How Oxidative Stress and the Hypothalamic-Pituitary-Adrenal Axis May Play a Role by Dr Carrie Decker ND
Addiction: A Stressed, Nutritionally Depleted System
It likely is not a stretch to envision the stressors that the entire human body and mind must endure during battles with addictive substances and/or behaviours. Be it a drug like heroin or cocaine, or a behaviour such as gambling, the addiction takes front and centre. Biological necessities such as sleep and eating recede into the background, predisposing to nutritional deficiencies. Subclinical or even gross malnutrition puts every cell under a state of stress as the body tries to maintain normal function in a state of deficiency. Although nutritional status varies considerably among individuals with substance use disorders and is impacted by the substance of choice, use patterns, and socioeconomic factors, certain facts are worthy of note.
When the substance of choice is alcohol or a drug, the burden on the liver and the kidneys to detoxify these toxins easily multiplies by many factors the encumbrances of nutritional deficiencies. Excessive alcohol intake alters lipid, glucose, and protein metabolism: it inhibits lipolysis, promotes glucose intolerance, and increases protein turnover. Nutritional deficiencies are in part due to dietary inadequacies, but malabsorption, altered hepatobiliary metabolism, and increased renal excretion can also play a role. Deficiencies of folate and phosphatidylcholine (PC) are often seen with excessive ethanol ingestion. The conversion of methionine to S-adenosylmethionine (SAMe), another crucial methyl donor that can assist in glutathione production, is also inhibited with excessive alcohol intake, particularly when it has led to liver disease. With each of these, the methylation of DNA and other processes of methylation become impaired.
In addition to causing deficiencies of folate, PC, and SAMe, which adversely impact methylation and numerous other chemical reactions, excessive alcohol use can also deplete thiamin (vitamin B1), iron, and pyridoxine (vitamin B6). Studies have shown that up to 80% of binge or chronic heavy drinkers experience thiamin deficiency, more than half experience vitamin B6 deficiency, and two-thirds have folate deficiency.,, Deficiencies of other water- and fat-soluble vitamins, as well as minerals and trace elements, can also occur, particularly when higher intake contributes to liver and pancreatic disease.
Statistics on specific nutrient deficiencies with the use of addictive substances other than alcohol are harder to come by, as there is often overlapping use of a variety of addictive substances with alcohol. That being said, one study showed that more than 74% of individuals entering treatment for drug addiction had clinical signs of nutrient deficiency, while testing and symptoms showed multiple nutrient deficiencies in more than 60% of individuals. Significantly lower levels of important nutrients with antioxidant potential (vitamins A, C, and E) were also shown in this population, and were not found to be associated with other potential factors such as income and age. Glutathione, the body’s primary intracellular antioxidant that protects the liver from oxidative stress, has been shown to be significantly lower in chronic alcohol users, with or without the presence of cirrhosis.,
However, the stress of substance use disorders goes beyond nutritional deficiencies and free radicals, and some of these factors, if neglected, can also have an adverse effect on recovery., Dysregulated function of the hypothalamic-pituitary-adrenal (HPA) axis has been identified in both substance use disorders and other behaviours of addiction.,,, Imbalances in the autonomic nervous system response, both prior and subsequent to alcohol use cessation, have also been documented, and are linked to increased cravings.,, Heart rate variability (HRV), a marker of autonomic nervous system tone, is reduced in alcohol-dependent individuals, with an even greater reduction in individuals with comorbid symptoms of anxiety and depression. HRV is generally higher with increased parasympathetic tone, suggesting a high sympathetic state in these populations.
The Often-Neglected Stresses in Psychiatric Disorders
Many similar systemic stressors, including nutritional deficiencies, oxidative stress, and HPA axis and autonomic nervous system dysfunction, also exist in psychiatric illnesses. Mood disorders such as anxiety, depression, and bipolar disorder also often come with altered eating patterns, although usually to a lesser extent than substance use disorders. Depression is associated with lower levels of zinc,.
