Abstract
Purpose of Review
This report provides an update on clinical and preclinical findings for the efficacy of exercise to prevent substance use disorder with a focus on recent evidence for sex differences and neurobiological mechanisms.
Recent Findings
Exercise/physical activity is associated with decreased drug use in humans. Preclinical results further indicate that exercise decreases vulnerability to drug use and the development of features of substance use disorder, and suggest that females have an enhanced sensitivity to its reward-substitution effects. However, certain exercise conditions may sensitize the reward pathway and enhance vulnerability suggesting that parallel observations in humans (e.g., increased prescription opioid misuse and heroin use in high-school athletes) may be biologically based.
Summary
Exercise is a promising prevention strategy for substance use disorder. Further work is needed to establish its efficacy as a sex-specific strategy using larger samples and to understand the exercise conditions that induce beneficial versus risk-enhancing effects.
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Introduction
Exercise has been suggested as a prevention for substance use disorder that also has secondary health benefits (e.g., prevention of obesity; [1]). It is also viewed as an attractive alternative to pharmacotherapy that can be safely used in both adult and adolescent populations [2]. Exercise may be a particularly attractive option for adolescent females and women given that weight gain, which can be offset by exercise, is a significant contributor for both initiation and maintenance of drug use, particularly for stimulant drug use, in these populations [3].
Evidence supporting exercise as a prevention for substance use disorder is indicated by epidemiological data demonstrating a negative association between levels of exercise/physical activity and risk of smoking and illicit drug use in adolescent and young adult males and females [4,5,6,7]. Results from studies in male and female animals corroborate these findings and demonstrate that exercise, such as wheel and treadmill running, decreases the acquisition of drug self-administration and levels of drug use (e.g., [8]). Results from preclinical studies have also shown that exercise can prevent the development of addiction-like behaviors, such escalation, or the progressive increase in drug use over time [9•], indicating that exercise may not only prevent drug use initiation but may also prevent the development of features of substance use disorder. Exercise has also been suggested as a sex-specific treatment for substance use disorder, and evidence for these effects was reviewed in Part II ([10]; also see [11]).
Despite these promising results, recent data from both humans and animals suggest that certain exercise conditions may enhance risk of drug use (e.g., [9•, 12•]). For example, involvement in certain sports is associated with higher levels of drug and alcohol use, with findings that vary between males and females and between different sports [12•, 13]. While such findings are likely attributable, at least in part, to socio-cultural factors [14,15,16], findings in animals have also revealed that certain exercise conditions enhance vulnerability to drug use and the development of features of addiction [9•] suggesting that biological factors also contribute. The occurrence of protective versus risk-enhancing effects is likely determined by the underlying neurobiology [17], which can depend on a number of factors including the exercise type and schedule of availability, substance used/self-administered, phase of substance use disorder, and sex.
The objective of this report is to summarize recent findings (2012–2017) on the efficacy of exercise as a prevention for substance use disorder with the goal being to provide a better understanding of the conditions that lead to beneficial versus risk-enhancing effects. Findings from both human and animal studies are included in order to examine the biological basis for the efficacy of exercise. This review also highlights recent evidence for sex-specific differences in the efficacy and neurobiological basis of exercise as a prevention for substance use disorder. We conclude with suggestions for future studies to help guide the development of exercise as a sex-specific prevention strategy.
Overview of Recent Findings in Human Males and Females
Epidemiological studies have long reported negative associations between levels of exercise/physical activity and substance use among adolescents and young adults (for review see [17]), populations known to be vulnerable to the initiation of substance use [18, 19]. Similar associations are also revealed in recent cross-sectional and longitudinal studies, but with effects that differ between males and females and populations/cultures ([4, 6, 7]; Table 1). For example, in Polish high-school students, regular physical activity was negatively associated with cigarette and marijuana use in males, but not females [7]; whereas, in Slovak and Czech high-school students, physical activity was negatively associated with cigarette and marijuana use in females, but not males [4, 6]. While socio-cultural factors likely contribute these differential effects [29], levels of exercise/physical activity also differ between males and females and populations [4, 6, 7]; thus, exercise may interact with socio-cultural factors to differentially influence the use to drugs in males versus females within different populations.
