Michael W. Jann, PharmD, FCP

While the country’s headlines shone a light on the troublesome opioid epidemic, another drug epidemic was slowly emerging. Methamphetamine is now among the most abused illicit drugs in the United States. According to the Centers for Disease Control (CDC), methamphetamine use 

 in the United States from 2015 to 2018, rising to an annual use rate of 59.7 per 1000 adults, or 14,686,900 individuals per year.

The continued escalation of methamphetamine use, alone or with opioids, presents providers with complex medical challenges and difficult consequences for patients, families, and the legal and health care systems. Separately, each drug represents an epidemic and a crisis. Together, they magnify the medical complications facing our society.

Unlike opioids, methamphetamine lacks US Food and Drug Administration (FDA)-approved pharmacological treatment interventions. Nevertheless, amphetamine-type stimulants (ATS), including methamphetamine, have a unique history that began during World War II; they were then used in the 1950s and 1960s for depression and obesity.

 ATS use declined in the 1970s after its reclassification to a more restrictive schedule by the Comprehensive Drug Abuse Prevention and Control Act.

Figure 1. Percentage of Treatment Admissions Due to Methamphetamine Use

Figure 2. US Fatalities Associated With Narcotics

Table. Summary of Methamphetamine Pharmacokinetics by Administration Route

Legal restrictions led to new drug forms, and the number of individuals who used methamphetamine grew. Postamphetamine rescheduling led to manufacturing methamphetamine using phenyl-2-propane (P2P) and methylamine. When P2P became a schedule II controlled substance, ephedrine and pseudoephedrine became the predominant agents used for methamphetamine synthesis. The Combat Methamphetamine Epidemic Act of 2005 limited pseudoephedrine access and banned ephedrine, but these regulations resulted in only a temporary decline in use. In 2005, there were 192,000 new methamphetamine users per year, whereas by 2012, the number had markedly increased to 440,000 individuals per year.

, methamphetamine use was higher in men compared with women (8.7 vs 4.7 per 1000 adults, respectively).

 Adults aged 26 to 34 years had the highest rates of methamphetamine use (11.0 per 1000 adults), followed by those aged 18 to 25 years and 35 to 49 years (9.9 and 8.3 per 1000 adults, respectively). The prevalence of methamphetamine use was greater for those making either less than $20,000 per year or between $20,000 and $49,999 per year (15.6 and 7.6 per 1000 adults, respectively), compared with those at other income levels. For almost 45% of those who used the drug, duration of use was greater than 100 days per year; nearly 25% of all individuals who used methamphetamine reported administering the drug intravenously. About 53% met the DSM-5 criteria for methamphetamine use disorder and only 31.5% received substance abuse treatment.

The CDC also compared 2008 hospital admissions with 2017 admissions, finding 15,747,334 drug-related treatment admissions in individuals 12 years or older in 2017.

 The number of treatment admissions due to methamphetamine increased substantially (

These increases in use and treatment translate into a huge economic burden. Using 2005 

, the RAND Corporation estimated total economic costs of $23.4 billion, including indirect costs of about $12.6 billion.

 Based upon increasing usage in the past decade, undoubtedly the economic burden of the drug has substantially increased.

The opioid epidemic in the United States has been well documented for a decade. The CDC reported that 70,630 fatalities was associated with drug overdoses in 2019, including all drugs.

 That year, the second-highest number of fatalities were associated with stimulant drugs, largely methamphetamine (

Based upon the methamphetamine use and fatality data, it is apparent that it has become a 

 To complicate matters, an increasing number of individuals abuse both opioids and methamphetamine.

 The CDC reported that between 2015 and 2018, 57% of those who used methamphetamine also abused either heroin or prescription opioids.

 Similarly, hospital admissions among individuals who primarily used heroin (but also reported methamphetamine use) increased by 490% from 2008 to 2017. The most common administration routes were by (intravenous) IV injection (47.1%) and smoking (46.0%).

A survey in rural Oregon reported that 96% of participants (N = 112) who used opioids in the past 30 days also noted methamphetamine use, and 50% injected both opioids and methamphetamine.

