CHAPTER TEN

Exercise and substance abuse

Li Zhanga, Ti-Fei Yuanb,*
a
GHM Institute of CNS Regeneration, Jinan University, China
b
Shanghai Key Laboratory for Psychotic disorders, Shanghai Mental Health Center, Shanghai Jiaotong
University School of Medicine, China
*Corresponding author: e-mail address: ytf0707@126.com

Contents
1. Introduction 269
2. Animal studies for exercise intervention for drug addiction 270
3. Exercise intervention for drug addiction in humans 272
4. Neurobiological mechanisms of exercise intervention on drug addiction 274
5. Conclusion and future perspectives 275
Acknowledgments 276
References 276

Abstract
Exercise intervention has long been used as one adjunctive treatment for drug abuse.
Both animal studies and human trials suggest that exercise training effectively prevents
addiction formation, suppresses drug-seeking behaviors, and ceases addictions. More-
over, exercise improves both mental and cognitive deficits that commonly occur during
drug withdrawal. Those observations are supported by neurobiological studies in which
exercise training modulates several neural networks including the dopaminergic reward
system, and regulates neurogenesis and spinogenesis that affect cognitive behaviors
and mental health. In sum, exercise training is a safe and effective way to relieve sub-
stance abuse, although both intervention guideline and biomarkers warrants further
investigation.

1. Introduction
The use of physical exercise as the intervention for substance abuse
disorders has been widely accepted. One meta-analysis covering 22 indepen-
dent studies has shown that high-intensity training increases the abstinence
rate and relieves the withdrawal symptoms (Wang, Wang, Wang, Li, &
Zhou, 2014). Dozens of surveys suggest that active participation in physical
exercise decreases the risk of substance abuse and addiction (Mattila,

International Review of Neurobiology, Volume 147 # 2019 Elsevier Inc. 269

ISSN 0074-7742 All rights reserved.
https://doi.org/10.1016/bs.irn.2019.07.007
270 Li Zhang and Ti-Fei Yuan

Raisamo, Pihlajamaki, Mantysaari, & Rimpela, 2012; Rodriguez Garcia,

Lopez Villalba, Lopez Minarro, & Garcia Canto, 2014). Moreover, exercise
also helps to relieve mental disorders (Smelson et al., 2013) and cognitive
deficits (Miladi-Gorji et al., 2011). Those data suggest exercise training as
an effective way for both prevention and elimination of drug addiction.
To reveal the underlying mechanism, it has been suggested that exercise
training probably modulates the midbrain dopaminergic reward system to
antagonize the disruption by addicted drugs. Moreover, exercise may help
to promote neurogenesis and gliogenesis for relieving addiction behaviors.
Although studies strongly support the positive effect of exercise intervention
for addiction and substance abuse, major weakness still exist such as the lack
of guidelines for clinical use. In this chapter we will summarize major find-
ings of exercise intervention targeting substance abuse on both rodent
models and human subjects. The possible neurobiological mechanisms
underlying the effect of exercise training will also be described.

2. Animal studies for exercise intervention

for drug addiction
Ample animal studies have studied the effects of exercise intervention on
drug addiction including morphine, 3,4-methylenedioxymethamphetamine
(MDMA), heroin, cocaine, amphetamine and METH. An early study in
2002 found that 2-h daily access to the running wheel for 8 days abolished
the conditioned place preference (CPP) induced by 1 mg/kg morphine
(Lett, Grant, Koh, & Flynn, 2002). In a similar study, enriched environment
attenuated 10mg/kg morphine-induced behavioral sensitization (Xu, Hou,
Gao, He, & Zhang, 2007). Those results imply the generation of addiction
tolerance by prior exercise training, although another study showed that exer-
cise after acquisition of CPP enhanced such associative learning in the later test
phase (Eisenstein & Holmes, 2007). Using a self-administration apparatus,
prior exercise on the treadmill also decreases morphine intake behaviors
(Hosseini, Alaei, Naderi, Sharifi, & Zahed, 2009). In addition to the attenu-
ation of addictive behaviors, voluntary exercise training also relieves cognitive
deficits in morphine-dependent rats (Miladi-Gorji et al., 2011). Based on pre-
vious findings showing that exercise enhances cortical synaptogenesis (Chen
et al., 2017), it is hypothesized that exercise training can relieve cognitive dys-
functions in individuals with drug addiction via enhancing synaptic plasticity.
Exercise training can also relieve cocaine addiction syndromes after
acquisition. For example, enriched environment in juvenile rats remarkably
Exercise and substance abuse 271

