Heavy Metal Toxicity 

 

• Arsenic

• Lead

• Cadmium

• Mercury 

 

Research has found that exposure to the heavy metals particularly arsenic, lead, and cadmium interfere with the brain’s dopamine system. Studies have shown that when mice were exposed to these metals in their drinking water, dopamine levels in the striatum dropped noticeably. This occurred because the metals reduced the activity of enzymes and transport proteins needed to make, move, and store dopamine. While each metal alone caused a reduction in dopamine, the combined exposure had a much stronger effect, leading to significant dopamine loss. [75]

 

Further studies have also demonstrated Mercury reduces dopamine uptake in rat brain, interfering with the ability of brain cells to reabsorb dopamine after release, which is essential for normal neurotransmission. [76]

Chronic Marijuana use 

 

Initial exposure to cannabinoids, such as those in marijuana, increases dopamine activity by reducing GABAergic inhibition. This disinhibition allows dopamine neurons to fire more readily, temporarily enhancing dopamine release. However, with chronic use, particularly of THC, the primary psychoactive compound, this effect becomes detrimental.

 

Long-term THC exposure overstimulates CB1 receptors, leading to dopaminergic downregulation and receptor desensitization. These neuroadaptations disrupt the brain’s dopamine balance, 

contributing to low motivation, cognitive impairment, and attention deficits.

 

Functional neuroimaging studies have also shown reduced dopamine synthesis and signaling in chronic cannabis users, especially in regions such as the ventral striatum and prefrontal cortex. These changes diminish responsiveness to natural rewards, resulting in an increased reliance on cannabis to achieve pleasurable or motivating effects.

 

Furthermore, THC withdrawal exacerbates dopamine suppression, producing symptoms like depression, irritability, sleep disturbances, and cravings. These effects contribute to the cycle of 

continued use and relapse.

 

Over time, chronic cannabis use impairs the brain’s reward circuitry and diminishes its capacity to recover, potentially leading to long-lasting or persistent dopaminergic dysfunction if use is not moderated or discontinued [29,30].

 

Chronic Alcohol Consumption

 

In the early stages of drinking, alcohol increases dopamine release in brain areas like the nucleus accumbens, which creates feelings of pleasure and reward. This dopamine surge helps reinforce alcohol use, making the brain learn to associate alcohol and related cues, like people and places with reward and motivation.

 

However, with repeated heavy drinking, the brain undergoes significant changes. Tolerance develops, and alcohol’s ability to stimulate dopamine and produce pleasure decreases. Over time, dopamine signaling becomes blunted, meaning the brain releases less dopamine and becomes less responsive to natural rewards. 

 

In parallel, chronic alcohol use leads to a shift in brain control from the prefrontal cortex, involved in conscious decision-making, to habitual circuits in the basal ganglia, where behaviors become automatic, even if the experience of alcohol brings no pleasure itself.

 

In the long term, chronic alcohol consumption leads to persistent dopaminergic dysfunction, where the brain becomes less sensitive to both alcohol and natural rewards and compulsive drinking patterns form [31].

 

Cigarettes

 

When nicotine first enters the body, it stimulates the release of dopamine, particularly within the brain’s mesolimbic reward system, a key pathway involved in pleasure and reinforcement. In addition to triggering dopamine release, nicotine also inhibits the enzymes monoamine oxidase A and B (MAO-A and MAO-B), which normally break down dopamine. This dual action leads to a short-term surge in dopamine levels, contributing to the immediate pleasurable effects of smoking.

 

However, with repeated exposure, the brain undergoes significant adaptations. One major change is the desensitization and subsequent upregulation of nicotinic acetylcholine receptors (nAChRs), especially the α4β2* subtype, which plays a critical role in regulating dopamine release. Although more of these receptors are produced, they are less functional. As a result, the brain’s ability to release dopamine diminishes sharply, by up to 70%, even when exposed to strong reward-related stimuli [32,33].

 

This reduction in dopamine activity weakens the brain’s capacity to experience pleasure naturally. Over time, nicotine use becomes necessary not to feel good, but simply to feel normal, reinforcing the cycle of addiction.

 

Addictive Drugs

 

Overall all major addictive drugs, such as opiates, amphetamines and cocaine disrupt normal dopamine function. It has been hypothesised that these altercations in dopamine take place to balance the unnatural drug-induced highs, but ultimately it leads to a dopamine-impoverished brain, causing a loss of pleasure from normal activities, and further drug-seeking behaviour [34]. 

 

Chronic Stress 

 

Dopamine shows dynamic changes during stress, where initially, stress increases dopamine levels, supporting active coping strategies like escape or resistance. However, in situations that are perceived as uncontrollable or inescapable, dopamine levels drop.

 

One study demonstrated that people with long-term exposure to psychosocial stress, such as childhood trauma, discrimination, and adult life adversity, show reduced dopamine synthesis in the brain’s striatum, particularly in regions linked to emotion and motivation. 