 Participants indicated that methamphetamine was more widely available, less expensive, and less stigmatized compared with opioids. Individuals discharged from substance abuse programs perceived methamphetamine as a drug that prevented opioid overdose. Individuals who used both opioids and methamphetamine reported that the latter could serve as an opioid substitute, provide a synergistic high, and balance out the sedation from the opioids.6 On the other hand, individuals who used methamphetamine stated that opioids can be used to mitigate the former’s negative adverse effects. They believed that the addition of small amounts of methamphetamine could prolong opioid intoxication effects, and coinjection of both had a more desirable intoxication effect than using either substance alone.

Methamphetamine exists in 2 stereoisomer forms, the D- and L-forms; the D-form is 3 to 5 times more potent than the L-form (

 the dopamine, serotonin, and noradrenaline transporters, as well as the vesicular monoamine transporter-2.

 Heroin and other opioids are opioid receptor agonists.

 The opioid receptors are widely distributed in the central nervous system, including the nucleus accumbens (NAcc) and ventral tegmental area (VTA).

 Both methamphetamine and opioids promote the release of dopamine in the NAcc and VTA, indicating a common pharmacological pathway for both drugs regarding reward and reinforcement properties.

 When these agents are taken together, a pharmacodynamic synergy can occur in which dopamine release may be greater than with either agent taken alone. Further, stimulant actions may attenuate an opioid’s sedative actions, whereas opioids can prevent overstimulation by methamphetamine.

The route of methamphetamine administration affects its pharmacokinetics (

 For instance, the IV route produces the most rapid onset of effects, whereas smoking promotes a slightly slower onset (about 20 minutes). The elimination half-life of methamphetamine is between 9 and 12 hours. Its metabolism, shown in 

, is converted to 2 main metabolites: amphetamine (AMP) and the 4-hydroxy (OH) methamphetamine by the cytochrome P450 (CYP) 2D6 enzyme.

 The CYP2D6 system is prone to many possible drug-drug interactions and genetic polymorphisms (eg, extensive and poor metabolizers). Although CYP2D6 genotyping has not been conducted in methamphetamine pharmacokinetic studies, in one study, a single participant was reported to have an extremely low formation of AMP and 4-OH methamphetamine compared with the other 11 participants; it was suggested that this individual could be a poor metabolizer of CYP2D6.

A wide range of adverse effects (eg, psychological issues, withdrawal, overdose, cardiac and other medical problems) is associated with methamphetamine use.

 The most common psychological effects are agitation, psychosis, and suicidal ideation. Acute methamphetamine-induced psychosis is indistinguishable from acute paranoid schizophrenia with hallucinations and delusions. Hallucinations can be auditory, visual, and tactile, with delusions of persecution and reference. Psychosis can occur with doses greater than 50 mg, with an onset ranging from 7 minutes to 34 hours post drug administration. Fatalities from severe psychological effects include those related to accidents, suicides, and homicides. Withdrawal symptoms include insomnia, depressed mood/anxiety, cravings, reduced energy, and cognitive impairment. Agitation, dilated pupils, hypertension, tachycardia, and rapid respiration occur in overdose situations. The cardiac effects can include arrhythmias, hypertension, and sudden death. Other medical problems include pulmonary damage from smoking, pulmonary hypertension, rhabdomyolysis, cerebrovascular strokes, and seizures.

 Unlike other drugs of abuse, methamphetamine has been shown to cause significant neurotoxicity and possible brain injury by modulating at least 3 molecular cascades that involve oxidative stress, neurotoxic and excitotoxic effects, and neuroinflammation.

 Briefly, it alters sigma-1 receptors that increase reactive oxygen and peroxide formation, which leads to oxidative stress. Methamphetamine promotes glutamate transmission, increasing Ca+2 intracellular concentration, resulting in neurotoxic and excitotoxic effects. The third mechanism involves the drug binding to toll-like receptor 4 and activating proinflammatory cytokines (eg, interleukin-6) leading to neuroinflammation. It has been suggested that chronic methamphetamine exposure prior to a 

 (TBI) can magnify the injury and worsens outcomes. Conversely, individuals with a TBI seem to be more vulnerable to the neurotoxic effects of methamphetamine use.