Higher levels of oxidative stress have been shown in psychiatric disorders including anxiety, depression, bipolar disorder, and schizophrenia.,, Oxidative stress is inherently associated with inflammation, and, perhaps not surprisingly, higher levels of pro-inflammatory cytokines and/or acute-phase reactants such as C-reactive protein (CRP) have been seen in depression,, bipolar disorder, and in men and elderly persons with anxiety. Oxidative damage to cellular membranes alters their fluidity (and, with this, functionality) and contributes to mitochondrial dysfunction; these two effects may play a role in the pathogenesis of psychiatric illness.,, Interestingly, antidepressants have been shown to possibly impact depression by their anti-inflammatory and antioxidative effects.,
Hyperactivity of the HPA axis and increased basal cortisol levels are commonly found in patients with depression. Studies have shown a reduced sensitivity of the glucocorticoid receptor at the level of the hypothalamus and pituitary in depressed individuals, leading to impaired negative feedback., In long-standing anxiety disorders, a lower cortisol awakening response has been observed, although findings from studies investigating total cortisol response are inconsistent. Autonomic nervous system dysfunction also is common in psychiatric illness, and HRV has been shown to be reduced across psychiatric disorders compared to healthy controls.[45
Restoring Balance to the Stressed System
There are many important tools that must be implemented when one chooses, or is forced, to cease the abuse of substances. These include psychiatric therapy, acute medical care (if needed), nutritional support, lifestyle changes, and a variety of medications. For many individuals, problems of substance use coexist with mental health struggles, necessitating an individualised approach to treatment. Unfortunately, relapse rates across all types of addiction are high, and the incidence of substance dependency continues to grow. This leads us to question what evidence exists for directed supplement therapies to help promote long-term recovery.
Reducing Free Radicals with Vitamin C and N-Acetylcysteine
Although in clinic we are often faced with an array of options for antioxidant support, there are some very specific antioxidants that should be considered in settings of mental health and addiction. Two primary powerhouses, with evidence backing their use for both mental health and addiction, are vitamin C and N-acetylcysteine (NAC).
Vitamin C is an important cofactor for the synthesis of several hormones and neurotransmitters made in the adrenal gland. Perhaps not surprisingly, the adrenal glands are among the organs with the highest concentration of vitamin C. Ascorbic acid enhances the production of norepinephrine from dopamine, and ascorbic acid deficiency has been shown to be associated with lower levels of dopamine and serotonin metabolites. Studies suggest vitamin C may be useful in settings of stress: multiple animal studies show reduced depressive-like behaviour and oxidative stress when animals are supplemented with vitamin C.,
Low plasma ascorbic acid levels have been shown to exist in patients with major depression, as well as in patients entering therapy for drug addiction.10, Vitamin C has been shown to positively impact symptoms of anxiety and depression in multiple randomised, double-blind, placebo-controlled trials (RDBPCTs). It also has been studied in settings of addiction, although RDBPCTs are lacking.
In one RDBPCT, high school students not previously described to have anxiety were evaluated at baseline for heart rate and anxiety with the Beck Anxiety Inventory. Students were then given 500 mg of vitamin C or placebo daily for two weeks. When the same parameters were re-evaluated the day after completing the intervention, it was found that both anxiety and heart rate were significantly reduced in the individuals receiving vitamin C. In another RDBPCT, paediatric patients with major depressive disorder were given 1,000 mg of vitamin C or placebo daily as an adjunctive therapy to the medication fluoxetine. In the children receiving the vitamin C, there was a significant decrease in depressive symptoms as measured by the Children’s Depression Rating Scale and Children’s Depression Inventory. Finally, in a randomised, single-blind study, individuals with type 2 diabetes were given 1,000 mg of vitamin C, 400 IU of vitamin E (alpha-tocopherol form), or placebo daily for six weeks. Patients were evaluated with the Depression Anxiety Stress Scale 21-item questionnaire prior to and at the end of the study. Out of all the groups, the only significant change was a reduction in anxiety for the individuals taking vitamin C.
