Psychedelics for treating psychiatric disorders: Are they safe?
Though generally well-tolerated, these agents have been associated with a range of adverse effects.
A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.38 Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 339). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.40
Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.41 Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.42
The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.39 Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.39A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).43 The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.43 Concerns regarding acute ketamine withdrawal have also been described in case reports.44
Other safety considerations of psychedelics
Hallucinogen persisting perception disorder
Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.45 Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.46 HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.45 HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.47
Serotonin toxicity and other serotonergic interactions
Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.48 Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.48
Boundary violations in psychedelic-assisted psychotherapy
A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al49 argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”
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