Part of the recent increase in methamphetamine use may be associated with sex. Drug use before and during sex is known as chemsex, and methamphetamine is the most commonly abused drug for 

among men who have sex with men (MSM). It is frequently used along with gamma-hydroxybutyric acid to enhance the sexual experience.

 In one study, it was reported that of MSM aged 36 to 44 years, 36% had had chemsex with multiple partners. Some reported having chemsex with more than 10 partners during 1 session. The same study reported that methamphetamine use is typically associated with unprotected sex. MSM who participated in chemsex reported use more than 2 times per month with experiences taking place over the course of years. HIV, other sexually transmitted infections, and other medical complications become major concerns for individuals who engage in chemsex.

Individuals with substance use problems have been especially affected by COVID-19, and those who use methamphetamine are no exception. The drug can cause pulmonary damage, pulmonary hypertension, and cardiomyopathy, and it compromises pulmonary function, which may make patients more prone to chronic respiratory disease and may put them at risk for more severe illness from COVID-19. Methamphetamine can also impact the immune system by decreasing the efficiency of B cells, macrophages, and other defense mechanisms, further increasing the risk of fatality from COVID-19.

 Risks for and from COVID-19 are even higher for individuals who have HIV and use methamphetamine, because individuals with HIV already have a compromised immune system.

Besides the pulmonary and cardiac damage it causes, methamphetamine use can cause vulnerability to COVID-19 in an additional way: It can further impair an individual’s judgment when used in chemsex by affecting their decisions regarding pre-exposure prophylaxis or postexposure prophylaxis HIV treatment. This, in turn, enhances vulnerability to contracting COVID-19 and may lead to faster COVID-19 progression.

Treatment for drug addictions requires behavioral and, when appropriate, pharmacological interventions. The various 

 used in individuals with addictions include cognitive behavioral therapy, matrix model, contingency management, motivational enhancement therapy, acceptance and commitment therapy, and 12-step facilitation therapy.

 Each of these behavioral interventions can be effective in reducing methamphetamine use, but the patient must remain in a given treatment program for the best chance of success.

Although the FDA has made recommendations for medications to counteract opioid abuse, it has not yet done so for methamphetamine abuse. Although many different medications have been tested in randomized clinical trials, only 4 agents—methylphenidate, bupropion, modafinil, and naltrexone—displayed any benefits, and those were limited. None demonstrated adequate and consistent evidence for efficacy.

 Preliminary pilot studies with small numbers of participants looked at oral naltrexone 50 mg/day, bupropion 300 mg/day, and buprenorphine 8 mg/day; modest reductions were reported in all participants’ methamphetamine withdrawal cravings.

 Ultimately, some of these agents may have specific uses for addiction interventions.

 in individuals who were methamphetamine-dependent but were low-severity users (ie, less than daily).

 Topiramate 200 mg/day was unable to promote abstinence in those who used methamphetamine but did reduce the amount taken as well as relapse rates in those who were already abstinent.

 Mirtazapine 30 mg/day, when used in conjunction with substance use counseling, was associated with decreases in risky sexual activity.

 A comprehensive pharmacologic therapeutic review article on methamphetamine and amphetamine dependence yielded an absence of proven efficacy, although the studies were underpowered with low treatment completion rates.

Combination therapy may be more effective than individual agents. A large multicenter, double-blind, placebo-controlled, randomized clinical trial in individuals with methamphetamine use disorder (N = 403) evaluated the combination treatment of bupropion 450 mg/day and long-acting injection naltrexone 380 mg every 3 weeks.

