Student Scholarship – Honorable Mention Research Review

Jocelyn Faydenko, ND
Fraser Smith, MATD, ND

Drug addiction has become an increasing problem in the United States. David Sheff, in his book Clean, published in 2013, mentions the Centers for Disease Control and Prevention (CDC)’s findings at the time that drug-related deaths had doubled since the 1980s and that drug-associated mortality was higher than for any other non-natural cause.¹ Nearly 135 000 deaths were directly associated with drug abuse every year (a large portion being alcohol), and other deaths that can be causally linked to drugs – such as related suicides, automobile and other accidents, pulmonary disorders, heart attacks, homicides, strokes, liver disease, kidney disease, septicemia, and other infections – accounted for an additional 100 000 fatalities.¹ These numbers unfortunately only seem to increase over time.

While drug addiction is a devastating health problem that weighs heavily on individuals that are addicted, as well as those close to them, contemporary research reveals how and why addiction develops, including many factors that contribute to addiction susceptibility. As William S. Burroughs said, “You don’t wake up one morning and decide to be a drug addict.” Myriad influences create “the perfect storm” for addictive tendencies, and since every person is unique, the combination of an individual’s psychology, biology, and environment can result in variations in addiction predilection.¹  Genetic predisposition, environmental exposures, nutrition, and psychosocial dynamics are all determinants that can play a key role in drug addiction mechanisms. As naturopathic practitioners, grounding individualized care in the determinants of health, as well as understanding the root cause of disease, is essential for both prevention and treatment for people with active addiction.

Inborn/Genetic Factors

Drug addiction is now understood to be a neurobehavioral disorder, and abnormal changes in gene expression may be responsible for changes in brain function. Nearly half of the risk associated with developing addiction may be attributable to inherited genetic differences²; twin studies have demonstrated addiction heritability ranging from 0.39 (for hallucinogens) to 0.79 (for cocaine).³ While there is no specific “addiction gene,” a combination of genes, chromosomal regions, and variations in alleles likely contributes to addiction. Genome-wide association studies have sought to discover these genetic linkages, and several gene clusters have been implicated in the transgenerational inheritance of drug abuse risk.^4,5

Genetic factors can impact how substances are metabolized in the body, including receptor availability and responsiveness to neurotransmitters, temperament and personality, as well as how a person responds to stress, impulsivity, and risk-taking.¹ Based on studies of twins, while genetic determinants may differ, genes influence each stage in the drug abuse process, from initiation to dependence and addiction.³

Several single nucleotide polymorphisms (SNPs) have been implicated in vulnerability to addiction, including those regulating the serotonin transporter (SLC6A4), mu opioid receptor (OPRM1), and catechol-O-methyltransferase (COMT).^3,5 The COMT Val allele (of the Val158Met polymorphism) has been associated with inefficient frontal lobe function,⁶ and has been found more frequently among nicotine, methamphetamine, and polysubstance addicts.⁵ The SNP A118G, in the OPRM1 gene, has been linked to the prevalence of opioid abuse in patients.⁵ The most frequently studied locus in psychiatric genetics is a variable-number tandem repeat (VNTR) in the promoter region (HTTLPR) of SLC6A4; the low-transcribing genotypes have been associated with depression, anxiety, and alcoholism.³ Additionally, the HTTLPR low-activity “s” allele has been shown to be associated with decreased amygdala volume, increased reactivity to fearful stimuli, and reduced inhibition of amygdala activation as a result of enhanced functional coupling between the prefrontal cortex and the amygdala.³ This suggests that such genetic modulation of the stress response, emotions, and behavioral control may be important in the mechanisms of addiction.³

Environmental/Epigenetic Factors

Environmental exposures appear to play a role in addiction by activating susceptibility genes, even if a person does not have an inherited risk. Specifically, epigenetic modulation of gene networks, particularly DNA and histone methylation in the nucleus accumbens, is thought to play a key role in drug addiction mechanisms.⁷ Epigenetics is simply defined as the ways in which environment affects genetic expression. This includes the biochemical processes that change gene expression throughout an individual’s lifetime without changing the DNA sequence itself, though phenotypic changes can still be inherited by offspring. This alteration in expression can either enhance or suppress genes, and if transcription is changed in some way, protein formation, and therefore enzyme and hormonal changes, can also result.⁸

Prenatal factors can contribute to addiction susceptibility and drug dependence. Substance abuse during pregnancy has been linked to fetal developmental issues and dependence post-delivery, and these deleterious effects can cause congenital anomalies, dysregulation between stress and reward neuronal circuits, and increased risk for drug abuse and addiction.⁹

