Psychedelics for Treating Psychiatric Disorders: Are they Safe?

Though generally well-tolerated, these agents have been associated with a range of adverse effects

Madonna Thakur, MBBS; Jeffrey A. Lam, MD; Prakash Mishra, MD; Awais Aftab, MD

Disclosures

Curr Psychiatr. 2022;21(12):15-22.

Abstract and Introduction

Introduction

Psychedelics represent a distinctive class of substances recognized for their profound capacity to alter consciousness and perception. Over the past two decades, scientific inquiry into psychedelics has experienced a significant resurgence, capturing the attention of researchers, therapists, entrepreneurs, and the broader public. While many of these compounds currently remain illicit in the United States and numerous other global jurisdictions ([[Box]] page 16), the renewed emphasis on psychedelic research has prompted the U.S. Food and Drug Administration (FDA) to grant "breakthrough therapy" designation to several psychedelic compounds. This designation is crucial, as it accelerates the investigation, development, and review processes for these promising therapeutic modalities.

Mounting evidence suggests that psychedelics hold considerable potential for effectively treating a diverse array of psychiatric disorders. These potential clinical applications encompass various forms of depression, including treatment-resistant cases, as well as post-traumatic stress disorder (PTSD), and a range of substance use disorders ([[Table 1]] page 17). In most contemporary clinical investigations, psychedelics are being explored and administered within the structured framework of psychedelic-assisted psychotherapy. However, ketamine stands out as a notable exception, as it is already widely utilized for the treatment of depression. With further FDA approvals anticipated for other psychedelic compounds, a comprehensive examination of their safety profiles in the context of psychiatric treatment is both pertinent and timely.

This article systematically reviews the adverse effect profiles of both classical psychedelics, such as psilocybin (commonly known as "mushrooms"), lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) found in ayahuasca, and nonclassical psychedelics. The nonclassical agents discussed include the empathogen 3,4-methylenedioxymethamphetamine (MDMA), often referred to as "ecstasy," and the dissociative anesthetic ketamine. Understanding the nuances of their safety considerations is paramount as these compounds move closer to mainstream clinical application, ensuring that clinicians can balance potential therapeutic benefits with prudent risk management.

Psilocybin

Psilocybin, a naturally occurring psychedelic compound found in certain fungi, has shown promise in treating various psychiatric conditions, including depression and end-of-life distress. Clinical trials suggest it is generally well-tolerated when administered in a controlled, therapeutic setting. However, as with all potent substances, adverse effects can occur. These typically manifest as transient physiological symptoms such as headache, nausea, and fatigue. While most effects are mild to moderate and resolve within hours, careful monitoring is essential, particularly for individuals with pre-existing conditions.

Psychologically, psilocybin can induce intense and sometimes challenging experiences, often referred to as "bad trips," characterized by anxiety, paranoia, or confusion. Though these are usually temporary and managed within a supportive therapeutic environment, they underscore the necessity of proper screening and preparation. Rare but more serious psychological risks include prolonged psychosis in predisposed individuals or the exacerbation of underlying psychiatric conditions. Therefore, careful patient selection, exclusion of those with personal or family histories of psychotic disorders, and robust clinical supervision are critical for safe psilocybin-assisted therapy.

The physiological adverse effects observed in controlled clinical trials, such as those for depression, highlight the importance of medical oversight. Common complaints include headache, nausea, and migraine, while less frequent effects like palpitations, sleep disorder, diarrhea, and vomiting have also been reported. These physical responses, detailed in Table 2, are generally manageable and reflect the acute pharmacological action of psilocybin. The transient nature of these effects, combined with the often profound psychological insights gained during the experience, necessitates a balanced assessment of risk versus therapeutic potential.

Lysergic Acid Diethylamide

Lysergic acid diethylamide (LSD) is a potent classical psychedelic, well-known for its profound alterations in perception, mood, and thought. In therapeutic contexts, LSD is administered at carefully controlled doses to mitigate risks while facilitating introspective experiences. Physiologically, LSD can cause temporary increases in heart rate and blood pressure, as well as mild nausea or dizziness. These effects are generally transient and not typically medically significant in healthy individuals, but they warrant cautious use in patients with cardiovascular conditions.