 The study was powered at 90% (N = 370 needed) to detect a 24% difference between the combination treatment and the placebo. Two study stages were designed, each 6 weeks long. Stage 1 assigned participants to the bupropion and naltrexone group (n = 109) or placebo (n = 294) for the first 6 weeks. Participants who did not have a placebo response were randomly assigned the bupropion and naltrexone and placebo (1:1 ratio) for a second 6-week time period. Urine samples were obtained and tested twice weekly, and the primary outcome was defined as at least 3 methamphetamine-negative samples out of 4 samples at the end of stage 1 or 2. The primary outcome response rate averaged for the 2 stages was 13.6% for the bupropion and naltrexone group and 2.5% for the placebo group, indicating an overall treatment effect of 11.1% (P < .0001). This clinical trial, unlike previous studies, did not lack statistical power and had adequate treatment completions. However, the bupropion and naltrexone response rate was rather low, albeit greater than with the placebo, and illustrates the enormous challenge in finding an effective treatment approach for methamphetamine use disorder.

Methamphetamine use has been underrecognized compared with the opioid use epidemic, but it is a major health care concern, due to rapidly increasing usage of this drug and its highly addictive pharmacologic properties. Methamphetamine use poses many psychological and physiological challenges to users. Although behavioral interventions can be effective, there are no FDA-approved drugs for treating methamphetamine addiction.

is a professor in the Department of Pharmacotherapy at the University of North Texas (UNT) System College of Pharmacy, UNT Health Science Center, Fort Worth, Texas

Patterns and characteristics of methamphetamine use among adults – United States, 2015-2018

2. Courtney KE, Ray LA. Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature. 

3. Jones CM, Olsen EO, O’Donnell J, Mustaquim D. Resurgent methamphetamine use at treatment admission in the United States, 2008-2017. 

4. Mattson CL, Tanz LJ, Quinn K, Kariisa M, Patel P, Davis NL. Trends and geographic patterns in drug and synthetic opioid overdose deaths – United States, 2013-2019. 

5. The Lancet. Opioids and methamphetamine: a tale of two crises [editorial]. 

Twin epidemics: the surging rise of methamphetamine use in chronic opioid users

7. Jones CM, Underwood N, Compton WM. Increases in methamphetamine use among heroin treatment admissions in the United States, 2008-17. 

8. Baker R, Leichtling G, Hildebran C, et al. “Like Yin and Yang”: perceptions of methamphetamine benefits and consequences among people who use opioids in rural communities. 

9. Palmer A, Scott N, Dietze P, Higgs P. Motivations for crystal methamphetamine–opioid co-injection/co-use amongst community-recruited people who inject drugs: a qualitative study. 

10. Li L, Everhart T, Jacob P III, Jones R, Mendelson J. Stereoselectivity in the human metabolism of methamphetamine. 

A review of the clinical pharmacology of methamphetamine

12. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. 

13. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. 

14. Paulus MP, Stewart JL. Neurobiology, clinical presentation, and treatment of methamphetamine use disorder: a review. 

15. El Hayek S, Allouch F, Razafsha M, et al. Traumatic brain injury and methamphetamine: a double-hit neurological insult. 

16. Giorgetti R, Tagliabracci A, Schifano F, Zaami S, Marinelli E, Busardò FP. When “chems” meet sex: a rising phenomenon called “chemsex.” 

17. Sexualized drug use (chemsex and methamphetamine) and men who have sex with men. Ontario HIV Treatment Network. May 2019. Accessed April 23, 2021. http://www.ohtn.on.ca/wp-content/uploads/2019/06/RR138_MSMSDU_June17.pdf

18. Evers YJ, Hoebe CJPA, Dukers-Muijrers NHTM, et al. Sexual, addiction and mental health care needs among men who have sex with men practicing chemsex – a cross-sectional study in the Netherlands. 

19. Hossain MK, Hassanzadeganroudsari M, Apostolopoulos V. Why METH users are at high risk of fatality due to COVID-19 infection? 

20. Carrico AW, Horvath KJ, Grov C, et al. Double jeopardy: methamphetamine use and HIV as risk factors for COVID-19. 

21. Starks TJ, Jones SS, Sauermilch D, et al. Evaluating the impact of COVID-19: a cohort comparison study of drug use and risky sexual behavior among sexual minority men in the 

22. National Institute on Drug Abuse. Principles of Drug Addiction Treatment: A Research-Based Guide (Third Edition). June 1, 2020. Accessed March 26, 2021. 

https://www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/evidence-based-approaches-to-drug-addiction-treatment/behavioral-therapies

23. Santos G-M, Coffin P, Santos D, et al. Feasibility, acceptability, and tolerability of targeted naltrexone for nondependent methamphetamine-using and binge-drinking men who have sex with men. 

