Addictive Behaviour is on The Rise: How Integrated Genetics Can Help

Several months of non-stop uncertainty, stress and constant readjustment are taking its toll on mental health. Levels of stress and anxiety are skyrocketing across the globe. What’s else is going up in direct correlation to stress levels? Addictive behaviour.

Beyond Drugs and Alcohol: Expanding Our View of Addictions

A shocking 20% of the population will experience an addiction during their lifetime. And while drugs, alcohol and food are the most recognized, the truth is, we can become addicted to any substance or activity that provides a ‘dopamine reward’. For example, renowned addiction and trauma therapist Dr. Gabor Mate MD has spoken frankly about his own addiction to buying classical music CDs, spending as much as $8,000 per week²¹. 

Broadening our view of what constitutes an addiction can help us see addiction patterns in patients that we may not have recognized before. Are your patients compulsively engaging in any of these activities?

• Exercise
• Work
• Gambling
• Sex
• Internet use
• Shopping 
• Pornography

We must consider the impact that engaging in these activities has on quality of life. Are compulsive behaviours negatively affecting patients’ work performance? Are they socially isolating to engage in these behaviours? Are there adverse health consequences?

Long before the pandemic, addictive behaviour was widespread throughout Canada and the U.S. Now, with the additional stress of the current crisis, your patients that were already struggling with addictions are now at serious risk of relapse. You may even find that some patients have developed addictions during the pandemic that they hadn’t presented with before.

As health care practitioners, we recognize addictions as maladaptive coping mechanisms. How can you support your patients struggling with addictions through integrated genetics? Let’s take a look at how genetics can help you reduce your patients’ addiction risk, curb cravings, and vastly improve their quality of life.

How Reward Pathways Work: The Role of the Ventral Tegmental Area

Do you have points cards for your favourite stores? Do you collect Air Miles? Rewards are so integral a part of our lives that we scarcely realize their power. It is this reward system that is central to our understanding of addictions. 

The complex nature our reward system is demonstrated by the fact that it incorporates so many areas and pathways in the brain. The Ventral Tegmental Area (VTA) is the initial site of activation through opioid, nicotinic and cannabinoid receptors. Dopamine (DA) is then released through the mesolimbic dopamine system (MDS) to the nucleus accumbens (NAc) and limbic system. This is the initial key pathway involved in reward and addiction. Its primary role is to promote motivational behaviour in response to reward-predicting stimuli. 

In humans, certain drugs such as cocaine and alcohol, or certain energy-dense foods such as sweets and saturated fats, release DA into the NAc leading to an artificial reward. The amygdala then processes this information for its perceived metabolic value, i.e. hedonistic or pleasurable value of taste. Such situational, emotional and hedonistic cues often drive our behaviours. Have you ever had an after-dinner piece of chocolate cake even though you feel full? That’s the power of our reward pathways at work.

Disruption of the dopamine reward pathways can predispose to further addiction. Drugs such as cocaine, alcohol and nicotine reduce dopamine receptor availability, while cannabis results in impaired dopamine reactivity to stimuli²³. The long-term effect on brain neurochemistry leads to increased dependence and risk of “gateway effect”. This is most marked in younger individuals (teens and twenties) where the brain is still maturing.

“44.7% of individuals with lifetime cannabis use progressed to other illicit drug use”¹⁶

Recent Ventral Tegmental Area (VTA) Research

A number of studies have demonstrated the primary role of the VTA in promoting motivational behaviour in response to reward-predicting stimuli. An April 2020 study¹¹found an accumulation of histone H3 glutamine 5 dopaminylation (H3Q5dop) in the VTA of rats in cocaine withdrawal. When the H3Q5dop in the VTA was reduced during withdrawal, cocaine-mediated gene expression changes were reversed, attenuating dopamine release in the NAc, and reducing cocaine-seeking behaviour.

The VTA is contains 60 – 65% dopaminergic neurons, the primary focus of most addiction research. However, a 2017 review¹⁰demonstrated that the non-dopamineVTA neurons (30% GABA and 5% glutamate) strongly impact dopamine signalling, thus also playing a role in addictive behaviour.They also note the association between diminished dopamine levels in the NAc and dysphoric and negative feelings of drug withdrawal, which play an important role in compulsive cravings and relapse risk.