The primary safety considerations for LSD involve its psychological effects. Users may experience intense emotional states, including anxiety, fear, or panic, particularly if they are unprepared or in an unsupportive environment. While these "challenging experiences" are often integrated as part of the therapeutic process, they underscore the need for psychological support before, during, and after administration. A more persistent, though rare, adverse effect is Hallucinogen Persisting Perception Disorder (HPPD), characterized by recurrent, distressing visual disturbances, which can significantly impair daily functioning.

Furthermore, LSD can exacerbate pre-existing psychiatric conditions, particularly psychotic disorders, in vulnerable individuals. It is strictly contraindicated in patients with a personal or family history of psychosis, schizophrenia, or severe personality disorders due to the risk of triggering or worsening such conditions. The long-term psychological safety of therapeutic LSD use is still under investigation, emphasizing the need for comprehensive screening and ongoing monitoring. The controlled clinical setting, with trained therapists, is crucial to manage acute reactions and mitigate potential long-term risks associated with its powerful effects on the mind.

DMT/Ayahuasca

N,N-dimethyltryptamine (DMT) is an endogenous psychedelic compound capable of inducing rapid and intensely immersive visionary experiences. When inhaled or injected, its effects are typically brief, lasting only minutes. Conversely, when consumed orally as part of the Amazonian brew ayahuasca, its effects are significantly prolonged due to the presence of monoamine oxidase inhibitors (MAOIs), allowing DMT to become orally active. Both forms of administration elicit powerful psychological shifts, including profound insights, emotional breakthroughs, and encounters with altered realities, which are the basis for their therapeutic potential.

From a safety standpoint, DMT and ayahuasca present distinct considerations. Physiologically, ayahuasca commonly induces significant gastrointestinal distress, including nausea, vomiting, and diarrhea. While often considered a "purging" aspect of the experience by traditional users, these effects necessitate careful hydration and medical readiness in a clinical setting. Cardiovascular effects, such as temporary increases in heart rate and blood pressure, are also observed, requiring screening for cardiac conditions. The MAOI component of ayahuasca also introduces potential drug-drug interactions, particularly with serotonergic medications, which can lead to serotonin syndrome.

Psychologically, the intensity and rapid onset of DMT’s effects, especially in ayahuasca, can be overwhelming. This may lead to acute anxiety, panic, or disorientation, particularly for those unprepared for such a profound alteration of consciousness. While these challenging experiences are often viewed as part of the healing process within traditional contexts, they demand expert guidance and a supportive environment in a therapeutic setting. Individuals with a history of psychotic disorders or severe anxiety should be carefully excluded, as the profound psychological activation could trigger or exacerbate these conditions, highlighting the need for rigorous participant screening and clinical oversight.

MDMA

3,4-methylenedioxymethamphetamine (MDMA), often termed an empathogen or entactogen, is being extensively investigated for its potential in treating post-traumatic stress disorder (PTSD). Unlike classical psychedelics, MDMA primarily fosters feelings of empathy, connection, and emotional openness, rather than inducing strong hallucinations. A meta-analysis of five randomized controlled trials (RCTs) examining MDMA-assisted therapy for PTSD has demonstrated that the compound is generally well-tolerated, with a notably low incidence of serious adverse effects when administered in a controlled, clinical environment.

Despite its favorable safety profile in therapeutic settings, MDMA carries specific physiological risks, particularly at higher doses or with recreational, uncontrolled use. The most prominent physical adverse effects include temporary increases in heart rate and blood pressure, hyperthermia (elevated body temperature), and hyponatremia (low sodium levels) due to excessive water intake during recreational use. While these are carefully managed in a clinical setting through hydration protocols and monitoring, individuals with pre-existing cardiovascular conditions, hypertension, or kidney impairments require stringent screening and careful consideration before MDMA administration.

Psychologically, MDMA can induce transient anxiety, confusion, or insomnia, particularly as its effects wane. There is also a concern for potential neurotoxicity with chronic recreational use, impacting serotonin pathways, though this risk appears minimal in controlled, infrequent therapeutic doses. The greatest safety advantage of MDMA lies in its ability to facilitate emotional processing without inducing profound dissociative or hallucinatory states that might overwhelm some patients. The supportive psychotherapeutic framework is essential to navigate the emotional release and integration, ensuring that the experience remains contained and therapeutically beneficial while mitigating potential distress.