While studies have yet to investigate addiction prevalence in human offspring of parents who were exposed to drugs prior to conception, several mouse studies have demonstrated a link between parental exposures and epigenetic effects in the progeny. One study found that paternal substance use caused epigenetic alterations in sperm cells and that these modifications could lead to brain changes and addiction-like behaviors in the offspring.¹⁰ Other studies have shown that morphine-exposed parents have offspring with altered morphine responses, as well as structural and physiological changes within the brain.⁵

One of the brain regions that is key in the neurocircuitry of addiction is the hippocampus. Regulation of one epigenetic marker (trimethylation of histone H3 at lysine 4, or H3K4me3) has been linked to memory formation within the hippocampus.² Differentially expressed genes and transcripts that are targeted by H3K4me3, which is abundant at transcription start sites and associated with active transcription, may play important roles in addiction.² This suggests that changes in gene expression from epigenetic modulation may contribute to central nervous system (CNS) plasticity.² That is to say, what may appear to be a transitory mind- and mood-altering substance can become a longer-term gene, proteome, and brain circuitry-altering one. One study found that alterations in targeted expression of H3K4me3 included 1855 genetic changes due to cocaine addiction, and 848 changes due to alcoholism.² In addition, miR-9, a brain-specific microRNA involved in the neurobiology of disease, not only post-transcriptionally regulates genes that influence drug tolerance, but family members of this microRNA also have some of the strongest H3K4me3 targets within neuronal progenitor cells.²

Acute exposure can trigger addiction cravings, but, interestingly, long durations of abstinence can also lead to cravings, sometimes even more strongly than acute exposures. Particularly studied in cocaine cravings, cue-induced cravings have been shown in rats to progressively intensify rather than decay, demonstrating an “incubation” period during extended withdrawal periods.¹¹ As mentioned, the nucleus accumbens is associated with drug addiction mechanisms and is a central reward-related region shown to play a critical role in cravings such as for cocaine. In one study, prolonged cocaine withdrawal caused the number of differentially methylated promoters to be double that of those after early cocaine withdrawal.¹¹ A prior mouse study also found that global patterns of DNA methylation in the hippocampus of offspring was altered due to maternal cocaine administration, and behavioral phenotype development was affected by withdrawal.¹²

Long-lasting alterations in gene expression through DNA and histone methylation can affect behavior.¹³ One of the major ways in which methylation is controlled is by redox-based cellular metabolism, specifically via the folate- and vitamin B12-dependent enzyme methionine synthase, which both reduces homocysteine and produces S-adenosylmethionine, a major methyl donor. Glutathione is known for its antioxidant effects. The rate-limiting step in the synthesis of glutathione is cysteine. Drugs such as opioids can induce hypomethylation and affect transcription, thereby inhibiting cysteine uptake and reducing glutathione levels.¹³ Interestingly, one of the ways cysteine is made available is by being transported via excitatory amino acid transporter 3 (EAAT3). This transporter is involved in more than 200 methylation reactions, including histone and DNA methylation. Not only do drugs such as heroin and morphine deplete glutathione levels, but tolerance of these drugs has also been found to correlate with a decrease in the EAAT3 levels.¹³ This indicates that modulating glutathione and/or cysteine levels could be potentially therapeutic in the treatment of drug abuse and addiction.

Nutritional Factors

Dietary habits and nutrition affect every process within the body. For those struggling with drug abuse, poor nutrition can result in a number of deficiencies that can perpetuate addiction processes or make withdrawal symptoms more severe. Chronic use of addictive substances such as alcohol and heroin can damage the digestive tract or shut down the process of digestion, thereby impeding the absorption of vitamins, minerals, and amino acids.¹⁴ If the gut is not functioning properly, then the brain will not either. When the brain is not properly nourished, mental functions are reduced, stress responses are altered, and malfunctions in the reward centers of the brain occur, leading to cravings.¹⁴

B vitamins are known for their role in maintaining optimal neurological functioning and being essential for overall cognitive performance. Inadequate riboflavin (B2) and pyridoxine (B6) can result in excitotoxicity from excess glutamate production, resulting in neuronal death.¹⁴ In his 1986 article, Cleary estimated that 10% of people are severely deficient in the coenzyme NAD (nicotinamide adenine dinucleotide), and he cited examples of alcoholics being successfully treated with niacin.¹⁵ Since niacin is required in the metabolism of alcohol and also reduces acetaldehyde levels in the brain, supplementing the vitamin can help facilitate the breakdown of alcohol and prevent acetaldehyde from condensing with dopamine (and the new compounds from binding to opiate receptors), thus helping to reduce addiction.¹⁶ Thiamine has also been shown to work with other vitamins (A, C, E, and other B vitamins) and zinc to protect the brain from alcohol-induced neurodegeneration.¹⁴ Circulating levels of these nutrients have been shown to be depressed in individuals addicted to heroin.¹⁷

