The versatile vitamin’s mechanisms of action

 

This article serves as Part 3 in my series on vitamin C, pain, and opioid use disorder.

Check out Part 1 to learn about the vitamin’s use in the management of pain; in Part 2 I dive into its potential for easing opioid withdrawal symptoms and drug cravings.

 

A vitamin for drug cravings? Really?

Vitamin C (ascorbic acid, AA) is an essential nutrient in humans, meaning we cannot make the vitamin in our bodies and therefore need to consume it in our diets or from nutritional supplements. While most people know of vitamin C as an important nutrient for immune support, few people are aware of the vitamin’s role in the treatment of addictions.

Vitamin C is vital to a multitude of metabolic pathways — including those affecting mental health, addiction, stress response, and pain perception.

Specifically, vitamin C may help those with opioid use disorder (OUD, or “opioid addiction”) have fewer drug cravings and less intense symptoms of withdrawal when they either reduce their dosage of opioids or stop using them altogether. This is great news, especially when we consider that drug overdose is the leading cause of death among Americans under the age of 50,¹ and that opioids — drugs like oxycodone, hydrocodone, morphine, heroin, codeine, and fentanyl — are implicated in overdose deaths more than any other drug class, ending more lives than guns, breast cancer, or car accidents.² In short: OUD is the deadliest drug crisis in American history.^3,4

Opioid use disorder (opioid addiction) is the deadliest drug crisis in American history.

That’s in large part because it is incredibly difficult to overcome OUD. For the person with OUD, any significant reduction in their daily drug regimen can lead to debilitating cravings and at times horrifically unpleasant symptoms of withdrawal – symptoms like severe pain, abdominal cramping, diarrhea, nausea and vomiting, sweating, agitation, insomnia, and elevated blood pressure and heart rate.⁵ In fact, the term “quitting cold turkey” comes from a description of the goose bumps that can form on a person’s skin as they go through withdrawal, giving the skin an appearance similar to that of uncooked poultry.

There are a number of mechanisms by which vitamin C may help people with OUD reclaim their lives and their sobriety:

Antioxidant support

Vitamin C supports both the immune system and mental health through its antioxidant activity. By scavenging a variety of reactive oxygen species (ROS), vitamin C protects our cells (including those of the central nervous system) against oxidative damage.^6,7

A shockingly high number of psychiatric disorders – including anxiety,^8,9 depression,^10–12 bipolar disorder,^13,14 panic disorder,^15,16 obsessive-compulsive disorder (OCD),¹⁷ and schizophrenia – are associated with excess oxidative stress.^18,19 Antioxidants are therefore crucial for mental health.^20–22

The longer a person had been using heroin, the more oxidative stress their body was under.

A study of 137 individuals addicted to heroin revealed that this population experiences a high rate of oxidative injury as compared to healthy controls.²³ Another study found that the longer a person had been using heroin, the more oxidative stress their body was under – and the injury to the cells was correlated with low levels of vitamin C and other antioxidants.²⁴

Fortunately, numerous animal studies show that vitamin C can battle oxidative stress and reduce depression.^25,26 Vitamin C has also been shown in multiple randomized, double-blind, placebo-controlled trials in human subjects to help not only with opioid addiction, but also with depression and anxiety.^27–29 (People with mental health conditions like anxiety and depression are three times more likely to use opioids than the general population.³)

Glutathione recycling

Vitamin C also preserves glutathione, A.K.A. “the master antioxidant” in our red blood cells and liver cells.

Opioid medications deplete glutathione levels in the body, thus enabling a vicious cycle of worsening pain, which requires more opioid usage, which further depletes glutathione levels, and thus in turn perpetuates pain.^30,31

Just 500 mg of vitamin C supplemented daily was shown in one clinical trial to increase mean red blood cell glutathione levels by almost 50% after just two weeks.³² Vitamin C and glutathione have also been shown to completely reverse opiate-induced liver damage in rats.³³

Anti-inflammatory effects

Oxidative stress and inflammation are birds of a feather: where you find one, the other is soon to follow. Inflammatory markers like C-reactive protein (CRP) are often elevated in those with depression and other mood disorders.^34–37 Conventional pharmaceutical antidepressants (SSRIs, etc.) work in part by their anti-inflammatory and antioxidant effects,^39,40 further illuminating the role of inflammation on mood.