A buffered ascorbate compound has been studied as a supportive therapy for individuals seeking to detoxify from opiates and stimulants at the Haight-Ashbury Free Medical Clinic. Subjects were given a dosage of buffered vitamin C ranging from 1000 to 3000 mg daily and completed a daily questionnaire to track their detoxification symptoms and substance use. Over half of the clients reported at least 60% relief of their acute withdrawal symptoms, while aftercare clients reported symptom relief of 90%. Of note, it was found that the starting date of the buffered ascorbate compound supplement (during the first 10 days of substance cessation vs. after this time) was not a significant factor in the reported benefits of the therapy, and aftercare clients reported significantly greater benefits than those in active detox. The dosage of buffered ascorbate compound was not found to be a factor, suggesting fairly low dosages could be of benefit. In addition to the benefits of the antioxidants provided by this compound, it has been suggested that the use of alkalinising substances (provided in this compound as well) plays a significant role in promoting effective detoxification.
There also is substantial evidence backing the use of NAC in settings of psychiatric disorders and the cessation of addictive behavior and substance use. NAC itself has antioxidant and anti-inflammatory activity,, but possibly more importantly, it provides cysteine, the rate-limiting amino acid for the synthesis of glutathione, the body’s main antioxidant and master detoxifier. NAC has been shown to decrease oxidative stress levels in the body and to reduce homocysteine, which is also often high in individuals with depression and in those who abuse alcohol., Studies have shown that NAC is neuroprotective, crossing the blood–brain barrier and accumulating in the central nervous system; this gives it potential for use in other disorders, including cognitive impairment and traumatic brain injury. NAC has been shown to reduce compulsive behavior via modulation of glutamate, a primary excitatory neurotransmitter that has been demonstrated to be dysregulated in mood disorders and addiction.,,,
Animal and human studies support the use of NAC for the reduction of obsessive-compulsive behaviors. In animal models, NAC has been shown to reduce marble-burying behavior (a typical model used to investigate obsessive-compulsive disorder). Multiple clinical and individual trials in adults and children have been reported, with dosages ranging from 2,400 to 3,000 mg per day, usually for a period of about 12 weeks., Overall, NAC has been shown to reduce the severity of obsessive-compulsive symptoms and be well tolerated.
NAC has also been investigated in multiple clinical trials as an adjunctive treatment for bipolar disorder. At a dosage of 1,000 mg twice daily for 8 to 24 weeks, NAC was shown to significantly reduce the Montgomery-Åsberg Depression Rating Scale and Bipolar Depression Rating Scale scores. A subgroup analysis of patients with bipolar II found that six of seven patients achieved full remission from both depressive and manic symptoms in the NAC group, compared to two of seven in the placebo group. A 2016 systemic review and meta-analysis of the use of NAC for the treatment of depressive symptoms found that in the five studies that qualified for inclusion (including 574 patients), NAC ameliorated depressive symptoms, improved functionality, and was well tolerated.
Given the benefits seen with obsessive-compulsive behaviours and depression, it should not be surprising that an array of studies exists evaluating the potential use of NAC for disorders of addiction. In an open-label outpatient study of cocaine-dependent patients, NAC at dosages of 2,400 or 3,600 mg/day was found to support the termination or reduced use of cocaine. In an additional small, double-blind study in cocaine-dependent patients, NAC at a dose of 2,400 mg/day was found to significantly attenuate the reinforcing effects of cocaine use. In a systemic review of studies related to cocaine addiction, NAC was found in four of the six clinical trials to reduce craving, desire to use cocaine, cocaine-cue viewing time, and cocaine-related spending, with animal models showing a reversal of cocaine use–related disruption of glutamate homeostasis.
In addition to cocaine-use disorder, studies have also looked at the use of NAC for the treatment of smoking cessation, pathological gambling, and alcohol use during cannabis cessation. In a short-term pilot study of smoking cessation, compared to placebo, NAC (at a dosage of 3,600 mg/day) was found to significantly reduce the reward experienced with the first cigarette after a 3.5-day abstinence period. In an open-label study of 27 subjects being treated for gambling addiction, NAC was found to significantly reduce scores related to pathological gambling, with the mean effective dose being 1,476.9 ± 311.3 mg/day. The 16 responders to NAC then entered a double-blind placebo-controlled phase, and of those receiving NAC, 83.3% had improvement of behaviours, compared to 28.6% of those receiving placebo. Finally, in the setting of cannabis cessation (without diagnosed alcohol use disorders, and having no desire to alter alcohol habits), treatment with 1,200 mg of NAC twice daily was found to increase the odds of simultaneous alcohol abstinence, reduce weekly alcohol use, and decrease drinking days.
