The United States is experiencing a mental health crisis and psychedelics (ketamine, LSD, MDMA, psilocybin) have emerged as a potential new drug class to add to the treatment armamentarium. Approximately 21% of adults in the US have experienced mental illness in the last year.1 Major depressive disorder alone accounts for $326 billion in economic burden annually,2 with a national average of 22% of adults taking psychotropic medications in March 2022.3

The most commonly available medications for mental health — serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, antipsychotic agents — are not always effective in achieving complete remission of symptoms or restoring function. In fact, despite an increased utilization of prescription medications for mental health, the overall rate of suicide has climbed by 35% over the last 2 decades.4 In comparison to the scope and scale of the mental health crisis in the US, the current prescription drug development pipeline is incredibly small.5

Psychedelics as a Drug Class

Initially researched in the 1940s, psychedelics are reemerging as one potential solution in the treatment of depression, anxiety, post-traumatic stress disorder (PTSD), and substance use disorders.5 No widely agreed-upon definition of psychedelic exists, however, drugs with this classification generally are thought to have fundamental properties related to producing hallucinations, as well as providing an experience that expands consciousness.6


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At the chemical level, the efficacy of psychedelics is thought to derive from their role as psychoplastogens, compounds that promote neural plasticity as a function of chemical modulation within the brain.7 Psychedelics broadly encompass 3 drug classes: serotonin agonists, serotonin-releasing agents, and N-methyl-d-aspartate (NMDA) receptor antagonists (Table).6-11 Classic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), act as serotoninagonists.6-8 Entactogens, such as methylenedioxymethamphetamine (MDMA), act as serotonin-releasing agents.7,8 Dissociative anesthetic substances, such as phencyclidine (PCP) and ketamine, act as N-methyl-d-aspartate (NMDA) receptor antagonists.7,8

Table. Mechanism of Action and Potential Medical Applications of Psychedelics6-11

DrugChemical DerivationNeurologic EffectsClinical EffectsPotential UsesPotential Adverse Effects
Psilocybin8-10    Psilocybe and other types of mushroomsSerotonin agonist at 5-HT2A of pyramidal neurons  • Dizziness
• Weakness
• Tremor
• Paresthesias
• Altered consciousness (acute perceptual auditory or visual distortions)
• Altered mood (happiness, dysphoria, anxiety, panic)
• Distorted sense of space or time
• Sensation of having a mystical experience  
• Depression
• Anxiety related to terminal illness
• ETOH use disorder
• Psychosis
• Persistent hallucinogenic perceptions
• Nausea
• Headache
LSD8-10    Ergot fungusSerotonin agonist at 5-HT2A of pyramidal neurons• Dizziness
• Weakness
• Tremor
• Paresthesias
• Altered consciousness (visual hallucinations, audiovisual synesthesia, and positively experienced depersonalization and derealization)
• Altered mood (subjective wellbeing, openness, fear, or irritability)
• Distorted sense of space or time
• Anxiety related to terminal illness
• ETOH and tobacco use disorder
• Psychosis
• Persistent hallucinogenic perceptions
• Modest increases in blood pressure, heart rate, and body  temperature
MDMA8,9  Sassafras treeSerotonin, dopamine, and noradrenaline agonist• Weakness
• Fatigue
• Euphoria
• Arousal
• Perceptual alteration
• Enhanced empathy
• Enhanced sociability
• PTSD• Elevated blood pressure
• Potential neurocognitive deficits
• Memory impairment
• Sleep disruption
• Acute anxiety
• Short-term depression
• Toxicity / overdose
Ketamine7,9,11  SyntheticNMDA receptor antagonists• Dizziness
• Tremor
• Sedation
• Dose-related psychedelic or dissociative effects
• Short-term cognitive impairment
• Memory loss  
• Depression
• Refractory anxiety
• PTSD
• Substance use
• Acute suicidality
• Potential for abuse
• Increased blood pressure or heart rate
• Nausea
• Headache  
ETOH, ethyl alcohol; MDMA, methylenedioxymethamphetamine; NMDA, N-methyl-d-aspartate; PTSD, post-traumatic stress disorder