Stress and the Reward Pathway

Acute and chronic stress significantly affects VTA function and increases the risk of addiction relapse. Stress-induced increases in corticotropin-releasing factor (CRF) can modulate VTA dopamine neurons and enhance dopamine signaling in the NAc⁷, similar to many addictive drugs²⁰. It may thus contribute to feelings of withdrawal, leading to increased reward-seeking behaviour. 

Chronic stress can have very different effects on dopamine release, depending on the nature, intensity and frequency of the stressor. Even a single stress exposure can contribute to long-lasting neuroadaptive changes in VTA dopamine neurons, thus potentially altering neuron responsivity to future stress or reward stimulation⁶. 

Incentive Salience and Cravings

What happens when the body receives a steady stream of addictive foods or substances? The MDS undergoes neurochemical remodelling that reorganizes the reward and memory circuits. It is these changes that lead to the heightened responses and cravings known as “incentive salience”. 

These neuroadaptations in the dopamine incentive salience system can occur early in the addiction process⁴. This is the internal struggle that makes withdrawal so difficult. Seeing or even thinking about the substance can bring on cravings so powerful, they are almost impossible to ignore. 

“Alcohol: Statistics Canada reports 20% of the population are heavy drinkers”

Genes That Impact Addictions

Examining our patients’ genetic profiles can tell us who is most at risk of developing addictions, who may struggle with withdrawal the most, and who has a higher risk of relapse after recovery. It can also point us towards which lifestyle factors are most impactful, and which treatment strategies will have the greatest effect. Let’s take a closer look at 8 key genes.

DRD2 and ANKK1: Dopamine Receptor Availability

If dopamine is present but there aren’t enough receptors to bind it, the brain perceives this as a dopamine shortage. Where there is low DRD2 receptor availability (the receptors that bind DA), there is increased demand for dopaminergic stimulation leading to increased intake of a rewarding substance or higher frequency of rewarding activity. Similarly, low DA production can also lead to behaviours that promise dopamine stimulation.  

The genes DRD2 and DRD2/ANKK1 regulate the production of proteins that form the DRD2 receptor, and thus determine the strength of dopaminergic activity. Patients who are variant for DRD2 and ANKK1 genes have far fewer DRD2 receptors and dopamine potential activity. This means higher risk of addictive behaviours. 

A number of studies^{7, 9} have linked specific SNPs in these genes to increased risk of addiction and a 2019 study²linked DRD2 methylation, which impairs gene transcription,to increased alcohol use and dependence. 

COMT and MAOA: Dopamine Metabolism and Clearing

The genes COMT and MAOA are key dopaminergic players, controlling how quickly we can break down and clear DA from the body. Patients who are normal for COMT and MAOA clear dopamine very quickly, leading to lower overall levels of dopamine activity. Like those with a variant DRD2 and ANKK1 gene, this genetic coding can also lead to more addictive behaviour. 

Other genes also exert an influence, which, once again, speaks to the importance of integrated genetics. A 2019 study⁸found that those carrying both the BDNF (Brain Derived Neurotrophic Factor) and COMT gene variants drank significantly more alcohol, had more health problems, and showed lower motivation to change drinking patterns. Interestingly, these results were not replicated for variants of each gene alone. 

FKBP5 and NR3C2: How We Handle Stress
The link between stress and addictions is well-established. Chronic stress means chronic secretion of cortisol, adrenaline and noradrenaline, with a focus on cortisol. Cortisol inhibits DA production and turns an astonishing 90% of genes to their adverse position. 

Genes such as FKBP5 and NR3C2 that determine how quickly the stress response turns off after a stressor is resolved are key. Individuals, who code poorly for these genes, have a hard time shifting back to the parasympathetic side of the nervous system from the sympathetic side once the stressor is over. The longer stress hormones circulate, the more they block dopamine production, impair dopamine receptors and alter dopamine gene expression. 

