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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

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. 

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

What are the manifestations of methamphetamine toxicity?

Mini Quiz: Methamphetamine Neurotoxicity

For information on treatment of amphetamine related disorders, please refer to the articles at the end of this case.This case vignette illustrates some common features of patients presenting with methamphetamine dependence. Comorbidities are often present, with psychiatric comorbidites prominent throughout the addiction, and physical problems developing with persistent methamphetamine use.Although valiant efforts have been made to reduce access to the chemical precursors of methamphetamine, it is likely that methamphetamine use will remain accessible and inexpensive, and costs associated with increased use will continue to rise.This case is based on a Psychiatric Times article, "Treatment for Methamphetamine Dependence," by Kevin P. Hill, MD, MHS. Dr Hill is author of Marijuana: The Unbiased Truth about the World's Most Popular Weed (Hazelden, release date March 31, 2015). Twitter: @DrKevinHill.Also see: Intoxication With Street Drugs

A 28-year-old married mother of 2 with a history of depression is brought to the emergency department after 6 months of near-daily methamphetamine use.

Psychiatric Emergency: Methamphetamine Abuse

In this brief podcast, Dr Edward Nunes discusses the latest evidence from research studies on stimulant and cocaine dependence. Dr Nunes is Professor at Columbia University Medical Center Department of Psychiatry, in New York.

Along with presenters Andrew Saxon, MD, University of Washington; Theresa Winhusen, PhD, University of Cincinnati College of Medicine; and Madhukar Trivedi, MD, University of Texas Medical Center, Dr Edward Nunes will chair a symposium at the AAAP annual meeting titled "Cocaine and Stimulant Dependence: New Strategies for an Old Problem."

The symposium will cover some of the latest evidence on cocaine dependence, which is often difficult to treat. So far, there have been no medications that have clearly been effective for cocaine dependence, a frustrating fact in the field of addiction medicine. Tobacco dependence, opioid dependence, alcohol dependence-each has effective medications. Cocaine dependence does not yet have any effective medications. The National Institute of Drug Abuse and other agencies have been funding research to try to find medications.

This session will present some different studies that have been done very recently. One such study is of a combination of naltrexone and buprenorphine for treatment of cocaine dependence. The reason it is thought it might work is because buprenorphine is a kappa-opioid receptor antagonist and naltrexone is also an a kappa-opioid receptor antagonist. Naltrexone has the advantage blocking the other effects of buprenorphine. Because buprenorphine is an opiate, you do not want to give it to patients who are not opioid-dependent because you would risk making them opioid-dependent. Naltrexone gets rid of that because it blocks the new opiate receptor which is the main opiate receptor that produces addiction.

The idea here was to block kappa receptors. There are reasons to think that is important. Chronic cocaine dependence causes up-regulation in kappa receptors in the brain, and kappa receptors inhibit the release of dopamine in the brain and dopamine is important for motivation and energy. Dopamine is also depleted in chronic cocaine dependence. So this is an effort to correct the dopamine dysregulation that occurs in cocaine dependence.

The results are still a secret. We don't know what they are going to be but they will be presented at the meeting and so we will see what comes out of that session. This is what's fun about these up-to-date presentations and research studies because sometimes it's the first time the results are presented in a public forum.

A small pilot study on buspirone, which is an anti-anxiety medication that has been around for a long time for cocaine dependence, will be discussed. Buspirone was well tolerated but the results are inconclusive.

Finally, a study that was done, not on medication, but on exercise for cocaine dependence. Exercise is a compelling idea as a way of helping to treat addiction. There are many people in the field that are actually working with patients day to day who believe out of their experience that exercise is helpful for drug dependence.

For example, one of the residential treatment programs in New York City that [Columbia Psychiatry] collaborates with has a very robust exercise program as part of what they offer to their clients.

There are a number of animal models and animal research studies that have suggested that exercise might be helpful for tobacco dependence, cocaine dependence, and other addictions. One study was directed by Dr Madhukar Trivedi, and he knows the data much better than I do, but I have been a collaborator and I know the data, so I can talk a little bit about it. Patients who were cocaine dependent were randomly assigned either to an exercise condition or to a health education condition.

