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Abstract

The incidence of substance use and behavioral addictions continues to increase throughout the world. The Global Burden of Disease Study shows a growing impact in disability-adjusted life years due to substance use. Substance use impacts families, communities, health care, and legal systems; yet, the vast majority of individuals with substance use disorders do not seek treatment. Within the United States, new legislation has attempted to increase the availability of buprenorphine, but the impact of substance use continues. Although medications and group support therapy have been the mainstay of treatment for substance use, lifestyle medicine offers a valuable adjunct therapy that may help strengthen substance use recovery through healthy neuroplastic changes.

Keywords

substance use disorders lifestyle interventions dopamine reward pathway serotonin neuroinflammation pillars of lifestyle medicine

“Standard treatment approaches offer an important place in helping those struggling with unhealthy substance use but rarely address lifestyle factors.”

Introduction

The rise of opioid, methamphetamine, and alcohol use during the past decade continues to be alarming. It continues to exert a high cost within health care systems,¹ families and communities, and the justice system within the United States (U.S.)² and the world.³ The opioid epidemic has become increasingly more challenging with the introduction of fentanyl within the North American markets.⁴ According to the National Institute on Drug Abuse (NIDA), in 2019, over 20.4 million individuals in the U.S. were diagnosed with a substance use disorder, yet only 10.3% received treatment.⁵ Recent data from a Kaiser Family Foundation July 2023 poll showed that surveyed U.S. participants increased their substance use during the COVID-19 pandemic, and more than 67% felt they or someone in their family were personally struggling with alcohol or some type of substance.⁶ Regional patterns throughout the world do not show the same substance use trends.⁷ According to the 2019 Global Burden of Disease Study, the disability-adjusted life years (DALY) percent for substance use was higher in the U.S. than globally (5.52% (Range: 4.81%–6.31%) vs 1.38% (Range: 1.17%–1.60%)).⁸

The ability to “avoid” substances or behavioral addictions (i.e., emotional eating, food addiction, shopping, social media, or gaming) and change behavior is often limited due to the activities’ ability to impact the dopamine reward network, which causes neuroplastic changes,^9,10 increases neuroinflammation^11,12 and alters mitochondrial function.¹³ These changes can alter the brain’s executive control systems, including decision-making, impulse control, and emotions. Individuals struggle to make decisions and regulate one’s actions, emotions, and impulses. Individuals may become less deterred by negative consequences with increased focus on the short-term, reward-seeking nature of the substance, and their ability to experience non-drug rewards can be reduced.^10,14-16

Between 10%–15% of individuals diagnosed with a substance disorder (SUD) receive treatment.¹⁷ For those individuals who receive treatment, standard options may include medication-assisted detoxification, residential rehabilitation programs, partial hospitalization or intensive outpatient programs, attending support groups, or working with an individual provider.¹⁷ The American Society of Addiction Medicine (ASAM) has developed the ASAM criteria, a comprehensive tool, to link the individual in their current circumstance with an appropriate level of care.¹⁸ The initial phase may also include the use of medication-assisted therapies to help reduce physical cravings, which includes naltrexone, acamprosate, or disulfiram for alcohol use disorders (AUD), or methadone, buprenorphine, or naltrexone for opioid use disorders (OUD). Treatment recommendations from ASAM, Substance Abuse and Mental Health Service Administration (SAMHSA), and other organizations advocate the use of medication-assisted treatments (MAT). This effort was recently bolstered in the U.S. by the passage of the Mainstreaming Addiction Treatment Act (2023), which will hopefully increase the availability of buprenorphine.¹⁹

Although current standard treatments can be lifesaving, limited evidence shows long-term functional outcomes.²⁰ Lifestyle medicine interventions have been adopted by many medical societies to be used as first-line and/or adjunct for chronic medical conditions such as diabetes, hypertension, heart disease, and cancer.²¹ Often overlooked, these interventions can influence neuroplastic processes, including improved synaptogenesis, neurotrophic factors, mitochondrial function, and reduced neuroinflammation. We will provide an overview of the neuropathology that develops following sustained substance use and provide some of the resulting behavioral implications that impede change. Next, we will review how the lifestyle medicine pillars promote healthy neuroplasticity, which may mitigate substance use-induced neuropathology.²²