Associations between exercise/physical activity and drug use can also vary between studies based on how exercise/physical activity is defined [4,5,6,7]. For example, while physical activity specifically related to exercise/sports was negatively associated with cigarette and marijuana use, overall levels of physical activity, which includes exercise/sports as well as everyday physical activities during work and leisure time, was not associated with cigarette or marijuana use, and actually predicted at-risk alcohol use [5]. Furthermore, physical activity not related to exercise/sports (i.e., occupational activity) predicted an increased risk of cigarette and cannabis use [5]. Sports participation is also often used as a measure of exercise, yet levels of exercise/physical activity vary widely between different sports [30], and can be well-below recommended guidelines (≥ 60 min/day of moderate to vigorous physical activity; [31]) and similar to those observed in individuals not participating in sports [30].
Socio-cultural factors may also interact with exercise/physical activity to influence vulnerability to drug and alcohol use [14,15,16]. For example, while exercise is negatively associated with alcohol, cigarette, and marijuana and other illicit drug use [16], sports participation is positively associated with smokeless tobacco and alcohol use ([16, 20, 21]; for review see [32]). Associations between team sports participation and drug and alcohol use also differ between males and females and type of sport (e.g., [12•, 13]). Perhaps most alarming are results showing that middle- and high-school athletes participating in sports associated with a high risk of injury (e.g., football and wrestling) have an increased risk of prescription opioid misuse ([12•, 22]). Higher risk of heroin use have also been reported in high-school athletes participating in these types of high risk of injury sports (ice hockey, wrestling, weightlifting; [12•]). Participation in sports during high school, even if non-contact, also predicts increased binge alcohol use during adulthood, and participation in contact sports (e.g., football, wrestling, ice hockey) during high-school predicts not only increased binge drinking but also increased marijuana use, and prescription opioid misuse during adulthood [23, 24]. Although these findings have been observed in samples that include both males and females, the enhanced opioid use/misuse reported is likely associated with male athletes given that the sports identified are expected to be comprised predominantly of males (also see [13]). While these findings suggest that socio-cultural factors associated with team sport participation can offset the protective effects of exercise, it is also possible that biological factors induced by exercise contribute to the enhanced vulnerability.
It should be noted, however, that the majority of athletes do not participate in high-contact sports and are not at a higher risk of opioid use or misuse [25]. In fact, adolescent males and females who participate in sports/exercise have lower lifetime risk of prescription opioid misuse and heroin use as compared to adolescent males and females who do not participate in sports/exercise [25]. Similarly, levels of substance use among elite male and female athletes, who train for multiple hours each day, are low for not only cigarettes and illicit drugs but also for alcohol and smokeless tobacco [26]. These findings are also consistent with results showing that when physical activity was part of an intervention to increase healthy behaviors (i.e., increase physical activity and fruit and vegetable consumption; limit television watching), it decreased smoking and alcohol use initiation in both males and females and was more successful in doing so than a substance use intervention ([27]; but see [28]).
Together, these studies suggest that exercise decreases vulnerability to drug use, particularly cigarette and illicit drug use. Instances of enhanced sensitivity have been reported in males and females involved in certain sports, and while socio-cultural factors likely contribute, it is also possible that the enhanced sensitivity is, at least in part, biologically based.
Evidence for Sex Differences in Humans
Although clinical and epidemiological studies typically include both males and females, small sample sizes prevent most studies from being able to determine sex differences in the association/effect of exercise/physical activity on vulnerability to drug use [23, 26,27,28]. The few recent studies that have examined sex differences have focused on middle- and high-school students, with conflicting results that vary between populations [4, 6, 7]. Recent findings also suggest that risk of drug use from participating in certain sports differs between males and females, with evidence for reduced risk in females [13]. It is possible that exercise protects against alcohol and drug use in both males and females, but that socio-cultural factors associated with sports team participation interact with exercise to modify vulnerability. Thus, in females, either exercise provides greater protection against alcohol and drug use or socio-cultural factors induce less risk. Further studies are needed to determine sex differences in these interactive effects using larger samples. Randomized controlled trials of exercise as a prevention for drug and alcohol use are also needed in order to establish causal effects.