 

These individuals had a mismatched response to acute stress, where they felt more psychologically threatened but had a weaker physiological response, indicating the impact of low dopamine itself.

 

In contrast, people with low adversity exposure showed a balanced link between dopamine levels and both emotional and physiological stress responses. The study highlighted that chronic stress can biologically reshape dopamine function and affect the stress response systems [35,36].

 

Excessive Screen Time

 

When repeatedly engaging in compulsive dopamine surge behaviors, such as excessive screen time, the mesolimbic dopamine pathway, central to reward processing, becomes desensitized through constant artificial stimulation. This dysregulation is called the "anti-reward state", which means that more screen time is needed just to feel baseline pleasure, while genuine, healthy rewards lose their appeal. This pattern is a hallmark of dopamine dysfunction and behavioral addiction.

 

These changes are not just behavioral, they reflect deep neurochemical and structural adaptations in the brain’s reward circuitry, often reinforced by chronic stress.

 

As in example, in the COVID-19 pandemic, this was intensified by Social isolation, disrupted routines, and widespread reliance on digital "rewards", which increased compulsive behaviors worldwide. When people turned to digital content for comfort and stimulation, dopamine systems were "hijacked", reinforcing unhealthy habits that habituate more dopamine dysfunction [37,38]. 

 

Social Isolation 

 

Chronic social isolation has been shown to decrease levels of dopamine D2 receptor in the nucleus accumbens (NAcc) and medial prefrontal cortex. This exerted a decrease in activity within the regions of the brain responsible for eliciting reward value to social interactions and also navigating appropriate social responses, encouraging further social avoidance [39]. 

 

SIBO 

 

Small Intestinal Bacterial Overgrowth (SIBO) contributes to elevated levels of lipopolysaccharides (LPS), an inflammatory endotoxin produced from Gram-negative bacteria, which naturally produce LPS as part of their outer membrane. It has been demonstrated that LPS induced chronic inflammation causes:
 

• Reduces dopamine release in the striatum

• Decreases D2 receptor binding

• Leads to dopaminergic neuronal damage and loss

• Suppresses tyrosine hydroxylase activity, the enzyme crucial for dopamine synthesis [40]

 

Dysbiosis

 

Certain gut microbes can produce dopamine precursors like L-DOPA or express enzymes that facilitate dopamine synthesis. However, in circumstances of dysbiosis, when the gut microbiota becomes imbalanced, the abundance of these dopamine-producing bacteria declines, leading to reduced dopamine synthesis.

 

Experimental studies show that disrupting gut bacteria with antibiotics significantly lowers brain dopamine levels. Conversely, restoring a healthy microbiota via probiotics, fecal transplants, or dietary changes can reverse dopamine deficits and improve cognitive performance.

 

It is important to note that although gut produced dopamine itself cannot cross the blood–brain barrier, its precursor L-DOPA can, making the gut a key contributor to brain dopamine supply. Dysbiosis impairs both the production and transport of these essential precursors, potentially disrupting brain function and behavior [41].
 

High Fat Diets

 

High-fat foods activate the brain’s dopamine-based reward system, driving pleasure and motivation to eat. However, chronic overconsumption of fatty foods can dull this dopamine response by negatively impacting Oleoylethanolamine (OEA), which is part of the gut-brain communication system. The results of which demonstrate reduced reward sensitivity and prompts compensatory overeating [42]. 

 

Iron deficiency

 

In the prefrontal cortex, iron deficiency causes dopamine to be broken down too quickly due to higher activity of an enzyme called MAO. This means dopamine is cleared out faster than normal.

 

Furthermore, iron deficiency has been shown to reduce Phenylalanine hydroxylase (PAH) by 56%. PAH is a liver enzyme that enables the conversion of phenylalanine to tyrosine, and tyrosine is the amino acid required for dopamine synthesis.

 

Iron deficiency is also associated with lower production of the dopamine receptor D2, which is a dopamine regulator, preventing over-stimulus and aggravation. Clinical studies have demonstrated alleviating iron deficiency is effective for reducing restless leg syndrome as well as symptoms of ADHD, with a note that there is a 3.8 x greater risk of developing ADHD with iron deficiency [43,44,45,46,47]. 

 

Tyrosine deficiency

 

Tyrosine is used by the enzyme tyrosine hydroxylase, which is considered one of the most important enzymes for dopamine, due to its role in converting Tyrosine into L-DOPA, with L-DOPA beign the direct precursor to dopamine. 

 

Studies have demonstrated that tyrosine supplementation can boost dopamine, but only when tyrosine is deficient. Adding additional tyrosine will not improve dopamine production [48,49].

 

B6 Deficiency

 

Vitamin B6 (B6) plays a crucial role in dopamine synthesis, acting as a cofactor for the enzyme dopa-decarboxylase. This enzyme converts the amino acid L-dopa into dopamine. B6 deficiency therefore can disrupt dopamine production [50].