Ketamine/Esketamine

Ketamine, a dissociative anesthetic, has emerged as a rapid-acting antidepressant and is currently approved for treating treatment-resistant depression and suicidal ideation, with esketamine (a nasal spray formulation) also FDA-approved for these indications. Unlike other psychedelics under investigation, ketamine and esketamine are already in clinical use, making their safety profile particularly relevant. While effective, their administration necessitates careful monitoring due to a range of potential adverse effects, which are dose-dependent and typically transient, but can be significant.

Common acute adverse effects associated with ketamine and esketamine include dissociation, dizziness, and sedation. Patients may experience perceptual disturbances, changes in body image, and a feeling of being "disconnected" from reality. These dissociative effects, while sometimes therapeutic, can also be distressing and require close supervision. Other frequently reported effects include nausea, dysgeusia (altered taste), and transient increases in blood pressure, as detailed in Table 3. Monitoring vital signs, particularly blood pressure, is crucial during and after administration to manage hypertensive responses.

Long-term safety concerns with ketamine, especially with repeated or high-dose recreational use, include potential for cognitive impairment, neurotoxicity, and significant urinary tract issues, such as ketamine-induced cystitis. While these risks are minimized in controlled clinical settings with careful dosing schedules, they underscore the importance of judicious use and patient education. Furthermore, the potential for misuse or abuse, given its psychoactive properties, necessitates strict control and monitoring. The clinical environment ensures that the therapeutic benefits are maximized while mitigating the well-documented risks associated with these potent agents.

Other Safety Considerations of Psychedelics

Beyond the specific adverse effect profiles of individual psychedelic compounds, several overarching safety considerations warrant attention in the emerging landscape of psychedelic-assisted therapy. One crucial aspect is the potential for acute psychological distress during the psychedelic experience. While challenging experiences can be therapeutically beneficial when properly navigated, they can also lead to significant anxiety, panic, or paranoia if not managed by trained professionals in a supportive setting. Careful patient selection and comprehensive psychological preparation are paramount to minimize the risk of prolonged distress.

Another significant concern is the potential for inducing or exacerbating psychotic disorders. Individuals with a personal or strong family history of schizophrenia or other psychotic conditions are generally excluded from psychedelic therapy trials due to this elevated risk. Although rare, the profound alterations in perception and thought induced by psychedelics could trigger a lasting psychotic episode in vulnerable individuals. Comprehensive psychiatric evaluations are therefore essential to identify and mitigate this risk, ensuring that only suitable candidates receive treatment.

Furthermore, cardiovascular risks, though generally transient in healthy individuals, require careful consideration. Many psychedelics can cause temporary increases in heart rate and blood pressure, making thorough cardiac screening necessary, especially for patients with pre-existing cardiovascular disease. Potential drug-drug interactions, particularly with psychotropic medications, also pose a safety challenge. Some psychedelics interact with serotonin systems or metabolic pathways, requiring careful medication reconciliation and potential tapering of concomitant medications before treatment to prevent adverse events like serotonin syndrome or altered drug metabolism.

Caveats to Consider

As psychedelic-assisted therapies gain momentum, it is imperative to approach their integration into clinical practice with a balanced perspective and cautious optimism. While initial research findings are promising, a significant caveat is the limited availability of long-term safety data, particularly concerning the effects of repeated administrations over extended periods. Most clinical trials have focused on short-term outcomes, and more robust, longitudinal studies are necessary to fully understand any enduring psychological or physiological effects, both positive and negative, that may emerge years after treatment.

Another critical consideration revolves around the "set and setting" – the patient's mindset and the therapeutic environment – which profoundly influence the psychedelic experience. The efficacy and safety of these therapies are heavily reliant on highly trained and experienced therapists who can guide patients through profound emotional states and assist with the integration of insights. The intensive nature of psychedelic-assisted psychotherapy raises concerns about ethical boundaries and potential for therapist misconduct, underscoring the need for rigorous training standards, clear professional guidelines, and ongoing supervision to protect vulnerable patients.