Overview of Recent Findings in Male and Female Animals
Animal models of exercise and drug use have allowed for an examination of the biological effects of exercise separate from potential social factors [17]. Results from studies in male and female animals suggest that exercise may not only prevent drug use initiation [8] but also the development of features of addiction such as drug use escalation [9•]. Drug use initiation has been modeled in animals using acquisition procedures that measure how quickly animals acquire drug self-administration, and by measuring maintenance levels of intake, after acquisition has been established. Drug use escalation, or a progressive increase in drug intake over time, is believed to mimic excessive/uncontrolled drug use typical of human substance use disorder [33] and can be captured in animals by extending the access to the drug (≥ 6 h/day). While most of this work has focused on aerobic exercise via voluntary wheel running or forced treadmill running (e.g., [34, 35]), recent work has examined effects of resistance exercise using a weighted ladder-climbing procedure [36].
Recent studies show that exercise decreases rates of acquisition of drug self-administration and maintenance levels of intake ([8, 9•, 34,35,36,37,38,39,40,41,42,43]; Table 2). For example, concurrent unlimited access to a running wheel decreases acquisition and maintenance of alcohol consumption under 24-h free choice conditions in both males and females, and in both rats and mice [37,38,39]. Similarly, continuous access to a running wheel prior to and following each self-administration session decreases the acquisition and maintenance self-administration of numerous substances including methamphetamine, cocaine, heroin, and speedball (i.e., combination of heroin and cocaine); these effects have been observed in both males and females and adolescents and adults [9•, 40,41,42]. Modest exercise conditions also promote decreased acquisition and maintenance intake as demonstrated by recent findings showing that voluntary wheel running (2 h/day) prior to each self-administration session robustly attenuates acquisition of nicotine self-administration and its reinforcing effects in male rats [8]. Concurrent access to a wheel (1 h/day) during methamphetamine self-administration sessions also decreased acquisition and maintenance intake [24], and weighted ladder climbing (~ 2-h sessions) reduced cocaine self-administration in female rats [34]. While greater efficacy is observed with longer exercise access [35], individual differences within a particular condition generally do not predict the efficacy of exercise with results demonstrating beneficial effects even in animals with low exercise output (e.g., in aging hamsters, males versus females, Sprague Dawley versus Wistar rats; [34, 37, 43]). Together, these results indicate that even a modest amount of exercise (aerobic or resistance) can reduce drug use initiation.
Recent studies also show that exercise can block drug use escalation [9, 38, 39, 44]. For example, continuous access to a wheel prior to and following each self-administration session prevents escalation of methamphetamine intake and decreases its reinforcing effects in male rats [9•]. Similar results have been obtained for the effects of concurrent wheel access on escalation of cocaine self-administration in adolescent female rats [44], and free-access alcohol consumption in female mice [38, 39], indicating that exercise attenuates/blocks the development of features of substance use disorder. As in humans, however, effects on alcohol consumption in males are variable with results from one study showing decreased consumption [37], and another, showing no effect [39]. These findings are in contrast to those observed during acquisition, where exercise decreased alcohol consumption in both males and females [39], and suggest that its effects on alcohol differ by sex and between different phases of substance use disorder.
The efficacy of exercise at reducing drug use appears to be fairly transient [8, 9•, 34, 35, 42, 44]. For example, while wheel running markedly suppressed responding for nicotine in males, once wheel access was removed, responding increased to no-wheel control levels within 48 h [8]. Similar results have been observed in males and females, and for both cocaine and methamphetamine self-administration [9•, 34, 35, 42, 44], indicating that continuous exercise is necessary to maintain decreased drug intake. The time-line for the persistency of effects, however, may differ between substances given results showing that alcohol consumption remains decreased for up to 10 days after removal of wheel access [37]. It is also possible that other factors, such as age of the population studied, underlies the persistent decrease in alcohol consumption. Further research is needed to address this possibility.
Interestingly, a long history of exercise is not necessary to reduce drug intake [42, 43]. For example, a single wheel running session immediately prior to drug self-administration reduced methamphetamine, methylone, and MDMA self-administration in males and females [43]. However, Engleman et al. [9•] found that terminating wheel running sessions prior to methamphetamine self-administration training enhanced rates of acquisition in male rats that had a history of unlimited voluntary wheel running. Previous studies have reported similar reward-enhancing effects of exercise for cocaine in females and for morphine in males [45, 46] indicating that certain exercise conditions enhance vulnerability to drugs of abuse. These findings may also explain recent observations of increased prescription opioid misuse and heroin use in certain high-school athletes [12•] given that like the situation described above with rats, in human athletes, an injury would be expected to cause a break in the pattern of regular high-intensity exercise, which could then increase vulnerability to drug use. Other breaks in regular high-intensity exercise would also be expected to occur in high-school athletes, but injury may be a special case in that the likelihood of access to opioids would also be increased [13].