reduces cocaine-induced behavioral responses (Solinas, Thiriet, El Rawas,

Lardeux, & Jaber, 2009). As similar as those in morphine addiction, prior
experience on a running wheel for 15 days remarkably inhibits the acquisi-
tion of cocaine self-administration response (Smith & Pitts, 2011), and accel-
erates the extinction of CPP memory (Mustroph, Stobaugh, Miller,
DeYoung, & Rhodes, 2011). Chronic training on the running wheel also
protect rats from cocaine-induced behavioral sensitization (Renteria Diaz,
Siontas, Mendoza, & Arvanitogiannis, 2013). All those abovementioned
studies were performed on male rodents, so people have investigated the
effect on females. One study reported that running wheel access also reduces
cocaine self-administration in female rats (Smith & Witte, 2012). Further
studies compared the effect of exercise training on substance abuse between
males and females, but frequently displayed inconsistent results. For exam-
ple, 10-day running wheel access on rats suppressed self-administration of
cocaine in females but not in males (Cosgrove, Hunter, & Carroll, 2002),
whilst a second study found that males rats are more sensitive to exercise-
induced attenuation of cocaine-seeking behaviors (Peterson, Hivick, &
Lynch, 2014). The efficiency of exercise training thus varies between males
and females, and such sexual dimorphism may attribute to differential effec-
tive exercise working loads between males and females. Two similar studies
using 6-week daily access to the running wheel show that female rats expe-
rienced about twofold higher working loads when compared to their male
controls, and displayed better improvements in the extinction of CPP
(Smith, Pennock, Walker, & Lang, 2012; Smith, Walker, Cole, & Lang,
2011). Therefore, the efficiency of exercise training in suppressing addiction
could be positively correlated with exercise intensity or working load.
Exercise intervention also suppresses the addiction of other drugs or
substances. For example, prior voluntary exercise significantly reduced dam-
ages to dopaminergic and serotoninergic fibers caused by methamphetamine
(O’Dell, Galvez, Ball, & Marshall, 2012). In a similar way, running wheel
experience attenuated neuronal damages mediated by nitric oxide synthase
after methamphetamine treatment (Engelmann et al., 2014). In studying
alcoholic addiction, exercise intervention decreases the risk of seizures dur-
ing alcohol withdrawn (McCulley 3rd, Walls, Khurana, Rosenwasser, &
Devaud, 2012), and attenuates alcohol-induced spatial memory deficits in
adult male rats (Hashemi Nosrat Abadi, Vaghef, Babri, Mahmood-
Alilo, & Beirami, 2013). In female rats, voluntary wheel running reduces
alcohol consumption (Ehringer, Hoft, & Zunhammer, 2009). Notably,
the running wheel access relieves depressive-like behaviors in male alcoholic
272 Li Zhang and Ti-Fei Yuan

rats but not in females (Brocardo et al., 2012). Those studies can be summa-
rized as: (1) Exercise training experience prevents or suppresses addiction
behaviors of different drugs and substances, and relieves neural dysfunctions
associated with addiction. (2) The exercise paradigms (voluntary running
wheel vs. forced treadmill running) and research subjects (male vs. female)
remarkably affect the overall efficiency. Further mechanistic studies are thus
required to reveal molecular and cellular targets of exercise in addiction
intervention, thereby providing new insights and guidance for clinical
applications.

3. Exercise intervention for drug addiction in humans

Most of human studies support the advantages taken by physical exer-
cise in reducing addiction behaviors, and some reports even support the
prevention effect by endurance training. For example, reduced alcoholic
dependence occurs in people with high participation rate in regular training,
although the involvement of other psychosocial factors cannot be excluded
(Terry-McElrath, O’Malley, & Johnston, 2011). In the United States ado-
lescents, higher alcohol consumption was reported in teenagers with lower
physical activity (Pate, Heath, Dowda, & Trost, 1996). A study in Spanish
adolescents has also suggested an inverse relationship between physical activ-
ity and tobacco dependency (Rodriguez Garcia et al., 2014). In school-aged
population, higher physical activity is also associated with lower rates of
Marijuana-taken behaviors (Kulig, Brener, & McManus, 2003). Another
survey has also suggested that significant reduction of alcohol or tobacco
using rate was found in teenagers with more frequent physical training
(Collingwood, Sunderlin, Reynolds, & Kohl, 2000). Those opinions
received support from another study in Egypt show that physical activity
prevents smoking in adolescents and young adults (Charilaou, Karekla,
Constantinou, & Price, 2009). In addition to the suppression of substance
abuse in adolescents, physical exercise in younger age may also prevent
substance abuse in later adulthood. One nation-wide survey in the United
States middle schools found that students with active participation in popular
sports are less likely to become heavily smokers in adulthood (Escobedo,
Marcus, Holtzman, & Giovino, 1993). In another report, sedentary life in
adolescents effectively predicts higher rate of illicit drug abuse in early adult-
hood (Korhonen, Kujala, Rose, & Kaprio, 2009). Moreover, multi-module
life intervention strategy including exercise training can prevent substance
Exercise and substance abuse 273