24. Ahmadi J, Sahraian A, Biuseh M. A randomized clinical trial on the effects of bupropion and buprenorphine on the reduction of methamphetamine craving. 

25. Heinzerling KG, Swanson A-N, Hall TM, Yi Y, Wu Y, Shoptaw SJ. 

Randomized, placebo-controlled trial of bupropion in methamphetamine-dependent participants with less than daily methamphetamine use

26. Elkashef A, Kahn R, Yu E, et al. Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial. 

27. Colfax GN, Santos G-M, Das M, et al. Mirtazapine to reduce methamphetamine use: a randomized controlled trial. 

28. Siefried KJ, Acheson LS, Lintzeris N, Ezard N. Pharmacological treatment of methamphetamine/amphetamine dependence: a systematic review. 

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Articles

As all eyes were on the pandemic, another surge simmered below the surface.

Confronting the Methamphetamine Epidemic

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The goal of this activity is to inform readers about the latest research and clinical trials on psilocybin and outline its possible clinical uses.

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4. Identify the psychedelic-assisted psychotherapy method for psilocybin treatment.

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 and psilocin are the main psychedelic agents of the psychoactive mushroom genus Psilocybe.

 Historical and cultural use of these psychoactive mushrooms dates back 3000 years in Mexico and the Southwestern regional areas of the present-day United States. Scientifically, psilocybin was isolated and identified in 1958, synthesized in 1959, and used in various experimental research studies in the early 1960s. During that time, psilocybin and other 

 such as lysergic acid diethylamide (LSD) generated considerable controversy. Outside of recreational use, could they be used safely as therapeutic interventions?

The pharmaceutical company Sandoz ceased LSD and psilocybin manufacturing in 1965, and in 1970, the Controlled Substances Act placed psilocybin, LSD, and other psychedelic drugs under the Schedule I designation.

 This action resulted in a cessation of research associated with these agents. The revival of research into psilocybin and LSD began 25 years later under strict restrictions, when preliminary findings displayed promising results for a variety of psychiatric disorders. In the past several years, there have been more research studies on psychedelics than at any previous time.

The FDA approved the psychedelic agent, esketamine nasal spray for treatment-resistant depression (TRD) in 2019; this opened the door to the novel therapeutic approaches of psychedelic agents. In 2018, the FDA designated psilocybin for TRD and 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for 

 Based on these recent studies and approvals, psilocybin may have a growing role in the treatment of TRD and other psychiatric disorders.

Psilocybin reportedly has a low abuse potential and yields no physical dependence, based on the 8 factors of the Controlled Substances Act. It was recommended to be rescheduled as a Controlled Substance Schedule IV drug with a 

 (REMS) if approved by the regulatory agencies.

The structures of psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) and its active metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine) are shown in the 

, and they bothbelong to the group of tryptamine/indolamine hallucinogens that are related to serotonin.

 Psilocybin can be considered a prodrug, as it is rapidly converted to psilocin in the gastrointestinal (GI) tract by alkaline phosphatase and nonspecific esterases, where 1.0 mol of psilocin is equal to 1.4 mol of psilocybin.

 Psilocin is the active molecule that produces the pharmacologic effects of a selective agonist of serotonin (5-HT) receptors, which include 5-HT

 Compared to other similar 4-OH substituted tryptamines, psilocin has the most potent binding affinity (Ki) for 5-HT

 receptors (10 nM), and to a lesser extent, 5-HT

 receptor activation in the cortical and subcortical structures is the unifying mechanism by which psychedelics exert their hallucinogenic and other assorted psychological actions.

