Perspective

Neuropsychopharmacology (2008) 33, 209–218; doi:10.1038/sj.npp.1301412; published online 4 April 2007

Drugs of Abuse and the Aging Brain

Gayathri J Dowling1, Susan R B Weiss1 and Timothy P Condon1

1National Institute on Drug Abuse, NIH, DHHS, Bethesda, MD, USA

Correspondence: Dr GJ Dowling, Office of Science Policy and Communications, National Institute on Drug Abuse, 6001 Executive Boulevard, Room 5235, MSC 9591, Bethesda, MD 20892-9591, USA. Tel: +1 301 443 6071; Fax: +1 301 480 2485; E-mail: dowlingg@mail.nih.gov

Received 13 July 2006; Revised 1 March 2007; Accepted 5 March 2007; Published online 4 April 2007.

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Abstract

Substance abuse among older adults has received little attention in the past, presumably because this population has traditionally accounted for only a small percentage of the drug abuse problem in the United States. The aging of the baby boomer generation (born 1946–1964), however, will soon swell the ranks of older adults and dramatically alter the demography of American society. Several observations suggest that this expansion will likely be accompanied by a precipitous increase in the abuse of drugs, including prescription medications and illicit substances, among older adults. While it is now evident that the brain changes continuously across life, how drugs of abuse interact with these age-related changes remains unclear. The dynamic nature of brain function, however, suggests that substance abuse during older age may augment the risks and require unique considerations for diagnosis and treatment. In addition to describing current and projected prevalence estimates of substance abuse among older adults, the present review discusses how aging affects brain systems involved in drug abuse, and explores the potential impact of drug abuse on the aging brain. Future directions for substance abuse research among older adults will also be considered.

Keywords:

brain, aging, neurotoxicity, neuroprotection, neurotransmitters, addiction

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INTRODUCTION

Substance abuse among older adults (ie, aged 50 years and older) has received little attention in the recent past presumably because it has traditionally represented a relatively small percentage of the substance abuse problem in the United States, which has been viewed as primarily a problem of youth. Indeed, based on data from the Federal Bureau of Narcotics indicating a sharp decline in opiate abuse after the age of 36, Winick (1962) hypothesized that a substantial majority of opiate addicts ‘mature out' of their addiction as a result of the normal aging process (Winick, 1962). Subsequent findings, however, have not supported a cause-and-effect relationship between chronological age and the cessation of addiction (Rosenberg, 1995). Instead, it is now evident that addiction initiated in youth often persists into advanced age (Anderson and Levy, 2003; Rosenberg, 1995).

Several lines of evidence suggest that substance abuse among older adults is on the rise. The aging of the baby boomer generation, comprised of those born from 1946 to 1964, will soon swell the ranks of older adults to unprecedented numbers. Even if the proportion of older adults abusing drugs in coming years were to hold steady at current levels, the dramatic increase in the size of this population would produce an equally dramatic increase in the absolute number of older individuals with substance abuse disorders. Given several reasons, however, it appears that the proportion of older adults abusing drugs is increasing and will continue to do so for the foreseeable future.

With major advances in medicine over the last several decades, Americans are not only living longer, but are living healthier; longer; ironically, this laudable trend is weakening one of the strongest motivations for changing addictive behavior among older adults: the declining health and increasing frailty that have typically accompanied aging. Thus, individuals advancing into their later years may feel less compelled to alter their substance abuse practices and, as a result, may prolong their drug abuse careers. Substance abuse in older adults may be further facilitated by the alleviation of longstanding family responsibilities and the availability of greater disposable income. Additionally, substance abuse may be continued or even initiated in later years as a means of coping with the profound sense of loss many older adults experience as they retire, their children leave home, and they lose loved ones.

The baby boomers have also been the first generation indoctrinated with the views, values, and expectations of the ‘quick-fix’ culture. Part and parcel of this indoctrination has been the rise in the promise, awareness, and dispensation of prescription medications. The widespread use and effectiveness of many prescription medications has endorsed the view that many problems, medical and otherwise, have a quick and simple fix, and that rapid remedies frequently come in the form of a medication. There are now more medications available to treat more maladies than ever before, and increased awareness of these medications appears to be driving increased use. For example, in 2001, 30% of Americans spoke with their physicians about medications they saw advertised, and 44% of these patients received the prescription medications they inquired about (Kaiser Family Foundation, 2003). Indeed, from 1992 to 2002 the number of prescriptions filled increased 154% (National Center on Addiction and Substance Abuse (CASA), 2005). Alarmingly, there have also been large increases in the number of emergency department (ED) mentions of nonmedical use of prescription medications. For example, the number of ED mentions for abuse of hydrocodone more than doubled from 1994 to 2001 (Substance Abuse and Mental Health Services Administration, 2002), possibly reflecting its greater availability.