Potential Applications of Psychedelics in Mental Health

As a result of the potential effects on perception (eg, psychosis, fear, increased anxiety, and panic), the vast majority of research involving psychedelics has explored the impact of concurrent administration of various drug formulations within a clinical setting and the application of psychotherapy. Though the term “psychotherapy” is not standardized in either approach or application within the literature, ideally the process of psychedelic-assisted therapy should involve preparation, treatment, and integration phases.7 Minimizing adverse experiences may include screening to identify ideal candidates for this type of therapy, monitoring physiologic and psychological effects throughout therapy by multiple health care providers (medical and professional therapists), as well as providing a session targeted at assisting an individual to process and gain insight from the experience.7

In measuring outcomes, many available clinical rating tools have been found to demonstrate high variability and low sensitivity and/or specificity in the setting of psychedelic-assisted therapy.9 Tools demonstrating the most potential validity in this area may include the Hallucinogen Rating Scale (HRS), Mysticism Scale (MS), and Altered States of Consciousness Rating Scale (OAV), although even these scales have limited dose-response data firmly supporting their use in this context.9  

Psilocybin

Derived from psilocybe and other types of mushrooms, psilocybin undergoes biotransformation into active metabolites through first-pass hepatic metabolism, reaches peak plasma concentration 100 minutes after oral administration, and has a half-life of 160 minutes.9 Dose-dependent, primarily pleasant changes in mood and perception and production of a mystical experience commonly occur.9 Adverse effects tend to be minimal and transient but can include dose-dependent dysphoria, anxiety, panic, and delayed-onset headaches and nausea.8,9

The most well-researched applications for psilocybin are depression and anxiety; in particular, research has examined use of psilocybin in reducing anxiety and improving mood/quality of life among individuals with advanced-stage cancer.8-13 In a phase 2 randomized controlled trial (RCT) of psilocybin vs escitalopram (n=59) for the treatment of moderate to severe MDD, mean changes in 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16) scores were similar among the treatment arms: -8.0±1.0 points in the psilocybin group vs -6.0±1.0 in the escitalopram group with a between-group difference of 2.0 points (95% CI, -5.0 to 0.9; P = 0.17).14 A QIDS-SR-16 response occurred in 70% of the psilocybin group vs in 48% of the escitalopram group (this difference was not deemed to be statistically significant) and QIDS-SR-16 remission occurred in 57% vs 28%. Though outcomes appear encouraging, it is important to note that approximately 90% of patients screened (891 out of 1000) did not meet inclusion criteria (primarily because of another pre-existing psychiatric diagnosis), most self-referred, and many expressed a preference for treatment with psilocybin, which may have impacted perceived efficacy of the treatment. Five out of 29 patients in the escitalopram group did not complete the protocol requirements, including 4 who stopped taking the medication because of adverse events and 1 who guessed they were taking escitalopram and halved the dose because of perceived adverse events. In the psilocybin arm, 3 out of 30 patients did not complete all dosing procedures.  

Studies have demonstrated that psilocybin-assisted therapy may also be effective in treating alcohol and tobacco dependence, with study findings demonstrating reductions in mean drinking days, 50% reduction in heavy drinking days from baseline levels, and improved rates of smoking cessation in individuals who had failed in previous attempts.8

Psilocybin gained FDA-designated status as a breakthrough therapy for treatment-resistant depression in 2018 and major depressive disorder (MDD) in 2019. In addition to these conditions, current clinical trials are investigating use of psilocybin in PTSD, depression in Alzheimer disease, obsessive-compulsive disorder, anorexia nervosa, and substance use disorders (such as cocaine and opioids).5,12

LSD

Derived from multiple plant products (eg, ergot fungus, morning glory, wood rose), LSD has a high degree of biotransformation with peak plasma levels reached approximately 1.5 hours after administration and a variable half-life ranging from 3.6 to 12 hours.9 Initial studies largely looked to validate the effects of LSD (any vs good vs bad effects) with alterations in consciousness — visual hallucinations, audiovisual synesthesia, subjective wellbeing, openness to experience, and positive experiences with derealization and depersonalization — found to last approximately 12 hours.9

Studies have demonstrated improvements in state anxiety and depressed mood in patients with terminal illness treated with LSD-assisted psychotherapy, with sustained effects for up to 1 year and no adverse effects lasting more than 24 hours.6,10-13 In patients with alcohol use disorder, reductions in alcohol misuse and increased abstinence were associated with the administration of a single dose of LSD.10,12 In a study assessing the effects of a single dose of LSD in healthy individuals, the intervention was associated with increased positive life attitude, improved mood, altruistic effects, and life satisfaction at both 1- and 12-month intervals post-treatment.12 Ongoing clinical trials are evaluating LSD in the treatment of mood disorders, migraine headache, and anxiety associated with terminal illness.12