 Depending upon the dose used, the specific psychedelic agent, and possibly, the 5-HT

 receptor density in the different neuronal areas, psilocybin and other psychedelic agents can exert different modulatory actions across the various cortical regions. The administration of ketanserin (a 5-HT

 receptor antagonist) in human clinical studies attenuated the psychological effects of psilocybin, psilocin, and LSD.

 receptors in human psilocybin studies remain to be elucidated.

Besides 5-HT receptors, psychedelic agents may possess other pharmacologic actions that contribute to their behavioral and psychological effects. LSD was reported to interact with considerable affinity at the 

 with stereospecificity, as d-LSD was 1000 times more potent than l-LSD.

 examined the use of psilocybin in healthy volunteers (N = 7) and its effects on in vivo D2 receptor binding using 11C-raclopride in the striatum. Dosed at 0.25 mg/kg orally, psilocybin produced changes in mood, thinking disturbances, illusions, and visual hallucinations.

 Psilocybin also significantly decreased 11C-raclopride binding potential bilaterally in the caudate nucleus (19%) and putamen (20%), which was consistent with a reciprocal increase in endogenous dopamine. These findings indicate that 5-HT

 receptor activation can be a factor for modulating striatal dopamine release in acute psychosis. Psilocybin may be a useful pharmacologic agent for examining the complex interactions between serotonin-dopamine systems and various psychiatric conditions, such as schizophrenia.

 by psilocybin is also believed to increase glutamate release by the subsequent activation of postsynaptic α-amino-٣-hydroxy-٥-methyl-٤-isoxazole propionic acid (AMPA) receptors.

 The prefrontal cortex (PFC) and other cortical areas that highly express 5-HT

 receptors receive excitatory glutamatergic input from thalamic projections, but also send output to both the cortical and thalamic regions. The activation of presynaptic 5-HT

 receptors in the thalamocortical afferents contributes to the psychedelic-induced modulation of glutamatergic transmission to the PFC. Thus, these dual actions from the presynaptic and postsynaptic 5-HT

 receptors form a cyclic feedback process for 5-HT

 receptor activation of glutamate effects in the central nervous system, leading to a complex cortical-thalamic neurocircuitry.

Psilocybin is rapidly converted to the active molecule, psilocin. Specific bioanalytical assay methods have been developed to quantify psilocin, to determine its pharmacokinetic (PK) profile. An early study with psilocybin was conducted in healthy volunteers (N = 7), in which each participant received an intravenous (IV) dose of 1 mg and an oral dose of 0.224 mg/kg (range 10 to 20 mg).

 The estimated mean oral bioavailability of psilocin was 52.7% ± 20%. The following mean PK parameters reported from the oral route were the time to maximum effect/concentration (T

) of 105 ± 37 min; peak plasma concentration (C

) of 8.2 ± 2.8 ng/mL; and elimination half-life (T

) of 163.3 ± 63.5 min. An almost immediate phosphorylation of psilocybin takes place, and results from the IV administration noted a mean psilocin T

 of 74.1 ± 19.6 min. The psychological effects reportedly began at 20 to 90 min, and within 2 min from the oral and intravenous routes, respectively.

 formed via glucuronidation is psilocin glucuronide (psilocin-G), as shown in the 

 Psilocin-G is primarily eliminated from the body by renal excretion. The amount of psilocin-G produced was determined in another healthy volunteer (N = 8) PK 

, by giving a single oral dose of psilocybin 10 to 18 mg (mean 14 ± 3 mg), and urine samples were collected over the following 24 hours.

 was 3.3 ± 0.6 hours (closely resembling the 

) with the additional findings of a mean free psilocin amount of 3.4% ± 0.9% and mean psilocin-G excretion of 60.6% ± 27.1%, supporting the renal pathway as the primary elimination route.

In a population PK study, healthy volunteers (N = 12) were given escalating single oral doses of psilocybin at 0.3, 0.45, and 0.6 mg/kg, with a minimum of a 4-week interval between dosage administrations.

 The final model developed from the PK analysis was a single compartment model with linear absorption and clearance. The median area under the concentration-time curve (AUC) for psilocin was linear at 140 mg-hr/L, 213 mg-hr/L, and 267 mg-hr/L, corresponding to the doses of 0.3 mg/kg, 0.45 mg/kg, and 0.6 mg/kg, respectively.