Illicit substance abuse among older adults is also likely to increase as suggested by an apparent increase in the number of ED mentions for illicit drugs among this population (Substance Abuse and Mental Health Services Administration, 2002). This interpretation is consistent with projections of past year illicit drug abuse among older adults in the year 2020 (Colliver et al, 2006) and is further supported by an overall increased prevalence of illicit drug abuse among baby boomers that is persisting as this generation ages (Gfroerer et al, 2003). And while we now have evidence that the brain continues to change throughout life, there is little understanding of how drugs of abuse interact with these age-related changes. The dynamic nature of the brain, however, suggests that substance abuse in older adults may have unique consequences that influence drugs' effects in the brain and the treatment of substance abuse in this population.

The present review will describe the current and projected prevalence estimates of substance abuse in older adults, as well as the current understanding of how aging affects the predominant neural pathways involved in drug abuse. The potential impact of drug abuse on the aging brain will also be explored. The implications of age-related pharmacokinetic/dynamic changes and comorbid physical and mental health conditions will be considered and followed by a discussion of the unique considerations influencing the development of effective substance abuse screening and treatment programs targeted at older adults. As this is an emerging field of research, we conclude by discussing future directions for substance abuse research in this population.

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AGING EFFECTS ON THE PRIMARY NEUROTRANSMITTER SYSTEMS INVOLVED IN DRUG ABUSE

The brain changes in a variety of ways across the lifespan (Courchesne et al, 2000; Jernigan et al, 2001; Sowell et al, 2003). How these changes alter drug–brain interactions and what implications they may have for older adults who abuse drugs, however, is poorly understood. It is possible though that the aging process itself may create a distinct set of problems unique to older substance abusers. All drugs of abuse act by altering neurotransmission in the brain, most predominantly, the dopaminergic, serotonergic, and glutamatergic systems. These systems have also been shown to change with age. For example, the number of dopaminergic cell bodies in the substantia nigra (McGeer et al, 1977) as well as levels of striatal dopamine and homovanillic acid—a dopamine metabolite—all decline with age (Haycock et al, 2003; Reeves et al, 2002). Similarly, numerous studies have shown age-related decreases in dopamine receptor binding in the striatum (Antonini et al, 1993; Antonini and Leenders, 1993; Iyo and Yamasaki, 1993; Mukherjee et al, 2002; Rinne et al, 1990; Severson et al, 1982; Suhara et al, 1991; Volkow et al, 1996; Wang et al, 1998; Wong et al, 1997) and in extrastriatal regions including the frontal cortex, anterior cingulate gyrus, temporal insula, and thalamus (Inoue et al, 2001; Kaasinen et al, 2000, 2002; Mukherjee et al, 2002; Volkow et al, 2000; Wang et al, 1996). Although not clinically significant, these reductions are associated with modest changes in motor and cognitive functions (Volkow et al, 1998a, 1998b). Age-related decreases in dopamine receptor binding have been correlated with age-linked metabolic reductions in the frontal cortex and anterior cingulate gyrus, similar to that observed in cocaine abusers (Volkow et al, 1993, 2000), suggesting that the effects of reductions in dopamine receptor function with age may be exacerbated by drug abuse.

Dopamine transporter (DAT) binding also declines with age (Bannon and Whitty, 1997; Ishikawa et al, 1996; Kazumata et al, 1998; Kemppainen et al, 2001; Mozley et al, 1996, 1999; Pirker et al, 2000; van Dyck et al, 1995, 2002; Volkow et al, 1994). The consequences of normal reductions in DAT binding in the human brain are not known. One might hypothesize, however, that decreased DAT function could result in decreased responsiveness to drugs of abuse that interact with DAT such as amphetamine and cocaine (Bannon et al, 1992; Giros et al, 1996). For example, age-related decreases in methylphenidate-induced extracellular dopamine release may reflect reductions in DAT binding that are part of normal brain aging (Volkow et al, 2001). Interestingly, Wang et al (1997) reported that chronic cocaine abusers in their study did not exhibit age-related reductions in DAT. Although potential confounding factors remain to be examined, this finding suggests that cocaine abuse may interfere with at least some changes in neurotransmitter activity that appear to be a normal feature of aging (Wang et al, 1997).

