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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.

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

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

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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. 

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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. 

29. Trivedi MH, Walker R, Ling W, et al. Bupropion and naltrexone in methamphetamine use disorder. 

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

Confronting the Methamphetamine Epidemic

“The current opioid crisis has been responsible for the largest increase in deaths associate with opioids that we have ever known,” said Nora D. Volkow, MD, at the 2021 Virtual American Psychiatric Association Annual Meeting.

Volkow, Director of the National Institute on Drug Abuse (NIDA) at the National Institutes of Health, discussed how the pandemic has exacerbated the opioid crisis in the session, “

Collision of the Opioid Crisis and the COVID-19 Pandemic.”

In March 2020 during the outset of the pandemic, the number of people reporting drug use rose significantly.

 The top 4 drugs were nonprescribed fentanyl, cocaine, heroin, and methamphetamine. Overdoses increased up to 42% per month during the pandemic.

 If an individual had SUD and were infected with SARS-CoV-2, the likelihood of dying increased, especially for black men.

As the amount of drug use increased, so did the problems. The pandemic presented a number of key challenges for individuals with substance use disorder (SUD), Volkow noted, including: stigma, isolation, and loss of work/homes. These challenges prevented individuals with SUD from getting proper care, or worsened their condition. Volkow gave an overview of these issues and their impacts.

“We know that people with opioid use disorder… are terribly stigmatized,” Volkow stated. “It’s very hard sometimes to convince people with an opioid use disorder to go to a hospital because they don’t like to be discriminated against or mistreated.”

Stigma and the belief they will not receive thoughtful care already kept some individuals with SUD from checking into a hospital; the pandemic worsened this likelihood. Both hospitals and prisons became hotbeds for the SARS-CoV-2 virus, places often with higher concentrations of individuals with SUD.

“In order to reverse an overdose, someone has to give them naloxone,” Volkow said. “But if you are isolated, and start shooting by yourself, the likelihood of getting naloxone is much less likely.”

According to Volkow, reports from the community suggest an increased number of overdose deaths in homes where the individual was alone.

“Economic challenges are some of the stress source that leads people to take more drugs to try to cope,” Volkow relayed.

Homelessness was also associated with an increased likelihood of contracting the SARS-CoV-2 virus, due to social distancing problems.

Volkow wants to increase research on topics like telemedicine and changes in the justice system, and how they can be furthered post-pandemic. Expanding access to treatment of comorbid conditions via telemedicine, and releasing nonviolent inmates with SUD, are just a few ideas she has.

Volkow posed the following question for the audience to ponder: “What is the structure we need to provide for these individuals to be successful in adjusting to their community and not be at risk for relapse?”

1. Millennium Health. Signals report COVID-19 special edition. July 8, 2020. 

https://www.millenniumhealth.com/news/signalsreportcovid/

2. Overdose Detection Mapping Application Program. 

3. Wang QQ, Kaelber DC, Xu R, Volkow ND. COVID-19 risk and outcomes in patients with substance use disorders: analyses from electronic health records in the United States. 

According to Nora D. Volkow, MD, Director of the National Institute on Drug Abuse, drug use and overdose deaths have significantly increased since the outset of the pandemic. What made it worse?  

A Tale of Two Crises: Fighting the Overdose Problem During the Pandemic 

The US Food and Drug Administration (FDA) announced its commitment to advance tobacco product standards banning menthol cigarettes and all characterizing flavors in cigars. The decision to advance these proposed standards is based on evidence establishing the addictiveness and harm of these products, as well as previous actions banning other flavored cigarettes in 2009.

“Banning menthol—the last allowable flavor—in cigarettes and banning all flavors in cigars will help save lives, particularly among those disproportionately affected by these deadly products. With these actions, the FDA will help significantly reduce youth initiation, increase the chances of smoking cessation among current smokers, and address health disparities experienced by communities of color, low-income populations, and LGBTQ+ individuals, all of whom are far more likely to use these tobacco products,” Acting FDA Commissioner Janet Woodcock, MD, said in a press release. “Together, these actions represent powerful, science-based approaches that will have an extraordinary public health impact. Armed with strong scientific evidence, and with full support from the Administration, we believe these actions will launch us on a trajectory toward ending tobacco-related disease and death in the US.”