Decreased levels of tyrosine and tryptophan result in lower levels of dopamine and serotonin, negatively affecting behavior and mood. Drug and alcohol use prevent the body from normally processing these amino acids, thus compromising mental clarity, emotional stability, and well-being.¹⁴ In those undergoing early-stage alcohol detoxification, supplementing with tryptophan may help ameliorate withdrawal symptoms and improve cognition. Supplementing with tyrosine, or its precursor phenylalanine, has been shown to increase emotional/mental alertness and energy, elevate mood, and indirectly decrease drug cravings.¹⁴

Other nutrients that play a role in addiction include zinc, polyunsaturated fatty acids (PUFAs), and vitamin D. Zinc deficiency is common among those who use opioids, and animal studies have suggested the potential for zinc supplementation to both reduce morphine withdrawal symptoms and prevent addiction development in those taking opioids for pain management.¹⁸ PUFAs are one of the building blocks of cerebral membranes and are essential for maintaining membrane fluidity. Many addictive substances decrease the levels of these essential fats in the brain, leading to reduced signal transduction among neuronal synapses.¹⁴ Studies have shown that increased intake of omega-3 and omega-6 foods significantly lowers relapses among cocaine- and alcohol addicts over a 2-year timeframe.¹⁴ Vitamin D has neuroprotective effects and has been shown to be crucial for neurodevelopment.¹⁹ This vitamin increases the levels of tyrosine hydroxylase (the rate-limiting step in the conversion of tyrosine to DOPA), indicating it may modulate dopaminergic processes and protect the dopaminergic system against dopamine-depleting effects of some drugs, such as methamphetamine.¹⁹

Interestingly, excessive sugar intake has been implicated in reinforcing increased tolerance to drugs and addiction.²⁰ Ingestion of foods with highly satisfying yet rapidly diminishing taste sensations, such as sugar, may cause endogenous opioid dependence (ie, it acts as an external agent facilitating release of the brain’s own opioids); one rat study demonstrated opioid-mediated dependence on sugar at both the behavioral and neurochemical level.²¹ Sugar intake in the rats caused acetylcholine and dopamine imbalances similar to withdrawal from nicotine or morphine. Individuals already using drugs who consume high amounts of sugar may have an increased drug response as a result.²⁰ Furthermore, poor eating habits involving high sugar intake may be partly responsible for triggering CNS intoxication mechanisms and making it more difficult to overcome addiction.²⁰

Neurodevelopmental Factors

Evidence suggests that addictive behavior is more likely to manifest the earlier one is exposed to drugs. In fact, research has shown that the age of first use is one of the most important factors associated with susceptibility to addiction.^22,23 Since children and adolescents do not have fully formed brains, drugs may have a significant impact on neuronal plasticity.²⁴ The prefrontal cortex is the center for decision-making, judgment, and abstract thinking, and this area takes longer to mature. Due to its slower development, regulation of reward and impulse control systems is diminished.¹ Early exposure to drugs can insult developing dopaminergic pathways, and dysfunctional methylation of DNA and histones may be more likely to occur in younger populations.²⁴

In one study, ethanol administration in adolescent mice downregulated the dopamine D2 receptor in the prefrontal cortex, although this same effect was not seen in adult mice.²⁵ Ethanol administration in the adolescent mice also altered the acetylation of histones H3 and H4 in the nucleus accumbens, frontal cortex, and striatum. This implies that drug exposures may be more impactful and potentially damaging in younger individuals, and that abnormal plasticity in reward centers and reward-related processes likely contribute to adolescents’ greater vulnerability to drug addiction.

Psychosocial Factors

Drug use is probably not the only significant factor in addiction predisposition; if proper neurodevelopment is impaired or altered in some way, such as through traumatic experiences, family and emotional dysfunction, or behavioral disorders already present, then addictive behaviors in adulthood may be more likely.^1,24 People are more than the sum of their genes, and addiction is very much an expression of patients’ stories and circumstances. Substance use before pregnancy may also affect offspring in a negative way. For example, it has been shown that many parents who engage in excessive alcohol consumption have been shown to have children who exhibit drug use behaviors, and that early onset of drinking and the amount consumed by offspring were correlated with their parents drinking episodically or heavily.²⁶ The highest risk of drinking among adolescents was associated with parental consumption of 6-9 alcoholic beverages during the week (or 6-10 drinks on the weekend).