Fortunately, vitamin C has been shown to dramatically decrease various markers of inflammation, including CRP, tumor necrosis factor (TNF), interferon, and interleukins.³⁸

Neurotransmitter support

Vitamin C supplementation may thus support the body’s synthesis of important neurotransmitters.

Tetrahydrobiopterin (also known as THB or BH₄) is required for the biosynthesis of several neurotransmitters, including serotonin, melatonin, dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Vitamin C supports brain chemistry by recycling THB.^41,42

Vitamin C is also necessary for the body’s conversion of dopamine into norepinephrine. Perhaps unsurprisingly, animals deficient in vitamin C have been found to also have low levels of norepinephrine.^43–45

Vitamin C has also been shown in rats to modulate the actions of dopamine and glutamate, an excitatory neurotransmitter. This is yet another mechanism by which vitamin C may dampen tolerance and withdrawal,^46,47 as both the glutamatergic and dopaminergic systems are involved in opiate addiction.⁴⁸

Adrenal support

The adrenal glands, which sit atop each kidney, are central to our response to both physical and emotional stress. The cortex, or “crust” of these glands produces not only the stress hormone cortisol, but also vitamin C as part of the normal stress response.⁴⁹ Vitamin C helps the body bounce back from the cortisol surge that follows stress.⁵⁰ In fact, an inverse relationship between cortisol and vitamin C has been observed in humans, suggesting that high cortisol levels – and the poorer health outcomes associated with them – may be caused by vitamin C deficiency.⁵¹ Low vitamin C is also correlated with fatigue in humans.⁵²

Vitamin C helps the body bounce back from the cortisol surge that follows stress.

It is well accepted that substance use disorders are a maladaptation to trauma and stress.⁵³ This means that supporting adrenal health may both prevent and treat addictions.

While vitamin C is stored in many places throughout the body, the highest concentrations are found in the nervous system and in the adrenal glands.⁵⁴,⁵⁵ Because humans cannot endogenously synthesize the nutrient, however, and because the adrenals secrete vitamin C as part of the stress response,^49,55 our vitamin C stores become taxed in stressful situations. Supplementing with vitamin C through the diet and/or supplements may therefore be helpful during times of stress.⁵⁰

In the case of animals that can produce their own endogenous vitamin C, it has been observed that their production of the nutrient increases 300 to 500% during times of stress, disease, and injury.⁵⁶,⁵⁷,⁵⁸,⁵⁹

A randomized, placebo-controlled human trial found that those who took 3 grams of vitamin C daily enjoyed lower blood pressure, faster cortisol recovery, and fewer subjective feelings of being “stressed” than those who didn’t get vitamin C.⁵⁰

Endorphins

Finally, vitamin C may also help with OUD via analgesic (pain-killing) effects by playing a role in amidated opioid peptide production.⁶⁰,⁶¹ Vitamin C is a cofactor for the enzyme peptidylglycine α-amidating monooxygenase (PAM),⁶² the only known enzyme that makes essential modifications to peptide hormone precursors in humans.⁶³ Giving vitamin C to animals has been shown to increase the production of PAM-derived hormones.⁶⁴

Vitamin C supplementation may support the synthesis of endomorphins.

Vitamin C supplementation may thus support the synthesis of endomorphins, natural opioid neurotransmitters that relieve pain. Inadequate vitamin C levels may lead to a lack of analgesic neurotransmitters and neuropeptide hormones and thus result in pain.

Correcting nutritional deficiency

While severe vitamin C deficiency (hypoascorbemia) can lead to the “pirate’s disease” known as scurvy,⁶⁵ milder deficiencies of vitamin C can also wreak havoc our health.⁶⁶ Specifically, people entering drug treatment and those with major depressive disorder (MDD) have been observed to have low plasma levels of vitamin C and other antioxidants. ⁶⁷,⁶⁸,⁶⁹,⁷⁰

We know that people who use and abuse substances long term tend to have incomplete diets, compromised digestion, and resulting nutritional deficiencies.⁷¹ This is especially the case in OUD, as opioid drugs cause a slew of digestive troubles.⁷² Those digestive issues lead to poor nutritional intake, which then contributes to nutritional deficiencies, which cause poor stress coping and sub-optimal neurotransmitter production, which in turn reinforce addictive behavior.