Strong evidence suggests that a menthol ban will help people quit. According to studies, menthol increases the appeal and likelihood of regular smoking, particularly with youth. Menthol makes tobacco more palatable by masking potentially unpleasant flavors, thus making them easier to start using.

A study by Chung et al suggested that a menthol cigarette ban in the US would lead to an additional 923,000 people who stopped smoking. Included in that number are 230,000 African Americans who would likely quit in the first 13 to 17 months after a ban goes into effect.

 Levy et al estimated that about 633,000 deaths would be averted with a menthol cigarette ban.

“For far too long, certain populations, including African Americans, have been targeted, and disproportionately impacted by tobacco use. Despite the tremendous progress we’ve made in getting people to stop smoking over the past 55 years, that progress hasn’t been experienced by everyone equally,” said Mitch Zeller, JD, director of the FDA’s Center for Tobacco Products. “These flavor standards would reduce cigarette and cigar initiation and use, reduce health disparities, and promote health equity by addressing a significant and disparate source of harm. Taken together, these policies will help save lives and improve the public health of our country as we confront the leading cause of preventable disease and death.”

If these actions are implemented, the FDA’s ban on menthol cigarettes and all flavored cigars will only affect manufacturers, distributors, wholesalers, importers, and retailers. Individual consumer usage of menthol cigarettes and tobacco products cannot be enforced by the FDA, but the FDA will work to ensure unlawful tobacco products are kept off the market.

1. US Food and Drug Administration. Menthol and other flavors in tobacco products. Accessed April 29, 2021. 

https://www.fda.gov/tobacco-products/products-ingredients-components/menthol-and-other-flavors-tobacco-products

2. US Food and Drug Administration. FDA commits to evidence-based actions aimed at saving lives and preventing future generations of smokers. News release. April 29, 2021. 

https://content.govdelivery.com/accounts/USFDA/bulletins/2d6d785

3. Chung-Hall J, Fong GT, Meng G, et al. Evaluating the impact of menthol cigarette bans on cessation and smoking behaviours in Canada: longitudinal findings from the Canadian arm of the 2016–2018 ITC Four Country Smoking and Vaping Surveys. 

https://tobaccocontrol.bmj.com/content/early/2021/03/31/tobaccocontrol-2020-056259?utm_medium=email&utm_source=govdelivery

4. Levy DT, Pearson JL, Villanti AC, et al. Modeling the future effects of a menthol ban on smoking prevalence and smoking-attributable deaths in the United States. 

Looking to reduce youth initiation into tobacco products, the FDA takes steps against menthol cigarettes and flavored cigars.

Clearing the Smoke: FDA Working Toward Tobacco Flavor Ban to Save Lives, Promote Health Equity 

Binge drinking is defined as consumption of 5 or more standard drinks on 1 occasion for males, or 4 or more for females, bringing blood alcohol concentration to 0.08 grams of alcohol per deciliter or higher.

 These drinking patterns lead to serious health and safety risks, including 

 from unintentional injuries such as motor vehicle crashes,

 suicide attempts as well as other mental health issues, legal charges, and, over the long term, damage to the liver and other organs.

Perhaps not surprisingly, national surveys have found that half of full-time 

 aged 18 to 22 years consumed alcohol in the previous month, and one-third engaged in binge drinking.

 In addition to the previously noted negative impacts, academic performance is also compromised, with 1 in 4 students endorsing academic difficulties (ie, missing class or falling behind on assignments) due to alcohol consumption.

 to perform poorly on tests and projects compared with those who drink but do not binge (40% vs 7%) and are 5 times more likely to miss a class.

 Although not all individuals who drink develop an addiction, consumption and especially binge drinking patterns are often preludes to an addiction, with approximately 9% of college students meeting criteria for alcohol use disorder.

 Lack of screening may also underestimate the magnitude of the problem.

The first few weeks of freshman year are often a period of heavy drinking and alcohol-related consequences. Social pressures and expectations during new-found independence, widespread availability and access to alcohol, unstructured schedules with mounting academic pressure, and lack of parental interactions all play a role. Alongside these stressors, many students have preexisting personality traits that may account for the use and misuse of alcohol during college.

Neuroticism, 1 of the 5 higher order personality traits, is defined by high emotional instability, depressed mood, low frustration tolerance, and anxiety. It also has been found to positively predict alcohol consumption (social intake within recommended parameters)

 and alcohol use (intake beyond recommended parameters that can lead to addiction).