Many psychosocial risk factors contribute to the development of drug abuse, including parental/caregiver drug use and abuse, neglect, isolation, maltreatment and abuse, and other adverse experiences.⁹ Emotional, physical, and sexual abuse are some of the most damaging contributors to addiction susceptibility. Abuse can cause stress to the amygdala and lead to dysregulation of dopamine and suppressed function of the prefrontal cortex.²⁷

Relevance to Naturopathic Medicine

These examples demonstrate that the naturopathic approach to addiction must mirror the addictive phenomena. In other words, this approach should address the gene, proteome, cell and neural circuit level, as well as psychosocial context of the patient. As more is discovered about the mechanisms of drug addiction and how various disturbances and exposures can impact addiction risk, therapeutic guidelines will improve and become tailored to each patient’s individual needs. Understanding addiction in this way allows for the root cause of the problem to be unearthed – one of the cornerstones of naturopathic medicine. The more that is understood about how addiction works, the better the patient care will be.

References:

1. Sheff D. Clean: Overcoming Addiction and Ending America’s Greatest Tragedy. Boston, MA: Houghton Mifflin Harcourt; 2013.
2. Farris SP, Harris RA, Ponomarev I. Epigenetic modulation for cocaine and alcohol abuse. Front Neurosci. 2015;9:176.
3. Ducci F, Goldman D. The genetic basis of addictive disorders. Psychiatr Clin North Am. 2012;35(2):495-519.
4. Gorwood P, Le Strat Y, Ramoz N. Genetics of addictive behavior: the example of nicotine dependence. Dialogues Clin Neurosci. 2017;19(3):237-245.
5. Yohn NL, Bartolomei MS, Blendy JA. Multigenerational Inheritance of Drug Exposure: The effects of alcohol, opiates, cocaine, marijuana, and nicotine. Prog Biophys Mol Biol. 2015;118(1-2):21-33.
6. Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001;98(12):6917-6922.
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15. Cleary JP. The NAD deficiency diseases. J Orthomol Med. 1986;1(3):149-157. Available at: https://pdfs.semanticscholar.org/17c5/2b3ba41ac5b0897b9a940a6feb4671b069d8.pdf. Accessed September 7, 2019.
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18. Ciubotariu D, Ghiciuc CM, Lupusoru CE. Zinc involvement in opioid addiction and analgesia—should zinc supplementation be recommended for opioid-treated persons? Subst Abuse Treat Prev Policy. 2015;10:29.
19. Eserian JK. Vitamin D an effective treatment approach for drug abuse and addiction. J Med Hypotheses Ideas. 2013;7(2):35-39. Available at: https://www.sciencedirect.com/science/article/pii/S2251729413000050. Accessed December 12, 2018.
20. Saeland M, Haugen M, Eriksen FL, et al. High sugar consumption and poor nutrient intake among drug addicts in Oslo, Norway. Br J Nutr. 2011;105(4):618-624.
21. Colantuoni C, Rada P, McCarthy J, et al. Evidence that intermittent, excessive sugar intake causes endogenous Opiod dependence. Obes Res. 2002;10(6):478-488.
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26. Vermeulen-Smit E, Koning IM, Verdurmen JEE, et al. The influence of paternal and maternal drinking patterns within two-partner families on the initiation and development of adolescent drinking. Addict Behav. 2012;37(11):1248-1256.
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Jocelyn Faydenko, ND, was a 4th-year naturopathic and chiropractic medical student at the National University of Health Sciences in Lombard, IL, at the time this article was written. She recently graduated (August 2019) with her ND degree and is currently in her chiropractic internship. Her research interests include cardiovascular disease, addiction, pharmacognosy, and sexual health. Jocelyn was a naturopathic student intern at the Salvation Army Rehabilitation Center in downtown Chicago, where she served patients who are often afflicted with addiction. In addition to tutoring and practicing hapkido, she works as a research assistant to Dr Fraser Smith.

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Fraser Smith, MATD, ND, is the Assistant Dean of Naturopathic Medicine and Professor at the National University of Health Sciences (NUHS) in Lombard, IL. Prior to working at NUHS, he served as Dean of Naturopathic Medicine at the Canadian College of Naturopathic Medicine (CCNM) in Toronto, Ontario. Dr Smith is a licensed naturopathic physician and graduate of CCNM.