Dopamine Pathway

The dopamine reward pathway is well-known and has been reviewed extensively,^14,15 and it should be noted that dopamine does not function independently but is part of a multifaceted network of interconnected structures consisting of serotonergic, cannabinoid, opioidergic, GABAergic, glutamatergic, and dopaminergic systems. Independently and collectively, they each play a unique role in the reward-seeking pathway.²³ Dopamine is derived from the amino acid phenylalanine. Within the brain, dopamine is produced within the ventral tegmental area (VTA) and projects cells to the nucleus accumbens (NA), where it is stored. Dopamine mediates excitatory processes within the brain. The initial phasic dopamine release helps promote concentration, focus, and motivation as the NA projects to the prefrontal cortex (PFC).

However, repetitive dopamine-stimulating activities strengthen the connection between the behavior, various cues, and the predictable dopamine response, which can lead to undesired drug-seeking behaviors.²⁴ High amounts of dopamine concentration can impair executive functioning through NA-PFC projections. Additionally, NA projections to the limbic system, particularly the amygdala and hippocampus, consolidate memories, eventually promote “conditioning” and decrease hippocampal volume.²⁵ This process mediates withdrawal symptoms when dopamine levels drop below new normative baseline levels.^14,26 These withdrawals may be acute or insidious, and they are commonly described as nausea, anxiety, headaches, decreased concentration, irritability, agitation, tremors, sleep disturbances, dysphoria, or depression. The withdrawal can also be misdiagnosed as depression, anxiety, attention deficit, or insomnia. Long-term dopamine exposure leads to a downregulation of dopamine receptor density.²⁷ Although this downregulation is protective, the end consequence may increase dopamine-seeking behaviors.¹⁴ Hence, individuals may seek activities or a combination of stimuli that increase dopamine release.²⁸ They may also lose the ability to like and seek novel activities.^14,15 Apart from the behavior, a net consequence is a neuroplastic change affecting the synaptic strength of excitatory and inhibitory processes due to the local sprouting of axonal dendritic spines and new synaptic connections.²⁹

One of the potential mechanisms of neuroplastic change is neuroinflammation, which is mediated by cytokines, chemokines, and reactive oxygen species within the brain.³⁰ Chronically elevated levels of dopamine are a proposed mechanism of neuroinflammation. Dopamine receptors are located on astrocytes and microglia, which can lead to neuroinflammation via microglial phenotype switch.³¹ Similarly, dopamine can activate monocytes and macrophages, resulting in neuronal apoptosis.³¹ In rodent models, excessive dopamine can decrease serotonin function up to 75% in the PFC, dorsal striatum, nucleus accumbens, hippocampus, and hypothalamus.³² These changes may account for the altered hippocampal function and conditioning process common in individuals with substance use.³³ Potentially, some of these neuroplastic changes may be reversible, but they do not change spontaneously.²⁹

Lifestyle Medicine Interventions and Neuroplastic Change

Once neuronal pathways have been imprinted, they cannot spontaneously reverse or deconstruct themselves. Neuroplastic change is “the ability of the nervous system to change its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, functions, or connections.”³⁴ Clinically, these changes may be considered beneficial, restoring function, neutral with no clinical benefit, or negative, leading to worsening pathological consequences.³⁵ Mechanistically, neuroplasticity has two major pathways: neuronal regeneration or collateral sprouting, which includes concepts such as synaptic plasticity and neurogenesis, and functional reorganization, which includes concepts such as equipotentiality (all areas of the brain are equally able to perform a task), vicariation (areas of the brain with a different function can take over a function of an injured area of the brain), and diaschisis (a sudden change in brain function due to injury).³⁵