 Only 1 previous study of 200 college students evaluated the implications of personality types; that study found high neuroticism and low conscientiousness predicted more 

aimed to better understand the role of personality and neuroticism in college alcohol use/misuse among freshman, above and beyond the reported levels of stress. The starting hypothesis revolved around the notion that negative affect faces of neuroticism, and primarily 

, are more strongly associated with alcohol use and misuse than stress when accounting for other personality domains.

 conducted a cross-sectional outpatient study, which was approved by the Institutional Review Board. Survey data was collected from participants during the first 8 weeks of their first college semester. Participants included 211 female and 90 male matriculating college freshmen with an average age of 18.58 years (SD = 0.39) from 2 campuses of a private university in the southeastern United States, spanning both urban and rural areas. Students were recruited via fliers posted on campus and during frequent in-person undergraduate events.

Data was acquired via online surveys of behavioral, health questionnaires, and cognitive assessments. Most surveys were completed within 3 weeks of the study initiation, and participants received a $15 gift card for completion. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and the Alcohol Use Disorders Identification Test (AUDIT) were used to assess alcohol use and misuse (

Endorsement of use 1 or more times on the ASSIST prompted the administration of the AUDIT, a 10-item questionnaire with a maximum score of 40 for which the higher scores indicate more severe and hazardous, harmful, excessive alcohol use/misuse. Stress was assessed using the Perceived Stress Scale (PSS), a 14-item self-reported measure of stress with each stress symptom scored on a 4-point Likert scale, where 0 = never and 4 = very often (maximum score of 56). Personality was assessed using the 44-item version of the Big Five Inventory (BFI), which measures 5 dimensions of personality (openness to experience, conscientiousness, extraversion, agreeableness, and neuroticism).

Ten facet traits were also calculated to assess more specific personality characterization within the 5 domains: openness, aesthetics, and ideas; conscientiousness, order, and self-discipline; extraversion, assertiveness, and activity; agreeableness, altruism, and compliance; and neuroticism, anxiety, and depression.

Analyses controlled for campus site (rural vs urban), sex, and individual week of study enrollment (school obligations as potential stressors fluctuated between study weeks). The investigators examined partial correlations between predictions while controlling for covariates. They used multiple regression analysis to examine the conditional and joint effect of personality and stress on alcohol use and misuse.

Of the sample, 54% (or 164 individuals) endorsed use of 

 at least once in their lifetime. Descriptive statistics of all covariates were accounted for, and across covariates sex and week of study enrollment were only modestly associated with AUDIT scores (male gender and more weeks since college commencement somewhat associated with higher AUDIT scores); site of the campus was not. Despite this, a t-test concluded that there were no gender differences between alcohol use and misuse (t(161) = -1.89, P = .06). Among partial correlations, the participants’ AUDIT scores were positively correlated with PSS scores (r = .17, P = .003) and neuroticism (r =.31, P < .001), and negatively correlated with agreeableness (r = −.12, P = .031). Stress was significantly correlated with all the personality domain scores except for openness to experience.

Regression analyses provided less biased estimates of personality and stress on AUDIT. To elucidate the relationship between neuroticism, stress, and 

 and misuse (given the discrepancy between the partial correlation results and the multiple regression model), the neuroticism facets were explored as outcome measures. Analyses that used the neuroticism facets (depression or anxiety) in place of the neuroticism domain found that neuroticism-depression was positively associated with higher AUDIT scores when accounting for PSS and domain-level 5 personality traits (β = .23, P = .028; adjusted R

Exclusion of all personality traits except for neuroticism-depression did not explain more variance in AUDIT (adjusted R

= .10, F (5, 152) = 4.56, P < .001). Interaction effects found that neuroticism as a domain moderated the relationship between PSS and AUDIT (β = .16, P = .040; adjusted R

 = .12, F (10, 146) = 3.16, P = 0.001). This interaction was found to be unique. Neuroticism-depression score moderated the relationship between PSS and AUDIT-T (β = .18, P = .020; adjusted R

 = .14, F(11, 145) = 3.22, P < .001. At low levels of the depression facet, stress was negatively associated with alcohol use and misuse, but at high levels of the depression facet, stress was positively associated with alcohol use and misuse (

This study supports the notion that neuroticism, and specifically the neuroticism-depression facet, appear to be the most robust predictors of alcohol use and misuse among incoming freshmen and could serve as useful population risk indicators. At low levels of the depression facet, stress was negatively associated with 

 and misuse; at high levels of the depression facet, however, stress was positively associated with alcohol use and misuse.