Wired for C

In the human body, the highest concentrations of vitamin C are found in the nervous and endocrine systems,⁷³ where it is essential to our pain-relieving, addiction-fighting biochemistry.⁶¹

Vitamin C is a potent antioxidant and anti-inflammatory agent. It is also necessary for the body’s normal stress response, and supports the synthesis of important neurotransmitters and possibly even endomorphins. In these ways, vitamin C may help prevent and treat opioid addiction.

Check out my other blog posts on vitamin C – like studies on vitamin C’s potential in treating addiction, and information about vitamin C’s pain-relieving effects.

 

References

1. Cullen T. Opioid overdoses kill more people in U.S. than guns or breast cancer [Internet]. New York (NY): New York Daily News; 2017 [cited 2021 May 19]. Available from: https://www.nydailynews.com/news/national/opioid-overdoses-kill-people-u-s-car-accidents-article-1.3713354
2. Overdose death rates [Internet]. Bethesda (MD): National Institute on Drug Abuse (NIDA); 2021 [cited 2021 May 19]. Available from: https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates
3. Salmond S, Allread V. A population health approach to America’s opioid epidemic. Orthop Nurs. 2019;38(2):95-108.
4. Katz J. Short answers to hard questions about the opioid crisis [Internet]. New York (NY): The New York Times; 2017 [cited 2021 May 19]. Available from: https://www.nytimes.com/interactive/2017/08/03/upshot/opioid-drug-overdose-epidemic.html
5. Case-Lo C, Legg TJ. Opioid and opiate withdrawal: symptoms and treatments [Internet]. New York (NY): Healthline; 2019 [cited 2021 May 19]. Available from: https://www.healthline.com/health/opiate-withdrawal
6. Buettner GR. The pecking order of free radicals and antioxidants: lipid peroxidation, α-tocopherol, and ascorbate. Arch Biochem Biophys. 1993;300(2):535-43.
7. Carr A, Frei B. Does vitamin C act as a pro‐oxidant under physiological conditions? FASEB J. 1999;13(9):1007-24.
8. Vaváková M, et al. Markers of oxidative stress and neuroprogression in depression disorder. Oxid Med Cell Longev. 2015;2015:898393.
9. Bouayed J, et al. Oxidative stress and anxiety: relationship and cellular pathways. Oxid Med Cell Longev. 2009;2(2).
10. Maria Michel T, et al. The role of oxidative stress in depressive disorders. Curr Pharm Des. 2012;18(36):5890-9.
11. Black CN, et al. Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology. 2015;51:164-75.
12. Moylan S, et al. Oxidative & nitrosative stress in depression: why so much stress? Neurosci Biobehav Rev. 2014;45:46-62.
13. Berk M, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35(3):804-17.
14. Andreazza AC, et al. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord. 2008;111(2-3):135-44.
15. Ersoy MA, et al. Role of oxidative and antioxidative parameters in etiopathogenesis and prognosis of panic disorder. Int J Neurosci. 2008;118(7):1025-37.
16. Gul IG, et al. The effect of agoraphobia on oxidative stress in panic disorder. Psychiatry Investig. 2013;10(4):317-25.
17. Kandemir H, et al. Oxidative imbalance in child and adolescent patients with obsessive compulsive disorder. J Psychiatr Res. 2013;47(11):1831-4.
18. Ng F, et al. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol. 2008;11(6):851-76.
19. Smaga I, et al. Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism. Pharmacol Rep. 2015;67(3):569-80.
20. Allen J, et al. Mitochondria and mood: mitochondrial dysfunction as a key player in the manifestation of depression. Front Neurosci. 2018 Jun 6;12:386.
21. Jou S-H, et al. Mitochondrial dysfunction and psychiatric disorders. Chang Gung Med J. 2009;32(4):370-9.
22. Tsuboi H, et al. Depressive symptoms are independently correlated with lipid peroxidation in a female population: comparison with vitamins and carotenoids. J Psychosom Res. 2004;56(1):53-8.
23. Zhou J, et al. Primary studies on heroin abuse and injury induced by oxidation and lipoperoxidation. Chin Med J. 2001;114(3):297-302.