The exercise condition was pretty rigorous. The patients were asked to run on a treadmill for 30 to 45 minutes, 4 times a week, at 70% to 80% of VO2 max. So it was a fairly vigorous exercise program and it was obviously a pretty big time commitment. Patients were asked over a 6-month period to show up 4 times a week for very nice and knowledgeable exercise instructors . . . it was an attractive, welcoming exercise situation.

The study showed that there was no difference in cocaine outcome unfortunately between the patients assigned to exercise and the patients assigned to control condition. But there is a twist because participation in exercise was associated with less cocaine use so those patients who participated in the exercise used less cocaine over time than those in the control condition and those who did not participate in exercise.

What happened is that those who were assigned to exercise were more likely to drop out of treatment so being assigned to exercise caused more individuals to drop out. My hunch about this is that some people like to exercise inherently, they find it inherently fun and important. Many other individuals do not find it inherently fun, which may explain why being assigned to exercise resulted in a higher dropout rate. It is an intriguing study that indicates more work needs to be done to figure out how to make exercise fun and appealing for everybody and then we will get a better sense of what the impact can be on cocaine and other substance use disorders.

Exercise by the way has been shown to be effective for anxiety and depressive disorders, so for those mood and anxiety disorders, does have good evidence of being effective. In terms of the cocaine study that will be presented, it is an interesting first try and will make for interesting discussion.

Dr Edward Nunes discusses the latest evidence from research studies on stimulant and cocaine dependence in this podcast.

Treatment for Cocaine Dependence

It’s easy to give advice, hard to receive it, harder still to live it. The privilege of youth is action; of age, experience. Nature resists combining both. Experience is a comb you get when you’re bald.

I teach ignorance. Four years of medical school; and 4 more years of residency. Tens of thousands of dollars of debt, and years of minimum wage labor. You must think you have bought something with those funds and that toil; you must finally know something special. You graduate, and you get to work in this bewildering business. People pay you-and so you must know something. If decades pass and you keep getting paid and you don’t pause to reflect, you may end your life thinking that you know much. In fact, as newer generations come up, they see what you don’t.

I teach we don’t know; I teach that knowledge only increases our ignorance. This is what knowledge is: knowing what we know and, just as importantly, knowing what we don’t know.

Knowledge is 2-edged: it illuminates a fact or a part of experience. Usually, in so doing, it shows that what previously seemed sunlit truth is now utter darkness. As you learn something, you realize that much of what you “knew” was actually false. You become more ignorant as you become more wise.

Young psychiatrists need to learn, foremost, that they are ignorant. And they need to learn that their elders are even more ignorant, sometimes because they are wise-because the more you know, the more ignorant you are-sometimes because they are blind.

There is a beneficial and a baleful ignorance. The harmful kind is the ignorance of he who thinks he knows-end of story. This fellow doesn’t know and is simply “mind-blind.”

 He is not wisely ignorant: he doesn’t know that what seemed “true” is false; he just thinks it’s true. Most of your teachers are of this variety, and most of your patients, and most of your colleagues-and, most likely, you.

Look for the dogma. Whatever is believed by most, is likely to be untrue. The truth is not a matter of popular vote; it tends to prefer solitary homes.

Live on the sunny side of doubt. Some doubt darkly: they disbelieve everything and everyone; the truth saunters in front of them and is treated like a vagrant. Take a naive, childlike attitude toward ideas: accept everything-initially, then think on it and reject what seems wrong. Most of your colleagues do the reverse: they reject everything immediately, so as not to disrupt the feeble furniture of their minds; rarely, and with great languidity, do they ever come to accept a new idea.

Reject a superficial worldly skepticism: don’t read 

 as your main supply of psychiatric discourse. Read the old books and the journals-not the new books

 and the newspapers. Why do we all wrangle about the disputations in 

 is sent to an entire department e-mail list; the poor 

 meta-analysis sits ignored, except by an occasional half-dozen–member journal club.

So on our heels a fresh perfection treads
. . . born of us
And fated to excel us.

The best go unnoticed, and the least are loudest.

