedelic substances. A recent study has evidenced prognosis of patients with TTC is influenced by its primary trigger with emotional triggers having better prognosis compared with physical stress triggers in terms of short-term and long-term outcomes. Familiarity with the aetiology of TTC is important to ensure adequate follow-up to prevent recurrence and mortality once the trigger is established.21

The diagnosis of TTC may be challenging to make promptly in acute settings as the clinical presentation can often be vague and non-specific relying heavily on imaging modalities. Patients most often present with chest pain or breathing difficulties and ECG changes most commonly in precordial leads such as progressive anterior/lateral T-wave inversion and QT prolongation peaking at days 2–3 and resolving within 2–4 months.22 Furthermore, TTC demonstrates mild elevation of cardiac enzymes and returns to baseline faster, compared with more significant elevation seen in ACS, which may raise clinical suspicion and merit further investigation. Atypical presentations, as in the case described, may not exhibit classic chest pain and therefore delay diagnosis and treatment. Angiography and CMR are recommended imaging tools to exclude obstructive coronary disease and look for evidence of cardiac oedema, a common feature of TTC. This may be a particular challenge for female patients who often present with non-specific cardiac presentations, predisposing to delay in diagnosis and therefore poorer outcomes.23 Due to the absence of large randomised prospective studies surrounding the therapeutic benefit of early beta-blocker use in TTC and evidence from retrospective studies showing no significant benefit for beta-blockers in this patient group,24 there is currently little existing evidence supporting the use of commonly used drugs for heart failure in the treatment of TTC.25

The National Poisons Information Service is a UK Department of Health-approved and a Public Health England-commissioned national service. The agency played an integral role in identification of the causative agent for the patient’s initial hospital presentation. It aims to help guide healthcare professionals through complex and unfamiliar presentations via the TOXBASE database of existing evidence, and promotes collaboration. The rapid expert and advice service provided further information regarding P. semilanceata in question, encompassing up-to-date recommendations for acute and chronic poisonings, considered on a case-by-case basis.26

Contrary to previous perceptions, TTC has long-lasting health implications ranging from persistent heart failure phenotype to mild or severe symptomatic and functional cardiac impairment and dysfunction.27 Approximately 1%–2% patients develop recurrence with mortality ranging from 3% to 4%.3 While no established treatment guidelines exist for treatment of TTC due to its reversible nature, treatment remains largely supportive and can include: beta-blockade, antiplatelet therapy, ACE inhibitors and statins for up to 3 months after initial presentation.28 There is some existing evidence that LV akinesis may predispose to clot formation and therefore many patients are commenced on prophylactic anticoagulation; however, the evidence is limited.29 One in four people may experience complications which may include mitral regurgitation, left heart failure, cardiogenic shock, ventricular arrhythmias, development of LV mural thrombus or death.3