Apart from FDA treatment or the treatment of underlying mental health symptoms, many of the newer theories in the treatment of substance use disorder focus on reversing their dopamine pathways, for example, transmagnetic stimulation or other emerging treatments.³⁶ Less attention has focused on lifestyle changes, which may significantly impact SUD²² neuroplasticity and is often a preferred form of treatment.³⁷ Frequently, individuals with SUD experience more significant comorbid physical and mental health diseases.³⁸ Nevertheless, with behavior therapy (motivational interviewing and transtheoretical model of behavior change), they have been able to reverse chronic illness, including substance use.^39,40 Importantly, lifestyle medicine interventions promote neuroplastic change through the activation of serotonin, decrease in neuroinflammation, and promotion of neurotrophic factors, like BDNF, as will be discussed later.

Increase Movement

In a 2014 meta-analysis, Wang et al analyzed 22 studies with 1487 participants with varied substances. They reported that physical exercise can increase the abstinence rate (OR = 1.69 (95% CI: 1.44, 1.99), z = 6.33, P < .001), moderate withdrawal symptoms (SMD = −1.24 (95% CI: −2.46, −.02), z = −2, P < .05), and reduce anxiety levels in participants with SUD (SMD = −.31 (95% CI: −.45, −.16), z = −4.12, P < .001) as well as depressive symptoms in participants with SUD (SMD = −.47 (95% CI: −.80, −.14), z = −2.76, P < .01).⁴¹ In a 2017 meta-analysis, Hallgreen et al. evaluated 21 studies with 1204 participants, who all had alcohol use disorder. Their analysis shows that exercise did not reduce daily alcohol consumption, but it reduced depressive symptoms (RCTs = 4; SMD = −.867, P = .006, I2 = 63%) and improved participants’ physical fitness, measured VO2 (RCTs = 3; SMD = .564, P = .01, I2 = 46%).³⁸ Some authors question the direct benefits of exercise and substance use due to the lack of standardization among sample sizes and treatment modalities.⁴²

Apart from improving overall physical fitness, exercise consistently has shown benefit with depressive and anxiety symptoms.⁴³ Exercise has increased the release of neurotrophic factors, like BDNF, which has been linked with improved hippocampal function.^44,45 Additionally, exercise has been linked with improved cognitive health as it decreases the neuroinflammation response through modulating microglial activity and phenotype.⁴⁶ Also, exercise has been linked with improved mitochondria energy utilization, which is believed to delay the development of central fatigue.⁴⁷ Finally, exercise also modulates the endocannabinoid systems, which promote neuronal homeostasis and downregulates the stress response.⁴⁸

In addition to neurological factors, exercise has systemic benefits via improved cardioaerobic fitness, endothelial health, metabolic health, and body composition with improved lean muscle mass to visceral adiposity ratio and subsequent anti-inflammatory myokine and adipokine responses. For example, altered IL-6 secretion from adipose and muscle tissue influences astrocyte and microglia function and neuroinflammation.⁴⁹ Regular exercise can down-regulate cortisol, epinephrine, and norepinephrine.⁴⁵ Also, regular exercise can help improve the quality of sleep by reducing sleep latency and increasing slow-wave sleep.⁵⁰

Serotonin is another monoamine neuropeptide that has significant implications for mood and anxiety symptoms. Serotonin is derived from the amino acid tryptophan, and it plays a key role in promoting neuroplasticity and activating neurotrophic growth factors. Exercise has been shown to improve peripheral tryptophan levels and to increase the release of serotonin from the raphe nuclei, the storage center of serotonin within the brain.⁴⁴ Furthermore, serotonin has been shown to improve mitochondrial biogenesis in rodent models^51,52 and may help reverse changes in mitochondrial function with the NA and PFC in individuals with SUD.⁵³