The greatest danger for your work is not that you don’t know enough about mental illness . . . it’s that you think you know more than you do. The danger is complacency and conformity, above all-above everything else. You will constantly be pressed to comply, to go along. Do so, on all that is unimportant. But where it is important, resist. Kick up, kiss down-if you dare; the world will punish you, but you will improve it.

 You think you know, or you think you don’t know, but in either case, you’re satisfied. Be dissatisfied. Your profession has not lived up-for over a century-to what it could be. It has gerrymandered diagnoses like politicians make up voting districts: on “pragmatic” grounds, for the good of the profession.

 Nature doesn’t obey politicians, whether in state houses or hospitals. And so the genetic and drug and biology studies refuse to line up with DSM labels. Science was degraded (previously) or applauded (recently)-and ignored, for the good of the profession. Your profession hasn’t fully accepted that what is good for the profession is to get at the truth.

Some say there are no truths, only powers that seek to hide behind claims to truth. God is dead, we are told, but the pharmaceutical industry lives. And science is just another interest group: there is no scientific truth, just the opinions of scientists.

I would like to visit God’s grave; someone tell me where it is. I think I will find Reason interred next door, and Science just beneath a weeping angel. With Him died Truth. No capital T’s are allowed, and even small t’s are suspected. But when your patients die, because of something you did-or, more commonly, didn’t do-then there are truths. The dead body attests to it, as do the living bodies you could save.

This postmodern belief that there are no truths, only wills to power, produces a dangerously medieval mindset that imagines itself to be avant-garde. The mind becomes blind and a profession stands still.

 Half a century ago, you would have pledged allegiance to the Trinity of id, ego, and superego-and you would have spent your time and inheritance in formal psychoanalysis. Today, you will treat your patients with the Trinity of antidepressants, antipsychotics, and anxiolytics-and you will buy the drug textbooks with the appealing synaptic cartoons. In each epoch, you conform to your profession; it is the standard of care, and you will be legally protected. You’ll have to make a living, and you’ll have children and mortgages, and you’ll need to protect them. I don’t fault you. But the profession needs something else. 

Your drugs aren’t as good as your colleagues believe, nor are they as bad as our critics say. Your colleague will say it’s easy: give a drug for a symptom-an anxiolytic for anxiety, antidepressant for sadness, neuroleptic for mood swings, amphetamine for concentration and energy and sex. It’s easy-like being a Volkswagen mechanic.

 But your patients’ brains are Porsches. They break down if treated this way. It’s easy: you don’t need an MD for 

We disparage the “medical model,” as if the phrase itself is proof of its fallacy. But we use the MD degree as a badge of expertise, and we practice with a legal privilege of dispensing potentially harmful drugs. It’s no sin to acknowledge biology; it’s a sin to say it, and not mean it.

Our siblings in medicine have already shown us the way. A century ago, we didn’t understand diseases and everyone got potions for symptoms-bleeding in particular. About half a century ago, we began curing, with antibiotics, then with other specific drugs (such as insulin and steroids).

 In medicine, we sometimes understand diseases; in psychiatry, we distrust the concept of disease. In medicine, we sometimes use drugs that cure; in psychiatry, we disbelieve in cure.

Of course, not all psychiatric problems are diseases; most aren’t. But some are. Not all drugs cure; most don’t. But some do. Until we realize which is which-which syndrome is a disease and which is not, which drugs cure and which don’t-we’ll keep guessing, mostly wrongly, while we complacently conform with the profession.

The mental and social aspects of illness matter, you will say; certainly, but not always, and not in the same way for all conditions. Until we know what’s what, all generalizations are false. And since you will want to prescribe pills to make your living, you should at least try to understand well what is biological and what is not.

We despise ourselves too little, and too much. Too much because our medical colleagues disparage us and we have enemies in the public, making us feel inferior. We are criticized wrongly, and rightly, and we protest both criticisms equally instead of rebutting the first and embracing the second. Don’t respond to stigma with stigma, doubting yourself: reject it as worse than racism, the deepest human intolerance, based not on a moral baseness, but on pure ignorance.

We despise ourselves too little: we reject too much and circle around each other, back-to-back. Our colleagues act as if criticizing their drugs is a personal offense against them. Child psychiatry can survive without overuse of amphetamines, and adult psychiatry, without excess antidepressants and neuroleptics. Here is where our loss of science hurts most, for the essence of science is to be self-critical. It’s not about being conventionally honest with others, it’s about being utterly honest with yourself.