Together, these studies show that exercise reduces drug intake across multiple phases of substance use disorder including acquisition, maintenance, and escalation in both males and females. The protective effects of exercise are available after a single bout of exercise, and have been observed for multiple classes of drugs. Beneficial effects have also been observed following both forced and voluntary exercise indicating that exercise may not have to be rewarding to be effective. However, exercise may need to be maintained to provide protection, and its effects on alcohol are variable. Certain exercise conditions may also enhance vulnerability indicating that parallel findings in humans may be biologically based.
Evidence for Sex Differences in Laboratory Animals
Results from the few recent studies that have compared the effects of exercise on acquisition and maintenance drug intake between males and females have reported sex differences, with exercise benefiting females more than males [39, 43]. Although previous results have been more variable (for review see [11]), a comparison of all available studies indicates that the occurrence of sex differences may depend on exercise access conditions. Specifically, studies investigating effects of contemporaneous, but non-concurrent exercise, generally report equal efficacy of exercise at reducing drug intake in males versus females [43, 47]; whereas, studies using concurrent access conditions generally report greater efficacy in females versus males [39, 48]. These results suggest that while males and females equally benefit from the physiological effects that occur following exercise (and that persist during daily sessions), females have an enhanced sensitivity to the reward-substitution effects of exercise. This interpretation is consistent with previous work showing that concurrent access to non-drug rewards, such as palatable sweet solutions, produce greater decreases in drug intake in females as compared to males (for review see [49]). Females also run at higher levels than males (e.g., [48]), which both supports this idea since it demonstrates that females allocate greater time/energy to exercise as a non-drug alternative, and confounds the results since the “dose” of exercise is higher in females than males. Further work should control for sex differences in levels of exercise and include a large enough sample to ensure adequate power for the detection of sex differences. Moreover, given that ovarian hormones can influence both wheel running [50] and drug self-administration [51], additional studies are needed to determine their role in mediating the efficacy of exercise to prevent drug use.
Overview of Recent Findings for the Neurobiological Effects of Exercise in Males and Females
The efficacy of exercise as a prevention for substance use disorder is likely mediated via interactions with mesolimbic dopamine given the critical role this pathway plays in drug use initiation and substance use disorder [52]. The reinforcing effects of both drugs of abuse and exercise are dependent on activation of the mesolimbic dopamine system consisting of dopaminergic projections from the ventral tegmental area to the nucleus accumbens (NAc) and prefrontal cortex [52,53,54]. Inactivation of this pathway decreases drug self-administration (e.g., [55]), with recent findings demonstrating that such manipulations similarly disrupt wheel running in males and females [56]. Several markers of mesolimbic dopaminergic signaling predict sensitivity to drug reinforcement (enhanced D1/reduced D2 signaling in NAc; [57]), and recent findings indicate that such markers are also predictive of wheel running activity in males and females (excitatory/inhibitory dopamine mRNA expression in the NAc; [58]). Dopamine signaling in the NAc, in particular, is critical for mediating the reinforcing effects of drugs of abuse and exercise [52, 53]. Thus, exercise may function as an alternative reward that competes with the drug to decrease the probability of its use.
Exercise also activates similar signaling pathways as drugs of abuse [59] and induces long-term changes in plasticity that may protect against initial vulnerability (downregulation/upregulation of D1/D2 receptors; prevent/reverse dendritic spine loss in D2-containing medium spiny neurons; [60,61,62]). For example, chronic forced running prior to testing blocks the reinforcing effects of MDMA and MDMA-induced NAc dopamine release [63], indicating that exercise-induced adaptations may blunt the dopaminergic response to drugs of abuse. Exercise can also normalize glutamatergic signaling [64], and these effects may protect against drug use escalation and the development of substance use disorder (for review see [65]). For example, chronic treadmill running reduced markers of hyper-excitability (e.g., upregulation of GluA2/3, and downregulation of GluA1 receptors) in a Parkinson’s disease model, which is also characterized by depletion of dopamine and hyper-excitability/abnormal glutamatergic transmission [64]. Exercise can also produce modifications at the level of chromatin, which induce long-term changes in gene expression [66]. Effects on chromatin containing the Bdnf gene in particular has been implicated in mediating persistent protection against drug use, particularly in males [67]. Both drugs of abuse and exercise modulate Bdnf [68, 69], and recent evidence shows that resistance exercise affects drug-induced changes in Bdnf expression in female rats [36].