Rebalancing the HPA Axis and Parasympathetic Nervous System with Ashwagandha and Phosphatidylserine
In addition to addressing the stress on the system in settings of mental health and substance abuse from the perspective of antioxidant therapies, it also is imperative to address the stress-mediating activity of the HPA axis and parasympathetic nervous system dysregulation. Alterations in the HPA axis response are common with addiction and have been shown to be associated with shorter time to relapse.,, Dysregulation of the HPA axis may be a major contributor to insomnia, which is a robust predictor of increased relapse rates for alcohol use and possibly other substances, On the parasympathetic nervous system side, alcohol promotes GABA release from the central amygdala, a factor which plays a role in reinforcing patterns of alcohol use, particularly for anxiety-driven drinking patterns., GABA agonists have thus been proposed as a clinical target for the treatment of both alcohol and substance use disorders.
Indian ginseng (Withania somnifera), commonly known as ashwagandha, has been studied in a wide array of clinical and animal studies. Ashwagandha is considered a nerve tonic and adaptogen; that is, an herb that has been shown to help modulate the body’s response to physical, mental, and emotional stressors. A variety of mechanisms by which ashwagandha can help mediate substance use patterns, improve mental health, and support healthy sleep have been demonstrated in numerous clinical settings. Ashwagandha has been shown to blunt the stress-induced activation of the HPA axis and to interact with GABA receptors., The Latin naming of ashwagandha, somnifera, also reflects the ability of this herb to induce sleep, which may be mediated by both GABAergic signaling and regulation of HPA axis activity. GABAergic signaling is also involved in mediating pain, which ashwagandha has been shown to reduce in humans as well.
Ashwagandha has an array of clinical evidence in support of its use for mental health. A RDBPCT in patients with obsessive-compulsive disorder showed that 120 mg of ashwagandha daily (in addition to ongoing treatment with selective serotonin reuptake inhibitors) significantly improved symptoms as assessed by the Yale-Brown Obsessive Compulsive Scale when reassessed at six weeks. Multiple clinical trials have shown that ashwagandha reduces anxiety,, with a systemic review showing significant benefit of ashwagandha over placebo. Although ashwagandha has not been studied in clinical settings of substance use and addiction, animal models have shown that it helps to reduce alcohol withdrawal–associated symptoms,
Phosphatidylserine (PS) is another substance that has been shown to regulate the HPA axis response to stress. PS is a phospholipid found in the body’s cellular membranes, including the neurons and the myelin that protects them both centrally and peripherally. In the brain, PS plays an important role in neurotransmitter release and cellular signaling. PS has also been shown to stimulate GABA uptake in neuronal cells., Ethanol inhibits neuronal accumulation of PS, contributing to cellular apoptosis and possibly deficits in brain function. Essential fatty acid deficiencies further contribute to diminished levels of obligatory PS in the neuronal membranes.
Multiple clinical studies have demonstrated the impact PS has on the stress-related response as well as mood. PS has been shown to modulate the HPA axis response to both physical and social stressors; after a short period of supplementation, PS reduces the typical rise in both adrenocorticotropic hormone (ACTH) and cortisol from these typical stressors.99, In a RDBPCT with a population of males under chronic stress, a combination of PS with phosphatidic acid (PA), another phospholipid which comprises much of the cellular membrane, was shown to significantly normalize the ACTH and cortisol response in those under chronically higher levels of stress than the group as a whole. Improvements in mood have been seen in both healthy populations and those with mood-related issues. After one month of supplementation of 300 mg of PS daily, healthy young adults reported feeling less stressed and being in a better mood. Mood-related benefits of PS supplementation also have been seen in elderly women with depressive disorders (along with improvements in memory) and women with premenstrual syndrome.
Although the challenges when supporting patients with mental health issues and addiction are vast, vitamin C, NAC, ashwagandha, and PS each have many potential mechanisms by which they can help. Clinical evidence justifies their use on both a short- and a long-term basis in supporting these populations.
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