abuse (Werch, Moore, DiClemente, Bledsoe, & Jobli, 2005). Those studies
suggest that exercise training reduces the risk of addiction disorders.
In those people with drug-dependency, exercise training also has bene-
ficiary effects for the cessation of drugs, or the reduction of withdrawal
symptoms. Exercise has been widely used as one complementary strategy
to relive the adverse effects during drug abstinence as supported by some
observations. One group reported that the Qigong practice remarkably
reduced heroin withdrawal symptoms such as anxiety disorder, and resulted
in higher successful rate of drug detoxification (Li, Chen, & Mo, 2002). Sim-
ilar results have been reported in cocaine, as a greater reduction of drug
dependency occurred in exercised group, which also presented less depres-
sion syndrome (Smelson et al., 2013). Moreover, a survey of homeless
people showed that active participation in exercise training enhances the
retention of drug or alcohol abstinent (Burling, Seidner, Robbins-Sisco,
Krinsky, & Hanser, 1992). In a smoking cessation program, the intro-
duction of active exercise increases the overall successful rate (Linke,
Rutledge, & Myers, 2012). Besides Qigong intervention, a pilot study
suggested Yoga as one positive factor to reduce alcohol consumptions
(Hallgren, Romberg, Bakshi, & Andreasson, 2014). In general, activity
increase in substance abusers present less drug intake behaviors (Correia,
Benson, & Carey, 2005).
It is interesting that exercise training sometimes results in sexually dimor-
phic effects in the prevention and reduction of substance abuse. In a survey
of adolescents, only females with higher physical activity present lower
cigarette intake (Aaron et al., 1995). Other studies on females agreed that
moderate to high intensity of exercise training suppresses nicotine depen-
dence. In female smokers, moderate training with 3 days per week benefits
the overall smoking cessation course (Williams et al., 2011). The Qigong
course is also one effective way to improve the abstinent outcome, and it
is interesting that usually such training program is more effective in female
drug users than in males (Chen, Comerford, Shinnick, & Ziedonis, 2010).
Within methamphetamine dependent patients, however, opposite effects
have been obtained as males respond better and more quickly to exercise
trainings (Dolezal et al., 2013). Similar results occurred in nicotine users,
in which physical activity program enhanced the success rate of smoking
cessation in males (Horn et al., 2011). In one survey of United States high
school students, male sports participants are less likely to have nicotine,
cocaine or other drug abuse (Pate, Trost, Levin, & Dowda, 2000). Since
previous reports supported higher efficiency in preventing mental disorders
274 Li Zhang and Ti-Fei Yuan

by physical exercise in males compared to females (Strohle et al., 2007), the

sex-dependent effect is worth further studies.

4. Neurobiological mechanisms of exercise intervention

on drug addiction
The change of mesolimbic dopaminergic reward system underlies the
formation and consolidation of addiction behaviors (Feltenstein & See,
2013). The introduction of exercise training, on the other hand, modulates
the neuroplasticity of mesolimbic reward system. For example, wheel run-
ning increases the expression of c-Fos in mouse nucleus accumbens (NAc)
(Werme et al., 2002) and enhanced tyrosine hydroxylase (TH) expression in
the ventral tegmental area (VTA) (Greenwood et al., 2011). It is thus
expected that exercise can modulate the reward circuitry to antagonize
addiction behaviors. For example, methamphetamine infusion on rodents
leads to prominent decrease of TH and dopamine transporter (DAT) expres-
sions in striatal nuclei, whilst running exercise ameliorates such deficits of
dopaminergic system (O’Dell et al., 2012). In other midbrain nuclei such
as the periaqueductal gray (PAG), wheel running abolishes biochemical
changes caused by methamphetamine, in association with decreased drug
seeking behaviors (Sobieraj, Kim, Fannon, & Mandyam, 2016). In
MDMA-treated mice, dopamine release was elevated from NAc, and
12-week pre-exercise training corrected those changes (Chen et al.,
2008). Therefore, exercise intervention of substance abuse can be attributed
to the modulation of midbrain reward system. It is noted that voluntary
running wheel affects cocaine-induced c-Fos expression in VTA, medial
prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) (Zlebnik,
Hedges, Carroll, & Meisel, 2014), providing neurological basis for
exercise-attenuated addiction behaviors. People have already known that
the addiction behavior is correlated with changes of synaptic plasticity of
the mesolimbic system (Russo et al., 2010), exercise training thus may mod-
ulate the neuroplasticity of this reward system to suppress drug abuse. More-
over, the endocannabinoid system is also strongly activated in drug addiction
and is related with drug seeking behaviors (Maldonado, Valverde, &
Berrendero, 2006). Notably, exercise activates the endocannabinoid system
(Raichlen, Foster, Seillier, Giuffrida, & Gerdeman, 2013), providing an
alternative mechanistic explanation.
The neuroplasticity is also conferred by active adult neurogenesis,
which is remarkably delayed in individuals with cannabinoid dependency
Exercise and substance abuse 275