MDMA

Derived from the oil of the sassafras tree, MDMA consists of stereoisomers that undergo biotransformation at various rates via cytochrome P450 (CYP450; CYP2D6) and catechol-O-methyltransferase pathways.9 The half-life of a single dose is approximately 9 hours but due to a complex mechanism of inhibition, the drug has nonlinear pharmacokinetics that can reduce drug metabolism for weeks at a time with the administration of multiple doses.9 Phase 2 RCTs examining the efficacy of 2 MDMA-assisted psychotherapy sessions in the treatment of PTSD demonstrated reductions in symptoms of greater than 30% in a majority of participants, with some individuals no longer meeting the criteria for PTSD.8,12,15,16 Of note, three-quarters of participants in one of the studies showed sustained remission of symptoms for 3.5 years after initial treatment.8,12,16 In phase 3 a placebo-controlled RCT, two-thirds (67%) of participants who received MDMA-assisted therapy (28 out of 42) no longer qualified for a PTSD diagnosis after 18 weeks and three sessions vs 32% of participants in the placebo group.17

In 2017, the FDA granted MDMA breakthrough therapy designation for the treatment of PTSD.12 Since then, proposed treatment targets in ongoing studies of MDMA also include depression, anxiety related to life-threatening illness, and social anxiety in adults with autism spectrum disorder.9,12

Ketamine

As a synthetically produced combination of stereoisomers (S+/R-) with differing NMDA receptor affinity, ketamine does not appear to produce dose-dependent effects, which is not unexpected given more recent data demonstrating that binding likely occurs at a variety of non-NMDA mediated receptor sites as well.9,11 Women experience a more rapid rate of drug elimination (20% higher) resulting in men reporting more prominent side effects.9 The clinical effects and half-life of ketamine vary by administration route with intravenous administration having the most rapid onset and predictable linear dose-dependent plasma concentration.9

Esketamine nasal spray became the first fully FDA-approved psychedelic therapy in 2019 for treatment-resistant depression when used in combination with an antidepressant.7 The indication was later expanded to include depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior; however, the effectiveness of esketamine in preventing suicide or in reducing suicidal ideation or behavior had not been demonstrated when the drug went to market.18 The drug’s long-standing efficacy in the treatment of depression is marked by rapid onset of subanesthetic doses at 4 hours after infusion and at 2 to 4 hours with intranasal esketamine, sustained efficacy, sustained antidepressant effects with repeated treatment, and up to a 69% reduction of suicidal ideation demonstrated in subsequent studies.11,19

In a phase 3 RCT involving patients with treatment-resistant depression (non-response to 2 antidepressants), patients treated with esketamine plus an antidepressant had a significantly greater change in Montgomery-Åsberg Depression Rating Scale (MADRS) score compared with those given an antidepressant plus placebo at day 28 (difference of least square means=-4.0, 95% CI, -7.31 to -0.64).20 Clinically meaningful improvement was observed at earlier time points in the esketamine plus antidepressant group, and these results were consistent across various subgroups (age, sex, geography, baseline symptom severity, level of functional impairment, and class of oral antidepressants).

Potential Contraindications

Much of the evidence looking at the indications and contraindications of psychedelic use is primarily theoretical at this point. As such, several populations have been excluded from studies thus far due to concern for physiologic toxicity or the potential of acute psychological distress.9 This has included individuals with a personal or family history of psychosis or psychotic disorder and those with known cardiovascular disease (eg, hypertension, tachycardia, tachyarrhythmias).7,9 Use of concurrent psychiatric medications that may confound results has primarily excluded individuals currently receiving therapy with SSRIs, lithium, antipsychotics, and monoamine oxidase inhibitors (MAOIs).9 No studies to date have been inclusive of pediatric or older adult populations.

