
- Vol 38, Issue 5
- Volume 05
Confronting the Methamphetamine Epidemic
As all eyes were on the pandemic, another surge simmered below the surface.
CLINICAL
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
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.
History and Epidemiology
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.2 ATS use declined in the 1970s after its reclassification to a more restrictive schedule by the Comprehensive Drug Abuse Prevention and Control Act.
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.2
According to the
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 2017.3 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 Twin Epidemics
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.4 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
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.8 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.9
Pharmacology
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 (
Pharmacokinetics. The route of methamphetamine administration affects its pharmacokinetics (
Adverse effects. A wide range of adverse effects (eg, psychological issues, withdrawal, overdose, cardiac and other medical problems) is associated with methamphetamine use.2,11 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.
Neurotoxicity and brain injury. 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.14 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
Drug Use Chemsex
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
The COVID-19 Pandemic
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-19.19 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.20,21
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.20
Treatment
Treatment for drug addictions requires behavioral and, when appropriate, pharmacological interventions. The various
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.14 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.23,24 Ultimately, some of these agents may have specific uses for addiction interventions.
Bupropion 300 mg/day was reported to be
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.29 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.
Concluding Thoughts
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.
Dr Jann 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.
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