The glutamatergic and serotonergic systems—both of which have been implicated in substance abuse—also appear to change with age. Age-related decreases in N-methyl-D-aspartate-type glutamate receptor density and function have been observed in most cortical areas, striatum and hippocampus (Olney et al, 1997; Segovia et al, 2001; Villares and Stavale, 2001). How the serotonergic system changes with age is less clear: several investigators have reported age-related decreases in serotonin receptor and transporter binding in various brain regions (Adams et al, 2004; Allen et al, 1983; Arranz et al, 1993; Baeken et al, 1998; Blin et al, 1993; Cheetham et al, 1988; Gross-Isseroff et al, 1990a, 1990b; Hesse et al, 2003; Iyo and Yamasaki, 1993; Kuikka et al, 2001; Marcusson et al, 1984a, 1984b, 1987; Pirker et al, 2000; Sparks, 1989; van Dyck et al, 2000; Yamamoto et al, 2002); however, others have reported increases or no age-related changes (Allen et al, 1983; Andersson et al, 1992; Arranz et al, 1993; Marcusson et al, 1987; Severson et al, 1982, 1985).

The cannabinoid system is also of interest in this regard—originally identified for its role in mediating the effects of marijuana in the brain; the cannabinoid system has now been implicated in myriad functions from appetite to memory to pain, as well as reward and addiction. In the only relevant aging study we are aware of, investigators reported no differences in endocannabinoid levels or cannabinoid receptor density in old adult versus young adult mice (Wang et al, 2003). Older mice did exhibit decreased cannabinoid receptor coupling to the G-protein signaling cascade in the limbic forebrain compared to younger mice. This reduction in function was associated with decreased ethanol preference, which could be reversed by administration of a cannabinoid agonist (Wang et al, 2003), demonstrating highly specific age-related changes to a receptor system that result in decreased intake of an addictive substance.

With the exception of the study noted above, few studies of age-related changes in the brain have focused on how these changes affect the function of the reward system and/or its sensitivity to drugs of abuse. And, in those that have, the results have been mixed (Hicks et al, 1980; Kilbey et al, 1980; Kilbey and Ellinwood Jr, 1977; Smith et al, 1978; Warenycia and McKenzie, 1989). Jha et al (2004) reported that the brain-stimulation reward (BSR) threshold is lower in older than in younger rats suggesting the brain reward system becomes more sensitive with age; however, the authors found no significant age differences in the effects of morphine on BSR threshold (Jha et al, 2004). On the other hand, Knapp et al (2004) found that aged rats spent significantly more time engaged in stereotypic biting behaviors following repeated administration of moderately high doses of morphine than did younger rats suggesting that sensitivity to at least some effects of opioids may increase with age.

Thus, the overall impact of age-related changes in brain structure and function on the rewarding and other effects of abused drugs is difficult to predict at this time. And, it is further complicated by an individual's past history of drug exposure, since, for example, prolonged drug abuse can itself alter the function of various brain transmitters and systems, potentially compounding the effects of aging. Whether these alterations will lead to different patterns of drug abuse due to altered responsiveness requires further investigation in both animal models and humans.

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EFFECTS OF DRUGS OF ABUSE ON THE AGING BRAIN

Neurotoxicity

In addition to changes in drug responsiveness, animal studies suggest that susceptibility to drug-induced neurotoxicity may, at least in some cases, increase with age. For example, sensitivity to methamphetamine-induced toxicity has been shown to increase with age: compared with younger animals, older animals—despite lower exposure doses—show greater striatal dopamine reductions and morphological alterations as well as increased levels of glial fibrillary acid protein (Bowyer et al, 1993; Miller et al, 2000; Teuchert-Noodt and Dawirs, 1991). These changes may reflect age-related increases in drug accumulation in the brain such as occurs with amphetamine (Truex and Schmidt, 1980). Methamphetamine-induced neurotoxicity may also involve oxidative stress, which has been implicated in many age-related diseases (Barja, 2004). In one recent study, older rats exposed to methamphetamine showed increased oxidative damage, which correlated with increased methamphetamine-induced dopaminergic toxicity (Imam and Ali, 2001).