FKBP5 has been linked to the later effects of childhood trauma on the HPA axis, including increased adult risk of chronic stress, PTSD and addictions. A 2019 study¹⁴points to the role of methylation of FKBP5 in regulating adult HPA axis activity, while another study¹³suggests that variant allele carriers of the FKBP5 SNP who experience early life trauma may be at higher risk of heavy drinking as adults. A study exploring stress genes and addiction¹²concludes that variations in the FKBP5 gene contribute to the development of opiate addiction by modulating the stress response. 

FTO and MC4R: Food Addiction

These are the genes to examine in your patients who can’t stop eating, despite their best efforts. 

Ghrelin (the hunger and food-seeking hormone) directly stimulates the brain’s dopaminergic pathways just as a drug would do⁵. Patients who have variant and heterozygote coding for FTO and MC4R have high ghrelin levels making them far more prone to addictive behaviours, especially consumption of energy-dense foods. 

“20% of Canadians have food addiction”¹⁵

Hunger (ghrelin) and satiety (leptin) hormones may also play a role in alcohol addiction. In one study⁵individuals with one or two A alleles for the FTO SNP had increased odds of being diagnosed with alcohol dependence. Another study¹⁸demonstrated that reductions in blood ghrelin and increases in blood triglycerides were associated with reduced responses in brain regions associated with reward and feeding. This supports the finding of another study³showing that triglycerides may affect reward processes associated with eating foods high in fats and sugars.

“Having one MC4R variant gene allele (C) increases obesity risk by 8% ”

MC4R interacts with serotonin and dopamine pathways to influence food intake through both satiety and reward. There is also evidence that MC4R signaling may be involved in triggering stress-induced synaptic adaptations in the NAc. A 2015 study²²was the first to demonstrate the indirect effect of the MC4R SNP on increased BMI via emotional eating and strong food cravings.

Putting it all together, a 2018 review¹⁸notes the importance of hypothalamic neuropeptides such as the previously mentioned CRF, as well as propriomelanocortin (POMC), the orexigenic neuropeptide Y (NPY), agouti-related peptide (AgRP), and melanocortin receptors in both regulating the stress response and influencing eating behaviours. They conclude that “…the interactive dynamic effects of neurobehavioral adaptations in metabolic, motivation and stress neurobiology may further support food craving, excessive food intake and weight gain in a complex feed-forward manner.” 

Using Integrated Genetic Analysis to Ask the Right Questions

Knowing how your patients code genetically not only reveals their susceptibility but also the best way to treat them. Looking at these 8 genes can give you valuable information about:

• Dopamine production
• Dopamine receptor availability
• Dopamine clearance ability
• Stress hormone and ghrelin production
• Stress clearance ability

But how do you use this information to decide what treatment target to focus on? Is it by inhibiting the clearance of dopamine through COMT or MAOA, or by inhibiting the production of stress hormones that are blocking dopamine production? Throwing more dopamine into a system that has very few receptors is not always the answer, and can make things worse.

How about supporting dopamine by balancing ghrelin through FTO and MC4R? Is a combination of treatments needed to fully balance dopamine and conquer addiction once and for all? Leaving out even one variable can lead to ineffective treatment that that fails to fully address the problem.  

Get the Right Answers with the GeneRx Report

As with all health conditions, when considering genetics, it is key to integrate the genes together. Any genetic report will show your patients’ coding for these individual genes. But how do you analyze these 8 genes together to design treatment protocols that get results?

Addictions require a truly complete, integrated and individualized treatment. My GeneRx reportis structured so you can easily find the relevant genes, their variant coding and implications for patient care. For your patients struggling with addictive behaviour, the Metabolic, Diet and Neurotransmitter sections of the report will give you concrete supplement, dietary and lifestyle recommendations based on evidence-based, integrated genetic analysis. 

Addictions are frustrating and potentially harmful. Help your patients tackle their addictions head-on and improve their quality of life with GeneRx?

What’s in the full report? Take a look at this exampleor watch this short video.

Ready to get started? Learn how easy it is to create an account, upload a file and edit a report HERE. 

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