 This attitude, which is the scientific attitude, is completely unnatural. Often we aren’t scientific enough, and then our practice becomes uneducated guessing, which we comfortably accept as just the way it is: “Behold, I show you the most despicable man of all: he who cannot despise himself.”

You have entered a difficult profession, not an impossible one. It is a profession that deeply needs honest workers who are willing to seek a knowing ignorance, to be dissatisfied, and to refuse to conform-doing so in the interest of the truth and of the profession, seeing both as inseparable. You need to make a living, but you also need to breathe life into your profession.

In a word, half of what you know is true, and half false, and you don’t know which is which. If you know this, you know all you can now know-a good start. Act so that future generations can have a better starting place.

 Ghaemi SN. Volkswagen psychopharmacology. 

http://www.psychiatrictimes.com/display/article/10168/1870665

Bad Medicine: Doctors Doing Harm Since Hippocrates.

 New York: Oxford University Press; 2006.

 Feynman RP. Cargo cult science. Some remarks on science, pseudoscience, and learning how not to fool yourself. Caltech’s 1974 commencement address. 

http://calteches.library.caltech.edu/3043/1/CargoCult.pdf

 Del Caro A, ed. Pippin R, trans. Cambridge, United Kingdom: Cambridge University Press; 2006.

Psychiatry is a profession that deeply needs honest workers who are willing to seek a knowing ignorance, to be dissatisfied, and to refuse to conform-doing so in the interest of the truth and of the profession, seeing both as inseparable.

Letter to a Young Psychiatrist

Psychiatrists are waking up to the world of sleep and behavior. Just as the biological revolution witnessed a collapse of barriers between the physical and the mental, so the boundary between sleep and wakefulness is crumbling. The emerging discipline of sleep medicine, baptized in the discovery of REM sleep in 1953 and by the characterization of sleep cycles a few years later, initially focused on adult physiology and sleep disorders.

Only in the past 2 decades has the study of children produced a substantial, if sometimes controversial, body of knowledge concerning sleep and its effects on development. Although many findings have been perplexing, the relevance of sleep pathology for behavioral and mental development has been securely established, and some of the most interesting research developments concern the role of sleep in ADHD.

Serious sleep problems usually imply either too much or too little sleep. Too little sleep can mean abbreviated sleep episodes, as might be imposed by external demands or by insomnia, or longer episodes punctuated by arousals that fragment sleep. Pilcher and Huffcutt

 examined the effects of prolonged sleep deprivation (more than 45 hours), brief sleep deprivation (45 hours or less), or partial sleep deprivation (less than 5 hours of sleep in a 24-hour period) on measures of cognitive and motor performance or mood. The overall performance decrement for all measures was 1.37 standard deviations (SDs). This is comparable to a drop in IQ from 100 to about 80. Under the conditions of partial sleep deprivation-not unlike a typical Monday morning for many of us-mood scores dropped by over 4 SDs.

Although children are not suitable subjects for such experiments, Sadeh and colleagues

 demonstrated that very modest changes in sleep duration can substantially affect the neurobehavioral function of children. His team monitored 77 fourth and sixth graders in regular classrooms with actigraphy for 5 nights. For the first 2 nights, children slept as usual; on the remaining 3 nights, they were asked to either extend or restrict their sleep time by 1 hour. Children who failed to change their sleep duration by at least 30 minutes were analyzed as “no change.” On a simple reaction time test, performance of both the sleep restriction and no-change groups deteriorated, whereas on measures of digit span and continuous reaction time, children in the extended-sleep group performed significantly better than the others.

 applied a single hour’s sleep restriction to 11 children with ADHD and to 32 controls over 6 days, neurobehavioral function in both groups deteriorated, as assessed by a continuous performance test. For children with ADHD, two-thirds of the continuous performance test measures dropped from the subclinical to the clinical range of impairment.