Chronic abuse of some drugs may exacerbate normal age-related changes in the brain. For example, maturation of frontal and temporal lobe white matter between the ages of 20 and 50 appears to be arrested in chronic cocaine abusers. Thus, the natural decline in white matter volume observed after age 50 may be more dramatic in cocaine abusers than in the healthy aging population (Bartzokis et al, 2002). Similarly, the brains of cocaine-dependent subjects exhibit an increased number of age-related white matter lesions, thought to be linked to cognitive abnormalities. If so, these deficits would be more prevalent among aging addicts as compared with normal older adults (Bartzokis et al, 1999a, 1999b).

Neuroprotection

Some drugs of abuse may also possess neuroprotective properties. For example, epidemiological studies over the past 50 years have shown that cigarette smoking, despite a multitude of adverse health effects, is associated with a lower incidence of Parkinson's disease, a neurodegenerative disorder of aging. Nicotine, in particular, has been shown to be neuroprotective in a number of in vitro and in vivo systems and through a variety of mechanisms. Other components of cigarette smoke such as those that decrease brain monoamine oxidase B activity may also contribute to a lower incidence of Parkinson's disease (Fowler et al, 1996; Quik, 2004).

Marijuana may have neuroprotective properties as well. Although epidemiological studies have not correlated marijuana abuse with decreased disease prevalence, studies have shown that components of marijuana may protect against neuronal damage caused by glutamate-mediated excitotoxicity, free radicals and reactive oxygen species, and/or pro-inflammatory cytokines (Baker et al, 2003; Croxford, 2003; Fowler, 2003; Grundy et al, 2001; Grundy, 2002; Hampson et al, 1998, 2000; Lastres-Becker et al, 2002; Panikashvili et al, 2001). Oxidative and inflammatory damage are prevalent in aging and may contribute to numerous adverse health conditions associated with aging such as ischemic stroke, Parkinson's disease, Alzheimer's disease, and cardiovascular disease (Grimble, 2003). Delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, has been shown to decrease pro-inflammatory cytokine production. And, both THC and the nonpsychoactive marijuana constituent cannabinidiol were found to be comparable to if not more effective than standard antioxidants in preventing toxicity due to reactive oxygen species (Grundy et al, 2001; Hampson et al, 1998, 2000).

Although these drugs may have neuroprotective properties, they also have adverse health consequences that may outweigh their potential benefits. Understanding the mechanisms by which these drugs might be neuroprotective, however, may lead to the development of new, more targeted pharmacotherapies aimed at preventing and/or treating a variety of diseases associated with aging.

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CONSEQUENCES OF PHARMACOKINETIC/DYNAMIC CHANGES WITH AGE

Because aging affects drug disposition and metabolism, even moderate use of alcohol, many prescription and over-the-counter medications and illicit drugs may have devastating consequences. Pharmacokinetics—the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body—are known to change with age. For example, the volume of drug distribution decreases with reductions in lean body mass and total body water content. Moreover, renal drug elimination is reduced. These age-related changes may lead to elevated drug serum levels and increased potential for adverse drug reactions. Age-related differences in pharmacokinetics, however, do not necessarily translate into differences in response to a drug. For example, analysis of age and opiate-induced pain relief in postoperative cancer patients found that there was no difference between young and old in maximum pain relief. However, pharmacokinetic differences due to age (ie slower clearance from the plasma) did result in a longer duration of drug action (Kornetsky, 2004).

Pharmacodynamics, such as drug–receptor interactions, receptor–membrane interactions, and postreceptor events also may change with age (Noble, 2003). For example, age-dependent changes in the GABAa–benzodiazepine receptor complex may underlie older patients' heightened sensitivity to benzodiazepines and the resulting sedation, confusion, ataxia, immobility, short-term memory loss, and other cognitive disturbances. Similarly, reduced homeostatic mechanisms may lengthen the time older adult patients require to regain steady-state levels following drug therapy (Turnheim, 2003). These pharmacokinetic/dynamic changes may place older adults who abuse drugs at elevated risk for potentially severe drug–drug and drug–disease interactions.