Interestingly, extreme and chronic levels of exercise may upregulate dopamine D1 receptor signaling in the mesolimbic, which has been linked to increased addiction vulnerability in rodents.^54,55 Also, chronic exercise has been linked with abnormal concentration levels of norepinephrine, serotonin, GABA, and endocannabinoids.⁴⁴ Where moderate aerobic exercise protects against SUD, there is a growing literature that humans can adopt exercise addiction behaviors that produce many of the same behavioral and neuroplastic changes as chronic exposure to substances.⁵⁶

Eat Healthier

The chronic effects of alcohol consumption and lack of thiamine and other B vitamins are well known. Individuals with chronic alcohol are screened for the development of Wernicke-Korsakoff syndrome and are frequently given replacement thiamine.⁵⁷ In addition to alcohol use, individuals with chronic substance use disorders have a greater tendency to experience food insecurity, suffer from nutrient deficiencies, and experience malnutrition, and their diets lack protein, fiber, vitamins (especially B1, B2, and B12), and essential minerals (iron and magnesium).⁵⁷ When they do consume food, some studies indicate that the majority of caloric intake is via ultra-processed foods.⁵⁶ Poor nutritional status in SUD severely impacts their physical and psychological health, which may impede their ability to resist substances of abuse and recover their health.⁵⁸ In a recent systematic review by Whatnall et al, the authors highlight the importance of addressing nutrition in SUD populations and note the need for more robust studies.⁵⁷

The brain-gut-microbiota (BGM) system is a bidirectional communication network connecting the gastrointestinal system and the brain that has emerged as a focal point linking nutrition, health, and well-being.^59,60 Similarly, the BGM system interacts bidirectionally with SUD through metabolomic, immune, neurological, and epigenetic mechanisms and can reinforce SUD behaviors.⁶¹ There is a growing literature that shows patterns of dysbiosis in individuals with AUD and OUD; their gut microbiota shows higher bacterial concentrations of specific bacteria, for example, Enterobacteriaceae.^62,63 The change in bacteria composition is significant for several reasons. First, Enterobacteriaceae release lipopolysaccharide (LPS) from their own cell membranes, worsening dysbiosis, decreasing blood-brain barrier integrity, and increasing neuroinflammation.⁶⁴ Second, Enterobacteriaceae are unable to ferment complex carbohydrates into short-chain fatty acids (SCFA) or metabolize tryptophan. SCFAs have a wide range of host activities, including metabolism, cell differentiation, gene regulation, and regulating anti-inflammatory and pro-inflammatory cytokines.⁶⁵

Tryptophan is an essential amino acid and is a precursor to serotonin and derivates of kynurenine, which contribute to neuroendocrine and neuroimmune mechanisms as they can act on the CNS either through the bloodstream or via vagal afferent signaling.⁶⁶ Specifically, about 95% of dietary tryptophan is converted to kynurenine, and only about 5% is converted to serotonin and nicotinamide adenine dinucleotide (NAD), which is involved in mitochondrial function, energy metabolism, and antioxidation of oxidative stress.⁶⁵ Kynurenine can convert to kynurenic acid via kynurenine aminotransferase (KAT), which is neuroprotective as it decreases excess glutamate clearance.⁶⁵ During periods of stress, kynurenine is converted to 3-hydroxyynreine acid via kynurenine monooxygenase (KMO), which produces byproducts, including quinolinic acid that is neurotoxic and promotes oxidative stress.^66,67 This pathway has also been linked to worsening clinical depressive symptoms.⁶⁸

Recent clinical studies have demonstrated the potential of the role of diet to impact neurophysiological and systemic function and, therefore, provide hope for future research in SUD. In 2017, Jacka et al. conducted one of the first randomized control studies on a nutritional intervention in major depression disorder. The Supporting the Modification of Lifestyle In Lowered Emotional States (SMILES) study showed how a modified Mediterranean diet that avoided UPF and fast food could improve symptoms in people with moderate-severe depression.⁶⁹ Future dietary studies that follow the SMILES design may replicate equally beneficial results for SUD.