If the slight manipulations in sleep duration have measurable effects after just 3 nights, what might the effects be when sleep is shortened or fragmented long-term by busy family schedules, sleep-related breathing disorders (SRBD), behavioral insomnia of childhood, or other sleep problems? Would it be possible to produce the full clinical picture of ADHD under such circumstances?

What is already known about the
correlation between ADHD and sleep disorders in children?


? ADHD has been linked to many types of sleep problems in numerous and methodologically diverse studies. Parent-reported sleep complaints may occur in as many as 50% of children with ADHD.

What new information does this article provide?


? This article reviews current thinking on the association between ADHD and sleep disorders that is especially relevant to practicing psychiatrists.

What are the implications for psychiatric practice?


? Children presenting with ADHD or ADHD symptoms frequently have sleep problems that parents can describe on a questionnaire or in an interview. Sleep disturbances may aggravate an underlying psychiatric disorder or even fully account for the psychiatric presentation; such information may be critical in diagnosis, referral, and treatment planning.

Sleep problems described in children with ADHD include behavioral problems that often manifest as resistance to bedtime or difficulty in going back to sleep in the middle of the night without caregiver presence, parasomnias, sleep-disordered breathing, restless legs and periodic leg movements, and circadian rhythm disorders.

 Similarly, children with ADHD experience alterations in sleep architecture, such as delayed onset of REM, reduced time in REM, and arousals with sleep fragmentation.

 Inattention, hyperactivity, neuropsychological deficits, syndromic ADHD, and behavior disorders are also common among children who present with sleep problems. Yet despite abundant evidence of these comorbidities, the extent and nature of possible causal relationships between disturbances in sleep and behavior remain largely a mystery.

Prevalence estimates vary because of the way sleep disorders are operationally defined. Subjective parent complaints about resistance to bedtime, a behavior that is not unusual in children, may be counted as a significant problem or disorder by one investigator but not by another. Laboratories may use different procedures or scoring schemes that produce somewhat inconsistent counts of polysomnographic events, such as leg movements and hypopneas. Similarly, heterogeneous diagnostic rules may yield disparate rates of disorder, ie, if 5 rather than 1 apnea or hypopnea episodes per hour define obstructive sleep apnea, fewer cases with more severe symptoms on average will result. Finally, deviations in sleep architecture detected on polysomnography may be consequential yet may not be indicative of a specific sleep diagnosis. Similarly, diagnoses of ADHD depend on the criteria set, subjective thresholds for counting a behavior as symptomatic, and whether diagnoses are based on rating scales, clinical interviews, or structured and comprehensive clinical assessments.

Rates of sleep disorder in ADHD also depend, sometimes dramatically, on how and where data are obtained. Parent checklists almost always generate high sleep symptom rates, exceeding those that can be demonstrated during formal sleep studies. Research subjects recruited in specialty clinics (such as psychiatry or sleep disorders clinics) often display both sleep and behavior problems, whereas children assessed in regular school settings exhibit fewer problems from either domain.

Further complexity arises from potential nonlinearity in the impact of sleep problems on both behavior and behavioral diagnosis. Thus, mild to moderate levels of sleepiness could produce excessive activity and reduced attention, while very high levels of sleep disturbance may cause torpor and inattention so obviously related to sleep that a separate diagnosis of ADHD would be improvident even if criteria were technically fulfilled.

For all of these reasons, the nature and extent of the relationship between ADHD and sleep remains unsettled. One widely quoted estimate for the prevalence of sleep disorders in ADHD places the rate of parent-reported sleep problems at 25% to 50% in the absence of medication.

citing this study, give a guess-estimated rate of sleep problems in children with ADHD as 5-fold greater than that in healthy controls.

High-end estimates of sleep disorder prevalence in ADHD populations include a report from an Italian clinic that yielded polysomnography-confirmed sleep disorders, such as periodic limb movements in 40%, restless legs syndrome in 26%, SRBD in 18%, and confusional arousals in 36%.

 Findings from one study showed that 73% of children with ADHD had sleep problems and 45% of those had moderate to severe problems.