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COMORBID HEALTH CONDITIONS

Psychiatric disorders and substance abuse often co-occur in younger and older adults. Indeed, one study reported that approximately 20% of hospitalized older adult psychiatric patients had a comorbid substance abuse disorder (Whitcup and Miller, 1987). Similarly, a geriatric outpatient study found that only 7.1% of substance abusing patients did not have a comorbid psychiatric diagnosis (Holroyd and Duryee, 1997). Drug abuse may affect older adults with psychiatric disorders in a variety of ways. For example, prolonged psychotropic drug use, specifically benzodiazepines, has been associated with depression (Dealberto et al, 1997; Hogan et al, 2003) and cognitive decline in older adults (Paterniti et al, 2002). In contrast, stimulants may improve some age-related cognitive deficits (Grottick and Higgins, 2002; Halliday et al, 1986).

Additionally, the prevalence of many medical conditions increases with age and may be affected by concomitant drug abuse. For example, amphetamine and cocaine abuse often lead to cardiovascular complications such as arrhythmias and myocardial infarction in young addicts. Long-term abuse may also predispose to premature atherosclerosis, ventricular hypertrophy, and cardiomyopathy. The presence of these effects in young adults suggest that drug abuse among older individuals, in whom cardiovascular disease is more prevalent, may have even more severe consequences (Frishman et al, 2003a, 2003b).

Similarly, illicit drug abuse has been shown to contribute to reductions in kidney function and end-stage renal disease (Perneger et al, 2001; Vupputuri et al, 2004). Indeed, the age and race-adjusted risk for mild kidney disease was three times greater among cocaine and crack users and four times greater among users of psychedelic drugs (Vupputuri et al, 2004). Thus, illicit drug abuse may also exacerbate declines in kidney function that frequently occur with increasing age. Drug abuse may also affect the onset and course of diabetes. A history of substance abuse is associated with an earlier age of onset for diabetes (Johnson et al, 2001). Similarly, diabetic ketoacidosis (DKA), a potentially fatal complication of diabetes, has been related to cocaine abuse in 14% of adult DKA admissions, suggesting that diabetics who abuse cocaine may be more prone to developing DKA (Warner et al, 1998).

Neurological and respiratory disorders, cancer, and many other age-associated diseases may also be exacerbated by drug abuse (de Rekeneire et al, 2003; Elwan et al, 1997; Sarkisian et al, 2000). Furthermore, comorbid drug abuse likely increases the risk of accidents and falls that frequently result in hip fractures and other injuries in older individuals. How drug abuse impacts common disorders that frequently accompany aging remains poorly understood. There is, however, significant reason to believe that as the number of substance abusing older adults increases, so may the prevalence of drug–disease complications in this population.

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CLINICAL IMPLICATIONS

Recognizing Substance Abuse in Older Adults

The potential for additional drug-related complications underscores the importance of recognizing and treating substance abuse in older adults. Recognizing inappropriate drug use in this population, however, can be complicated by a number of factors. For example, almost half of primary care physicians surveyed reported that they found it difficult to discuss prescription drug abuse with their patients (National Center on Addiction and Substance Abuse at Columbia University (CASA), 2000). This finding suggests that health-care professionals in the best position to identify and facilitate treatment of substance abuse disorders may not, as a matter of course, seek out a thorough knowledge of their patients' drug use behaviors. Furthermore, currently available diagnostic criteria for substance abuse were developed and validated in young- and middle-aged samples and thus may not be appropriate for older adults. For example, some DSM IV criteria for substance dependence, such as tolerance and activity reduction, may not apply to this population (American Psychiatric Association, 2000; Patterson and Jeste, 1999). Aging may interfere with the body's ability to develop tolerance (Beresford et al, 1990); an older person, therefore, may demonstrate greater drug-related problems even though their patterns of use have remained stable (Adams and Cox, 1995; Fingerhood, 2000; National Institute on Alcohol Abuse and Alcoholism, 1998). Additionally, older adults, by dint of normal age-related changes, may become less active rendering detection of substance abuse problems more difficult (Fingerhood, 2000). Finally, warning signs of drug abuse (eg sleep problems, falls, memory problems) may be confused with or masked by concurrent illnesses, or attributed to normal aging.

The challenge of recognizing substance abuse disorders in older adults is compounded by the relative dearth of screening instruments designed specifically for older adults. Screens such as the Two-Item Conjoint Screen for alcohol and other drug use or dependence (Brown et al, 2001) and the Drug Abuse Screening Test have not been tested in this population. The Michigan Alcohol Screening Test (MAST) has been modified for use in older adults (MAST-G), and has been shown to have excellent sensitivity and good specificity; however, it is specific for alcohol abuse and has not been modified for detecting other drug use (Widlitz and Marin, 2002). The CAGE screening test has been modified to include other substances of abuse; has been tested in adults over the age of 60; also has been shown to have excellent sensitivity; specificity, however, is poor (Hinkin et al, 2001). Additional studies are needed to develop and test the validity of other drug abuse screening instruments in older adults.