Once psilocin is formed, it is mainly metabolized to psilocin-G (90%), and a small portion is converted to psilocin (10%). This can partially explain the interpatient variability observed with psilocybin administration. The 

 only 1.7% of the psilocybin dose found as psilocin in the urine, with a calculated psilocin renal clearance of 1 mL/min/kg, which corresponds to
58% of the creatinine clearance.

 These findings suggest that psilocybin dosage reductions are not necessary in patients with mild to moderate renal impairment.

The metabolic profile of psilocybin is presented in the 

, several metabolic routes are possible. As noted, psilocin-G is the major pathway (bold arrow line) with 2 minor pathways.

 Psilocin-G formation occurs via phase 2 metabolism with hepatic uridine 5’-diphospho (UDP)-glucuronosyltransferase (UGT) 1A9 and the small intestine UGT1A10.

In the second minor pathway, psilocin can be metabolized to 4-hydroxy-indole-3-acetaldehyde by 2 enzymes: aldehyde dehydrogenase (ALDH) and monoamine oxidase (MAO). It should be noted that alcohol and MAO inhibitors such as phenelzine may suggest interesting questions regarding potential drug-drug interactions that can lead to pharmacokinetic and/or pharmacodynamic effects. The metabolite, 4-hydroxy-indole-3-acetaldehyde is then further converted to 4-hydroxyindole-3-acetic acid and 4-hydroxytryptophole.

The third minor metabolic pathway for psilocin takes place via the cytochrome oxidase enzymes (it is unknown whether this is related to the cytochrome P450 oxidase enzymes) and non-enzymatic Fe3+ to form psilocin iminoquinone.

Earlier PK studies established the initial parameters for psilocybin dosing and provided information on the onset of its psychological effects for drug and product development. The next steps are to correlate the psilocybin (psilocin) clinical PK effects with its pharmacodynamics. 

 conducted on healthy volunteers (N = 8) who were given oral psilocybin (doses ranging from 3 mg to 30 mg) evaluated plasma psilocin concentrations, while assessing 5-HT

 Participants self-assessed their intensity ratings for clinical effects using a Likert scale from 1 to 10 (1 = least intense and 10 = most intense). Plasma psilocin C

 values displayed a linear correlation with doses of 3 mg to 30 mg (2.3 mg/L to 19.3 mg/L, respectively). The 5-HT

 receptor occupancy (%) results displayed a sigmoidal relationship with doses of 3 mg (42.9%), 15 mg (63.2%), and 30 mg (65.2%). Investigators observed a wide interpatient variability in psilocin plasma concentrations. Generally, the intensity ratings > 5 occurred when receptor occupancy approached 60% and psilocin plasma concentrations > 7.5 ng/mL.

A phase 1 clinical trial with the psilocybin formulation COMP360 was conducted in healthy volunteers (N = 89), in which participants randomly received a single 10 mg or 25 mg dose of psilocybin or placebo.

 The study aimed to evaluate the emotional and cognitive responses of participants, along with the safety and tolerability under strict procedures. The study found that psilocybin was well tolerated, and mood alteration was the most frequently reported effect. The most notable adverse effects were hallucinations and illusions, with a slightly higher incidence in the 25 mg dose than the 10 mg dose. These adverse effects occurred in about 67% of the subjects on day 0 of drug dosing and were resolved with cessation of any remaining adverse effects by the next day. No significant changes were observed in vital signs.

These findings showed that COMP360 was well tolerated and the psychological effects were transient and consistent with those observed in previous studies. Although significant changes in vital signs were not found,

 8 to 12 mg: mydriasis, change in heart rate, hypotension or hypertension, nausea, reflex tendencies, and tremors.

 Furthermore, if participants experienced significant hallucinations, illusions, or other psychotic symptoms, treatment with second-generation antipsychotic agents, such as risperidone or olanzapine, was suggested.

 Haloperidol was reported to alleviate only the euphoric, depersonalization, or derealization effects and not the visual hallucinations.