Inconsistencies among reports have clouded interpretation of findings relative to sleep morbidity and ADHD. A recent meta-analysis produced compelling findings for both subjective and objective sleep measures in children with ADHD. In their analysis, Cortese and associates

 minimized the likelihood that comorbid conditions could account for sleep problems by excluding studies in which children were receiving pharmacological treatment or had comorbid depressive or anxiety disorders. Compared with controls, children with ADHD had significantly higher bedtime resistance and more sleep onset difficulties, night awakenings, morning wakening difficulty, sleep-disordered breathing, and daytime sleepiness. Among objective measures, sleep onset latency, stage shift frequency, and apnea-hypopnea index were increased in children with ADHD, while sleep efficiency, true sleep time, and average time to fall asleep were lower than in controls.

Notwithstanding our inability to identify true prevalence rates, studies purporting to show frequent sleep disorders are probably a fair reflection of the rate at which clinicians who see children with ADHD can expect to hear complaints of sleep problems after a careful inquiry using some combination of rating scale or checklist and interview. Children referred for diagnosis and treatment of sleep disorders or for adenotonsillectomy are likely to display psychiatric problems in which inattention, hyperactivity, or both are prominent.

Restless legs syndrome and periodic limb movements

In their meta-analyses, Sadeh and colleagues

 found that the frequency of periodic limb movements was consistently elevated in children with ADHD. The comorbidity of restless legs syndrome symptoms in ADHD has been reported to be as high as 24%.

 Frequent parent reports of prominent periodic limb movements, restless legs syndrome, and growing pains in their children with ADHD offer a plausible mechanistic link between sleep movement disorders and ADHD, namely, a functional dopamine deficit.

 Both restless legs syndrome and periodic limb movement disorder can be successfully treated with dopamine agonists, much as ADHD usually responds to stimulant medication.

The diagnosis of restless legs syndrome is based on history and requires that the child offer some description of subjective symptoms. Children describe the discomfort that compels movement in restless legs syndrome in idiosyncratic ways; patience and creativity may be needed to understand such communications.

Most patients who experience restless legs syndrome also have periodic limb movements, although the converse is not necessarily true. In contrast to the voluntary movements of restless legs syndrome, periodic limb movements are involuntary and have a distinctively “neurological” appearance. The movements last from 0.5 to 5 seconds and recur in cycles of 5 to 90 seconds, typically in clusters, during non-REM sleep.

Both restless legs syndrome and periodic limb movement disorder can reduce the amount or quality of sleep. Restless legs syndrome prevents sleep onset and the return to sleep after awakenings at night, whereas periodic limb movement disorder may cause arousal and sleep fragmentation. Occasional limb movements are not necessarily problematic. Treatment recommendations for periodic limb movement disorder and restless legs syndrome are sleep hygiene, iron supplementation, and medications.

The elements of good sleep hygiene are presented in the 

. Common over-the-counter drugs such as antihistamines, cold preparations, and antiemetics aggravate restless legs syndrome symptoms. Recently, SSRIs have been implicated as a cause of periodic limb movements in nearly one-third of the children who receive these drugs.

Iron deficiency, which is usually diagnosed in children as a ferritin level of 50 ng/mL or less, is associated with restless legs syndrome and periodic limb movement disorder. Small trials of iron supplementation have shown promise in children.

The literature contains limited guidance for treating children with medications commonly recommended for adults with restless legs syndrome, such as the first-line, nonergot dopamine agonists (ropinirole and pramipexole); levodopa/carbidopa; and other agents, including clonidine, clonazepam, opioids, and gabapentin. Ropinirole and gabapentin enacarbil, a gabapentin prodrug, are the only agents approved for the restless legs syndrome indication in adults. None of these drugs have been approved or systematically studied in children. Use of dopaminergic agents may be complicated by the phenomenon of augmentation, in which symptoms begin to develop earlier in the day or spread to other parts of the body, giving rise to a condition suspiciously similar to akathisia.

Obstructive sleep apnea is the prototypical SRBD that includes but is not limited to conditions characterized by conspicuous apneas. Most psychiatrists are familiar with the obstructive sleep apnea syndrome in adults, but the SRBD of children differs mechanistically from that of adult sleep apnea and the treatment is usually different as well. In many children with obstructive sleep apnea, enlarged adenoids and palatine tonsils are the underlying anatomic problem.

Described in vivid detail by Sir William Osler

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