Treatment of Substance Abuse in Older Adults

Significant increases in substance abuse among older adults, as may occur with the aging of the baby boomers, would increase the demand for relevant treatment services. Indeed, according to the 2003 Treatment Episodes Data Set, individuals aged 50 and older accounted for only 9% of treatment admissions. In contrast, in that same year, younger members of the baby boomer generation (aged 40–49) accounted for 25% of all treatment admissions (Substance Abuse and Mental Health Services Administration, 2004). Using regression modeling, with early onset drug use as a predictor, Gfroerer et al (2003) estimated that, due to a 50% increase in the number of older adults and a 70% increase in the rate of treatment need among older adults, the number of older adults in need of substance abuse treatment will increase from 1.7 million in 2000 and 2001 to 4.4 million in 2020.

As baby boomers age, the types of drugs abused by older adults will likely change accordingly and facilitate a shift in the specific treatment needs of this population. Currently, older adults most commonly seek treatment for alcohol, stimulants other than amphetamine, tranquilizers, and sedatives. In contrast, young baby boomers most frequently seek treatment for cocaine suggesting that specific treatment needs may change over time (Substance Abuse and Mental Health Services Administration, 2004).

Once in treatment, older adults have short- and long-term outcomes equivalent to or better than those of younger adults, suggesting that the primary barrier to recovery is diagnosis and treatment entry (Fleming et al, 1999; Hser et al, 1997; Lemke and Moos, 2003a, 2003b; Oslin et al, 2002; Satre et al, 2003, 2004). Older patients, however, may fare even better in programs tailored to older participants (Lemke and Moos, 2003a). Thus, treatment of substance abuse in older adults should reflect age-related brain changes as well as differences in the types of drugs abused in this population and in the settings in which these drugs are abused. Additionally, treatment outcomes for older adults may be further improved through the use of supportive and nonconfrontational approaches (Beresford et al, 1990), cognitive behavioral therapy (for those not cognitively disabled by drugs and/or disease) addressing negative affect, improving social support, and the use of specially trained providers (Schonfeld et al, 2000).

Pharmacological therapies should also be a critical component of drug treatment in older adults. Currently, a number of pharmacological therapies are available for the treatment of substance abuse including bupropion, nicotine replacement therapy, varenicline, naltrexone, methadone, and buprenorphine. None of these therapies, however, have been tested in older adults; thus, it is unclear if they retain their effectiveness or have unique adverse effects in this population.

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CONCLUSIONS

It seems likely that in the coming years, substance abuse among older adults will be an increasing problem in the United States. As baby boomers advance into older age they, as a population, carry with them both a strong history of youth drug abuse and the view that drugs—whether for medical purposes or recreation—are a ‘quick-fix’ panacea for whatever ails you. The increased prevalence of comorbid conditions with age as well as age-related changes in drug metabolism and neurotransmitter systems mediating drugs' effects in the brain suggest, however, that even moderate drug abuse may pose greater risks to older adults. Unfortunately, the interaction between drug abuse and the aging process is poorly understood. Increased abuse of drugs in general as well as increased abuse of illicit drugs not traditionally prevalent among older adults would place greater and unique challenges on already strained healthcare and drug treatment resources. Meeting these challenges requires a better understanding of the scope and effects of drug abuse in this population. Research in relevant animal models would aid in elucidating the unique effects of drug abuse in older populations. Brain imaging studies across the lifespan would provide new insight into the long-term effects of drug abuse in older adults. Additionally, human clinical trials are critical to understanding issues of poly-pharmacy, medical comorbidity, increased risk of adverse effects, as well as age-related changes in pharmacokinetics and pharmacodynamics. Successfully addressing increased drug abuse among older adults would also require heightening awareness of this issue among both health-care professionals and the general public.

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Acknowledgments

We gratefully acknowledge the assistance of Curtis Balmer in the preparation of this paper. His editorial and substantive comments significantly improved its content and clarity. The authors have no financial conflicts of interest that have the potential to bias this work.

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