Investigators branched off previous studies exploring the roles of personality or stress on college drinking. They analyzed survey results data from Wave I of the MAPme Project, a longitudinal study of biobehavioral health and substance use during college. Those findings showed that personality characteristics and 

 play a significant role in the severity of problematic alcohol use and misuse, but certain traits are more significantly associated with alcohol involvement than others. The neuroticism-depression facet was a better predictor of alcohol use and misuse than the neuroticism domain, and this facet accounted for unique variance even when controlling for stress and other personality facets and domains. Stress did not account for unique variance in harmful and hazardous alcohol use and misuse beyond personality traits.

Unfortunately, this study had a number of limitations. Due to issues with the sample population, the findings may not generalize to other student populations. This study was conducted using a primarily Caucasian group from a private university located in the southeast US, without ensuring varied socioeconomic statuses. Similarly, although the sample encompassed both urban and rural participants, they were located in the same part of the country. The study also included a greater proportion of women compared to men, which may have skewed the baseline starting characteristics and outcomes.

Other issues can impact the findings. For instance, there were fairly low numbers of reported alcohol use among the sample to confidently generalize findings. Compensation offered to participants may add external biases and contribute to participant selection and participation.

The authors used a single-domain, self-reported assessment of stress, associated with increased likelihood of response bias and social desirability bias. More comprehensive and objective measures of stress levels might include physiological assessment, such as skin conductivity, heart rate, or cortisol measures that have shown be strongly associated with perceived stress.

The study employed the AUDIT-Total score, which confounds alcohol consumption and problematic alcohol use behaviors. The study participants reported low alcohol use and misuse behaviors, but the tool was not well prepared to detect unique effects of each of these constructs. Thus, future research could expand on this study by examining alcohol consumption and problems separately.

This study is limited by its cross-sectional design. To best examine the relationship between stress and personality on alcohol use and misuse, future studies could take a longitudinal state-trait perspective, treating personality and neuroticism specifically as stable traits and stress as a state.

Fortunately, data from this sample will continue to be collected until the students graduate, allowing longitudinal examinations into alcohol use and misuse trajectories, and the associations between stress, personality traits, and hazardous and harmful alcohol use.

So what does this mean for clinical practice? When presented with highly stressful circumstances, high neuroticism-depression in individuals predicts propensity to use and misuse alcohol. Similarly, people with high neuroticism-depression are likely to drink more when stressed, but low neuroticism-depression seems to be protective, with these individuals using and misusing alcohol at lower rates. Finally, the BFI domains and faces seem to have a role in alcohol use/misuse, above stress levels. These could be used as screeners for population risk indicators among incoming freshmen.

is assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is Addiction Section Editor for

The author reports no conflicts of interest concerning the subject of this article.

An earlier version of this article appeared online on February 10, 2021, under the title Neuroticism-Depression: What Is It and Does It Play a Role in College Drinking? and has since been updated for print. -Ed

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The introduction of the heavy and frequent drinker: a proposed classification to increase accuracy of alcohol assessments in postsecondary educational settings

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Although college drinking develops into an addiction, overconsumption and especially binge drinking patterns are often preludes to alcohol use disorder, with approximately 1 in 10 students meeting criteria for AUD.

Exploring the Link Between Neuroticism-Depression and College Drinking

In 2018 more than 20 million Americans met criteria for substance use disorder, particularly alcohol abuse (73%). During the COVID-19 pandemic, alcohol sales have risen sharply, up 54% from the previous year.

In this Mental Health Minute, Judith J. Prochaska, PhD, MPH points out that the pandemic has made it difficult for patients to seek traditional forms of counseling. She discusses a digital therapeutic that can be an adjunct for traditional therapies, and 

 on the treatment’s efficacy for substance abuse and mood disorders.

 is a professor in the department of medicine at Stanford University with the Stanford Prevention Research Center and a member of the Stanford Cancer Institute.

Would you recommend a digital therapeutic to your patients? 

Share comments with your colleagues by emailing 

A recent study tested a new digital therapeutic for effectiveness on both substance abuse and depression. 

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