Preclinical evidence also indicates that certain exercise conditions can mimic the effects of chronic drug exposure (downregulating D2 receptors in NAc; [53]), and sensitize the reward pathway to later drug use. Similar effects may underlie vulnerability reported in rats with a history of high access/intense exercise [9•]. These findings suggest that cessation of regular exercise at a high level, which can also occur in human athletes following injury, may increase subsequent vulnerability to drugs by sensitizing the reward pathway.
Evidence for Sex Differences in the Neurobiological Effects of Exercise
There are likely sex differences in the neurobiological effects of exercise given behavioral evidence suggesting enhanced efficacy in females versus males, particularly under concurrent access conditions [39, 48]. This effect is likely reflective of a general increase in sensitivity to rewarding stimuli in females [49]. Given work demonstrating sex differences in the effects of drugs of abuse and natural rewards on mesolimbic dopaminergic signaling [70], it is possible that exercise may also induce a greater dopaminergic response in females versus males. It is also possible that, by running at higher levels, females induce/maintain greater activation of mesolimbic dopamine. Future research is needed to address these possibilities.
Most studies examining the neurobiological basis for the efficacy of exercise have focused on males or females and on dopaminergic signaling following stimulant use/exposure [53]. Future research is needed to address sex differences and the role of other signaling pathways, such as opioid, endocannabinoid, and Bdnf, given that each pathway contributes to the reinforcing effects of exercise and drugs of abuse [71, 72].
Conclusions and Future Directions
Epidemiological data demonstrates that engagement in exercise-related activities is associated with a lower risk of drug use, particularly cigarette and illicit drug use [4,5,6,7, 16, 26]. Animal studies have consistently shown that exercise decreases drug use during multiple phases including acquisition, maintenance, and escalation [34,35,36,37,38,39,40,41,42,43,44] indicating its potential as a prevention for substance use disorder. Beneficial effects have been reported for both males and females [39, 43, 47, 48], with evidence suggesting that females have an enhanced sensitivity to the reward-substitution effects of exercise as compared to males [39, 48]. However, future studies that include larger samples and that control for levels of exercise are needed to confirm this possibility. Concomitant with these studies, investigators should examine interventions that increase adherence to exercise, given that girls are less physically active than boys [73], and given that physical activity decreases throughout adolescence in both girls and boys [74]. Such efforts may be critical considering the preclinical results showing that continuous exercise is necessary to maintain beneficial effects [8, 9•].
While effects on alcohol are also promising, they are variable [37,38,39]. However, it is important to note that the recent preclinical results show that exercise either decreases or does not affect alcohol consumption [37,38,39]. This is important because it suggests that the increased alcohol use reported in boys and girls participating in certain sports is driven by socio-cultural factors rather than biological factors. Future research is needed to determine the exercise conditions that consistently and robustly decrease vulnerability to alcohol and other drug use in males and females. A better understanding of the neurobiological mechanisms that mediate the efficacy of exercise to decrease vulnerability to drug use is also needed in order to determine how to maximize its beneficial effects (e.g., in combination with pharmacological interventions).
Despite these promising results, both clinical and preclinical results suggest that certain exercise conditions may enhance vulnerability to drug use [9•]. Future research is needed to understand the underlying mechanisms for these effects so that interventions can be developed to prevent the enhanced vulnerability. For example, if cessation of regular high-intensity exercise sensitizes the reward pathway, then potential solutions to prevent the increase in vulnerability to drug use [9•, 12•] may include modified-exercise interventions, environmental enrichment, or brief educational interventions [75,76,77].
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Funding
Wendy J Lynch is supported by grants from National Institute on Drug Abuse (grants no. R01DA024716 and R01DA039093). Mark A. Smith is supported by a grant from the National Institute on Drug Abuse (grant no. DA031725).
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Lynch, W.J., Robinson, A.M., Abel, J. et al. Exercise as a Prevention for Substance Use Disorder: a Review of Sex Differences and Neurobiological Mechanisms. Curr Addict Rep 4, 455–466 (2017). https://doi.org/10.1007/s40429-017-0178-3
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DOI: https://doi.org/10.1007/s40429-017-0178-3