(Lee, Wainwright, Hill, Galea, & Gorzalka, 2014). Exercise is well-

established to stimulate neurogenesis via enhancing the secretion of neuro-
trophic factors (Ma, Hamadeh, Christie, Foster, & Tarnopolsky, 2012),
endurance training thus may relieve the addiction behaviors via recovering
hippocampal neurogenesis. On the other hand, the neural protection func-
tion cannot be ignored. The wheel-running exercise protects neurons from
oxidative stress and promotes neurogenesis of hippocampus in rats treated
with methamphetamine (Engelmann et al., 2014). Similar neuroprotective
effects have been observed in a rat alcohol addiction model (Leasure &
Nixon, 2010). Furthermore, the increased neurogenesis plays an important
role in the reduction of drug vulnerability and in the facilitation of
recovery (Mandyam & Koob, 2012). In addition to neurogenesis and
neuroprotection, gliogenesis is another important factor contributing to
addiction behaviors and can be affected by exercise training. In one study,
methamphetamine intake increased apoptosis and suppressed proliferation of
glial cells in mPFC, and such impaired gliogenesis was corrected by volun-
tary exercise training (Mandyam, Wee, Eisch, Richardson, & Koob, 2007).
Exercise also relieves related symptoms of addiction and during
drug withdrawal course, covering both mental and cognitive deficits. The
exercise training promotes neurogenesis and activates neuronal activities
in hippocampus (Chow, Epp, Lieblich, Barha, & Galea, 2013). Therefore,
correction of mental or cognitive dysfunctions by exercise training can
be explained by the modulation of neuroplasticity. For example, in
morphine-treated rats, voluntary exercise increases the long-term potentia-
tion (LTP) and spontaneous excitatory postsynaptic potentials (sEPSP) of
hippocampus (Miladi-Gorji, Rashidy-Pour, Fathollahi, Semnanian, &
Jadidi, 2014), thus improving cognitive functions. Moreover, chronic tread-
mill training remarkably increases the overall dendritic spine density and
arborization in mouse striatal neurons under drug-induced cognitive
dysfunctions (Toy et al., 2014). Those data suggest that exercise training
can be one effective way to relieve cognitive deficits during the course of
drug cessation.

5. Conclusion and future perspectives

In this chapter, we have summarized major findings of exercise inter-
vention on substance abuse, including reports on both rodent models and
those on human cohorts. In general, most of those studies agree that exercise
training is an effective way for the prevention and reduction of drug
276 Li Zhang and Ti-Fei Yuan

Fig. 1 Summary of current model for exercise intervention of drug addiction. Exercise
training can affect the reward system which is modified by drug addiction, thus exerting
effects on the neural plasticity. Depending on different brain regions and circuits,
exercise-modified network may modulate drug seeking behaviors and cognitive
functions.

addiction. Moreover, exercise helps to relieve withdrawal symptoms includ-

ing mental and cognitive deficits (Fig. 1). Major questions and challenges,
however, still exist to impede a large-scale adoption of exercise training.
First, we are not clear about the effect of exercise intensities and durations
in suppressing addiction behaviors; Second, no effective and objective bio-
markers have been identified for exercise intervention; Last, we have not
established a guideline for exercise paradigms on patients with different con-
ditions. To address those issues, we need to further analyze the neurobiolog-
ical mechanisms of exercise intervention. In particular, the modulation of
synaptic plasticity by exercise training requires more in vivo evidence on
addiction models. On the other hand, transcriptomic or proteomic works
can be performed to identify more factors involved in exercise intervention.
More importantly, the neural network in higher cortical regions such as
mPFC should be dissected under exercise paradigms to reveal the mecha-
nism of exercise-driven effects. By those studies it is hoped that more com-
prehensive understandings of exercise training can be obtained to accelerate
the application of endurance training on the clinical intervention of
substance abuse.

Acknowledgments
This work is funded by National Key Research and Development Program of China
(2016YFC1306702), National Natural Science Foundation of China (81771455) and
Science and Technology Program of Guangdong (2018B030334001).

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