Improve Sleep

Individuals with substance use disorders have a high likelihood of having a comorbid sleeping disorder. In adolescents who use substances, it has been estimated that 29% will develop a comorbid sleep disorder.⁷⁰ In adults, it has been estimated between 36%–91% will develop a comorbid sleeping disorder.⁷¹ The long-term consequences include difficulty falling asleep, frequent awakenings, poor sleep quality, reduced sleep time, changes in sleep architecture, and daytime sleepiness, which can impact health and social functioning.⁷² Sleep disturbances that continue into periods of sobriety correlate highly to a return to use due to their increased likelihood of impulsive behaviors.^71,73 As such, the long-term return to a stable and consistent sleep regimen may be vital. Additionally, the long-term restoration of sleep has been linked with increased hippocampal volume and function and improved cognition.⁷⁴ Cognitive behavioral therapy-insomnia (CBT-i) is emerging as the first-line therapy for insomnia.^75,76 A randomized control pilot study (N = 22) showed CBT-I improved insomnia among U.S. Veterans, but it did not reduce their alcohol-drinking behaviors.⁷⁷ Overall, there is still a shortage of research in the treatment of SUD-related insomnia and sleep disorders.⁷⁸

Decrease Stress

There is significant stress and anxiety related to substance use. Apart from the high comorbidity between substance use and anxiety disorders, a negative affect stage has been identified within the addiction cycle. During this phase, individuals start experiencing withdrawal symptoms and often experience a stress-like state as they are fearful about potential withdrawal.²⁶ The concern about a possible withdrawal leads to the activation of the amygdala response and triggers the eventual release of cortisol from the hypothalamic-pituitary axis (HPA). In addition to the neuroinflammatory response as previously described, chronic cortisol release increases dopamine release from the NA and intensifies the addiction cycle.⁷⁹

A person’s ability to tolerate stress and negative emotions is called distress tolerance, which has been linked with dysregulated behaviors in SUD. A recent meta-analysis by Mattingly et al showed a high correlation between low levels of distress tolerance and severe SUD.⁸⁰ Traditionally, dialectical behavioral therapy (DBT) is used to increase distress tolerance in the treatment of chronic suicidality and borderline personality disorder. However, recent studies have shown that DBT also has favorable outcomes in improving distress tolerance in individuals with SUD, offering preliminary support for substance use reduction and emotion regulation, though further studies are needed.⁸¹ The practice of mindfulness is a significant component of DBT. Mindfulness-based cognitive therapy (MBCT) and yoga can improve distress tolerance and reduce substance use.^82,83 Long-term MBCT also improves executive decision-making control.⁸³ Mindfulness-based practice and other metacognitive processes are thought to work on a top-down approach by increasing the function of the parietal lobe, posterior and anterior cingulate cortex, and the PFC.⁸³

Healthier Relationships

In 2023, the U.S. Surgeon General, Dr. Vivek Murthy, released the landmark document, “Our Epidemic of Loneliness and Isolation.”⁸⁴ He summarizes that individuals with isolation have worse mental health, increased mistrust of the community, an overreliance on social media, decreased physical activity, unpredictable food patterns, and poorer sleep.⁸⁴ Due to the nature of substance use, many individuals lose contact with their biological family, friends, and co-workers. As such, the rates of loneliness are higher among individuals with substance use disorders.⁸⁵ McWain et al compared isolated rodent populations to aged-matched controls that were given cocaine. Both populations demonstrated similar mesolimbic dopamine autoreceptor functioning. These results lead the authors to hypothesize that isolation contributes to the addiction pathway.⁸⁶

A systematic review by Vigdal et al. noted that in order for individuals to trust and attempt to engage in social connections, they needed social communities that were perceived as safe and non-stigmatizing.⁸⁷ Historically, many individuals have started this process in support groups like Alcoholics Anonymous. Many individuals describe that the closeness and safety of the group are more important than the content of the meetings.⁸⁸ Additional literature demonstrates how sharing an experience can create bonds and subsequently release oxytocin from the paraventricular nucleus of the hypothalamus and modulate dopamine activity at the VTA,⁸⁹ which may contribute to improved outcomes in those with a SUD when social connections are sustained.