Concern for Potential Abuse With Psychedelic Agents

The potential for abuse of psychedelic agents historically has been a topic of controversy. The majority of these drugs are classified as DEA Schedule I controlled substances (and are similarly scheduled in UK and Europe) with no approved medical uses and labeled as having a high potential for abuse.12 Yet, there is no existing data-driven research documenting the potential risks for abuse and/or dependence on psychedelics used in the clinical setting.6,12 In 2010 an expert panel in the UK, the Independent Scientific Committee on Drugs, reviewed data on 20 potential drugs of abuse to indicate the level of risk for harm to self and others and provided a harm score ranging from 0 to 100, with a higher score indicating an increased risk of morbidity, mortality, and dependence among several other measures.21 Alcohol received the highest score (72), followed by heroin (55), while cocaine was tied to moderate risk (27) and hallucinogens such as ketamine, MDMD, and LSD (15, 9, and 7, respectively) ranking substantially lower.21 Although direct clinical data is lagging, this suggests that existing drug scheduling may be more rooted in historic social biases than actual evidence of abuse potential for psychedelics.5 While we understand from prior evidence regarding the use of street drugs there is a potential for misuse or abuse, little supporting data exists outside of animal studies to determine the true potential for prescription psychedelic abuse, making it most likely to be determined in postmarketing analysis.6,12,21

Potential Risk vs Benefits of Psychedelic Therapy

Psychedelics present several potential advantages when compared to existing prescription drug therapy. When administered in conjunction with psychotherapeutic support, psychedelics have been relatively consistent in producing antidepressant and anxiolytic effects.12 In contrast to traditional psychopharmacologic options, the onset of action of psychedelics appears to be significantly faster, often providing immediate effects rather than waiting weeks or even months for clinical improvement.5,13 Perhaps most promising is initial data demonstrating a strong dose-response relationship with sustained benefits, such as a single dose of psilocybin reducing depression and anxiety for up to 1 year.5,7 The majority of evidence also demonstrates these drugs are generally well-tolerated with adverse effects that seem to be relatively minor and short lived (<72 hours) postadministration.13

Clinical research remains limited in this area with a small amount of well-controlled studies published to date, many lacking randomization and/or double blinding and most of which have small sample sizes and relatively short duration of treatment and follow-up.5,9,10,13 Most available studies provide minimal insight regarding the dose vs response as it relates to efficacy because the primary initial outcome of psychedelic research to date has focused on determining dosing as it relates to safety.9,12 Almost all studies look at psychedelic use in combination with psychotherapy — in most cases with well-trained and experienced staff — which on its own is traditionally considered a first-line treatment for most mental health conditions and may potentially represent a significant confounding factor.9

Moving forward, cost will be a large limitation in how widely available and easily assessable psychedelic therapies become. Coupled with the cost of administration, the initial month of esketamine treatment ranges between$4720 and $6785, with maintenance therapy continuing at $2360 to $3540 a month thereafter.7 Even with the potential for reduced dose frequency with newer agents such as psilocybin, the administration costs are estimated to be similar (or even more) because of the length of time required for the administration of a single dose (6 to 8 hours vs 2 hours for esketamine).7 Psychedelic drugs that are indicated exclusively for use in conjunction with psychotherapy may be effective but at the expense of limiting widespread use because of financial barriers and clinician availability, which may ultimately worsen already existing inequities in the health care system.

Conclusion

To reclassify psychedelics into the DEA Schedule II and move these agents into clinical trials and clinical practice, many gaps in both practice and research will need to be addressed.22 Because these drugs were recently approved or are early in the FDA approval process, clear clinical guidelines/expert recommendations on the application of research into practice are still forthcoming. Though the clinical impact is potentially promising, treatment involving psychedelics is largely theoretical at this point and thus not included in current professional training models for the majority of mainstream medical, nursing, or psychotherapy programs.

Moving forward clinical drug trials investigating the efficacy of psychedelics will need to more consistently include RCTs with large sample sizes and recruitment of diverse participants; double-blinded research will continue to present a challenge in this area as it is difficult to assign participants to a control group when obvious drug effects are absent.9 One practical consideration researchers may face moving forward is how to effectively uncouple hallucinogenic and therapeutic effects to maximize efficacy while minimizing abuse potential.7,9 Ultimately, the structure of our health care system as it stands now does not support the widespread application of psychedelics in terms of financial cost and given the paucity of currently available psychiatric care providers.7

Melissa Kalensky, DNP, APRN, FNP-BC, PMHNP-BC, CNE, is an assistant professor at Rush University College of Nursing in Chicago.

References

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This article originally appeared on Clinical Advisor