Finally, the evolving legal and regulatory landscape surrounding psychedelics presents a complex challenge. While some compounds are receiving breakthrough designations and decriminalization, their status remains largely illegal at a federal level, creating significant barriers to research, access, and broad clinical implementation. This legal ambiguity can also lead to uncontrolled, illicit use, where safety protocols are absent and risks are substantially higher. Therefore, continued public education, careful regulatory reform, and a commitment to rigorous, evidence-based research are essential to ensure the safe, ethical, and effective advancement of psychedelic therapies for psychiatric disorders.

Tables

Table 1. Potential psychiatric indications for psychedelics (including ketamine) Treatment-resistant depression

Chronic moderate-to-severe depression
Depression with suicidal ideation
End-of-life distress
Posttraumatic stress disorder
Substance use disorders (tobacco, alcohol)
Source: References 2,3

Tables

Table 2. Adverse effects associated with psilocybin use for depression in an RCT Headache (67%) Nausea (27%)

Migraine (10%)
Fatigue (7%)
Feeling jittery (7%)
Vomiting (7%)
Palpitations (3%)
Sleep disorder (3%)
Diarrhea (3%)
Source: Reference 12 RCT: randomized controlled trial

Tables

Table 3. Adverse effects reported in a trial of esketamine for treating major depressive disorder with acute suicidality	Esketamine and oral antidepressant (n = 227)	Placebo and oral antidepressant (n = 225)
Dissociation	108 (48%)	30 (13%)
Dizziness	103 (45%)	34 (15%)
Sedation	66 (29%)	27 (12%)
Nausea	61 (27%)	31 (14%)
Dysgeusia	46 (20%)	29 (13%)
Anxiety	34 (15%)	20 (9%)
Increase in blood pressure	34 (15%)	14 (6%)
Hypoesthesia	30 (13%)	4 (2%)
Vomiting	26 (11%)	12 (5%)
Constipation	22 (10%)	14 (6%)
Euphoric mood	17 (7%)	1 (0.4%)
Vertigo	14 (6%)	1 (0.4%)
Hyperhidrosis	11 (5%)	5 (2%)
Lethargy	10 (4%)	4 (2%)
Feeling drunk	8 (4%)	1 (0.4%)
Tachycardia	8 (4%)	2 (1%)
Intentional self-injury	7 (3%)	3 (1%)
Confusional state	5 (2%)	0 (0%)
Dysphoria	5 (2%)	0 (0%)
Pollakiuria	5 (2%)	2 (1%)
Source : Reference 39

Tables

Box. The legal status of psychedelics The legal landscape of psychedelics is rapidly evolving. Psilocybin use has been decriminalized in many cities in the United States (such as Denver), and some states (such as Oregon) have legalized it for therapeutic use.It is important to understand the difference between decriminalization and legalization. Decriminalization means the substance is still prohibited under existing laws, but the legal system will choose not to enforce the prohibition. Legalization is the rescinding of laws prohibiting the use of the substance. In the United States, these laws may be state or federal. Despite psilocybin legalization for therapeutic use in Oregon and decriminalization in various cities, psychedelics currently remain illegal under federal law.

Source: Reference 1

Authors and Disclosures

Authors and Disclosures

Madonna Thakur, MBBS Medical Graduate BGC Trust Medical College Chittagong, Bangladesh
Jeffrey A. Lam, MD PGY-1 Psychiatry Resident Cambridge Health Alliance Harvard Medical School Cambridge, Massachusetts
Prakash Mishra, MD Attending Psychiatrist Department of Psychiatry and Behavioral Health Sinai Health System Chicago, Illinois
Awais Aftab, MD Clinical Assistant Professor Department of Psychiatry Case Western University School of Medicine Cleveland, Ohio
Disclosures The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

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Clinical Point

Psilocybin and LSD both have a wide therapeutic index and similar agonistic action at the 5-HT2A brain receptors
A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD found MDMA was well-tolerated, with few serious adverse effects
Adverse effects associated with ketamine include dissociation, sedation, perceptual disturbances, and anxiety
Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills
Psychedelic treatments are typically offered with psychotherapy, which raises some concerns regarding boundary violations
Some may consider any unpleasant psychedelic experience an adverse reaction; others may consider it part of the therapy
Cautious optimism is warranted, but psychedelics' efficacy and safety need to be demonstrated in rigorous, long-term trials

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Related Resources

• American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
• Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
• Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/

Original written by from https://www.medscape.com/viewarticle/993529