Avoid Unhealthy Substances

Within the U.S. population, according to the National Epidemiological Survey of Alcohol and Related Conditions, it is estimated between 57% to 97% of individuals with SUD have at least one additional co-occurring SUD.⁹⁰ The use of multiple substances leads to higher mortality and morbidity.⁹¹ Although it is implied that recovery from multiple SUDs is more challenging than a single SUD, there is limited data regarding the treatment efficacy.⁹² Although it is often not correlated with SUD, there is a growing literature examining the addictive nature of sugar⁹³ and UPF.⁹⁴ As mentioned previously, individuals with SUD frequently obtain the majority of their food from UPF. The consumption patterns were consistent between gender and race,⁹⁵ and the global consumption of UPF have increased in the post-pandemic era.⁹⁶ Additionally, UPF affect the gut microbiota by worsening dysbiosis, decreasing the production of SCFA, affecting the absorption of key amino acids like tryptophan, and adversely affecting brain health.^60,67,85 Of note, UPF seem to activate mu opioid receptors within the NA, and some authors have considered these a potential “gateway drug,” a precursor to future substance use.^57,97 Additional studies are needed to validate this claim, hopefully requiring changes to the industrial food complex.

Going Forward

As mentioned, only a minority of individuals with SUD actually seek treatment.¹⁷ Barriers to seeking treatment include negative psychosocial consequences of substance use or behavioral addiction and personal shame or guilt leading to stigma surrounding treatment.⁹⁷ Addressing these barriers is an ongoing area needing further research. Standard treatment approaches offer an important place in helping those struggling with unhealthy substance use but rarely address lifestyle factors.

Lifestyle medicine offers an additional approach to treatment that may benefit patients on the spectrum of formal diagnosis or unhealthy substance use. One of the major advantages of the lifestyle medicine lens is that it focuses on the whole person and not just the SUD.^17,20 However, there is an increasing awareness that many illnesses have common risk factors or a common pathway that may contribute to the basis of many chronic conditions.⁹⁸ These risk factors can be modified through lifestyle changes⁹⁹ as they promote positive epigenetic and neuroplastic change.^100,101 Given this, lifestyle medicine can play a powerful role in the treatment of mental health disorders and potentially SUD and in improving overall public health.

As a step forward, lifestyle interventions for SUDs were mentioned in a landmark study from 2023. The Australasian Society of Lifestyle Medicine, in partnership with the World Federation of Societies for Biological Psychiatry, published guidelines for lifestyle interventions for major depressive disorders.¹⁰² As a next step, the authors encourage the scientific community to fund and conduct robust studies to validate the importance of exercise, whole-food, plant-predominant diets, improved sleep through CBT-I, decreased stress through DBT and other mindfulness modalities, and improved social connections for SUD treatment so that similar recommendations can be advocated for people with SUD. We further encourage the scientific community to challenge the production and marketing of UPF and to promote whole-food, plant-predominant diets.

Finally, the authors urge that lifestyle medicine ought to be integrated into health care education and specifically into mental health and addiction medicine training. We encourage the adoption of the biopsychosocial-lifestyle formulation. This model builds upon the traditional biopsychosocial model and includes assessing the lifestyle foundations as part of the initial patient formulation.¹⁰³

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Steven G Sugden

Gia Merlo

Sam Manger

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Strengthening Neuroplasticity in Substance Use Recovery Through Lifestyle Intervention

Abstract

Keywords

Introduction

Dopamine Pathway

Lifestyle Medicine Interventions and Neuroplastic Change

Increase Movement

Eat Healthier

Improve Sleep

Decrease Stress

Healthier Relationships

Avoid Unhealthy Substances

Going Forward

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References