 It would be interesting to deduce the actions of pimavanserin, an antagonist of 5-HT

 receptors. Pimavanserin is FDA-approved for 

, for which hallucinations (visual and auditory predominantly) and illusions occur.

Esketamine is a noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist that is FDA-approved for treatment-resistant depression (TRD). Esketamine underwent a phase 2 proof-of-concept study and then proceeded to the phase 3 clinical trials.

 TRD was defined as a failure to adequately respond to 2 different antidepressants.

Esketamine is administered twice weekly at doses of 56 mg or 84 mg. Each clinical trial had treatment groups administered placebo nasal spray plus an oral antidepressant or esketamine nasal spray plus an oral antidepressant. Therefore, each patient continued to receive treatment with an antidepressant as the standard of care. From a safety perspective, esketamine was well tolerated. However, the incidence of dissociation reactions was reported to be about 23%.

 Esketamine is available via the REMS program; patients must be monitored for 2 hours after nasal spray administration for safety.

These findings regarding esketamine led to the development of psilocybin for TRD. The drug and product development process for psilocybin will likely take a similar approach. An 

 in patients with TRD (N = 12) was conducted using 2 psilocybin doses of 10 mg and 25 mg.

 The psilocybin doses selected for TRD are comparable to those for other psychiatric disorders under evaluation (

Table 1. Summary of Psilocybin Clinical Studies

 treatment-resistant was defined as Hamilton Depression Rating Scale (HAM-D) scores > 17 and a lack of improvement with 2 different classes of antidepressant medications for at least 6 weeks within the current episode. A single dose of psilocybin 10 mg, followed by 25 mg 7 days later was administered. Clinical assessments were obtained at baseline, at 7 days with administration of the second dose, and at 3 months after the second dose. The primary efficacy outcome was determined by the Quick Inventory of Depressive Symptomatology (QIDS), and the secondary outcomes were determined by the HAM-D and Beck Depression Inventory (BDI).

Psilocybin significantly reduced the mean (± SD) QIDS scores at 1 week (−11.8 ± 4.9, P = .002) and at 3 months (−9.2 ± 6.0, P = .003). The 

 also resulted in significantly reduced HAM-D and scores.

 At the 1-week mark, remission (defined as reduction in BDI score of ≤ 9) was achieved in 8 patients (67%). At the 3-month follow-up, remission (defined as a 50% reduction in BDI scores) was achieved in 7 patients (58%); 5 patients (42%) reached complete remission. Psilocybin was well tolerated, with only mild transient confusion (N = 12) and/or transient anxiety (N = 9). Transient nausea (N = 4) was noted during the day of drug administration and subsided 1 to 2 days thereafter.

Because of these findings and the FDA’s designation of psilocybin as a breakthrough therapy, a phase 2b clinical trial is underway in the United States and Europe (N = 216), with additional phase 3 clinical trials planned.

 The phase 2b study design uses psilocybin 1 mg (considered placebo), 10 mg, and 25 mg, and the Montgomery-Asberg Depression Ratings Scales (MADRS) scores are considered the primary outcome.

As the psilocybin pharmacologic mechanism of action involves 5-HT

 receptor agonist effects, the study design for patients with TRD may differ from that of the esketamine program, in which antidepressants were continued. For the 

s, the use of antidepressants or other medications may need to be discontinued for safety reasons and to prevent the possible development of serotonin syndrome.

Another reason for antidepressant discontinuation is the suggestion that selective serotonin reuptake inhibitors (SSRIs) obstruct potential psilocybin benefits, as the pharmacological actions of an antidepressant may downregulate 5-HT

 The clinical psilocybin study may need to include a 2-week (at least) antidepressant withdrawal and washout phase to place patients, caregivers, and providers in a state of heightened alert to monitor and detect any significant changes in the patient’s status. After psilocybin administration, the next question would be when to restart the antidepressant or other medications that were previously discontinued, with appropriate safety monitoring.

Psilocybin may be useful for examining interactions between serotonin-dopamine systems and various psychiatric conditions, such as schizophrenia.

Michael W. Jann, PharmD, FCP

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