24. Zhou J, et al. Heroin abuse and nitric oxide, oxidation, peroxidation, lipoperoxidation. Biomed Env Sci. 2000;13(2):131-9.
25. Moretti M, et al. Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress. J Psychiatr Res. 2012;46(3):331-40.
26. Moretti M, et al. Protective effects of ascorbic acid on behavior and oxidative status of restraint-stressed mice. J Mol Neurosci. 2013;49(1):68-79.
27. de Oliveira IJL, et al. Effects of oral vitamin C supplementation on anxiety in students: A double-blind, randomized, placebo-controlled trial. Pakistan J Biol Sci. 2015;18(1):11-18.
28. Amr M, et al. Efficacy of vitamin C as an adjunct to fluoxetine therapy in pediatric major depressive disorder: a randomized, double-blind, placebo-controlled pilot study. Nutr J. 2013;12(1).
29. Mazloom Z, et al. Efficacy of supplementary vitamins C and E on anxiety, depression and stress in type 2 diabetic patients: a randomized, single-blind, placebo-controlled trial. Pakistan J Biol Sci. 2013;16(22):1597-1600.
30. Jairaj M, et al. The toxicity of opiates and their metabolites in HepG2 cells. Chem Biol Interact. 2003;146(2):121-9.
31. Mannelli P, et al. Opioid use affects antioxidant activity and purine metabolism: preliminary results. Hum Psychopharmacol. 2009;24(8):666-75.
32. Johnston C, et al. Vitamin C elevates red blood cell glutathione in healthy adults. Am J Clin Nutr. 1993;58(1):103-5.
33. Zhang Y-T, et al. Oxidative damage of biomolecules in mouse liver induced by morphine and protected by antioxidants. Pharmacol Toxicol. 2004;95(2):53-8.
34. Kim YK, et al. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord. 2007;104(1-3):91-5.
35. Vogelzangs N, et al. Anxiety disorders and inflammation in a large adult cohort. Transl Psychiatry. 2013;3(4).
36. Dowlati Y, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-57.
37. Pasco JA, Net al. Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry. 2010;197(5):372-7.
38. Mikirova N, et al. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J Transl Med. 2012;10(1):1-10.
39. Dinan TG. Inflammatory markers in depression. Curr Opin Psychiatry. 2009;22(1):32-6.
40. Caiaffo V, et al. Anti-inflammatory, antiapoptotic, and antioxidant activity of fluoxetine. Pharmacol Res Perspect. 2016;4(3):1-9.
41. May JM, et al. Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. Biochem Biophys Res Commun. 2012;426(1):148-52.
42. Ward MS, et al. Behavioral and monoamine changes following severe vitamin C deficiency. J Neurochem. 2013;124(3):363-75.
43. Hoehn S, Kanfer J. Effects of chronic ascorbic acid deficiency on guinea pig lysosomal hydrolase activities. J Nutr. 1980;110(10):2085-94.
44. Deana R, et al. Changes relevant to catecholamine metabolism in liver and brain of ascorbic acid deficient guinea-pigs. Int J Vitam Nutr Res. 1975;45(2):175-82.
45. Bornstein SR, et al. Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2). FASEB J. 2003;17(13):1-13.
46. Garcia MM, et al. Morphine induction of c-Fos expression in the rat forebrain through glutamatergic mechanisms: role of non-N-methyl-D-aspartate receptors. Neuroscience. 2003;119(3):787-94.
47. Alaei H, et al. Ascorbic acid decreases morphine self-administration and withdrawal symptoms in rats. Pathophysiology. 2005;12(2):103-7.
48. Aghajanian GK, et al. Opiate withdrawal increases glutamate and aspartate efflux in the locus coeruleus: an in vivo microdialysis study. Brain Res. 1994;636(1):126-30.
49. Padayatty SJ, et al. Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone. Am J Clin Nutr. 2007;86(1):145-9.
50. Brody S, et al. A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress. Psychopharmacology (Berl). 2002;159(3):319-24.
51. Hooper MH, et al. The adrenal-vitamin C axis: from fish to guinea pigs and primates. Crit Care. 2019;23(1).
52. Cheraskin E, et al. Daily vitamin C consumption and fatigability. J Am Geriatr Soc. 1976;24(3):136-7.
53. Maté G. In the Realm of Hungry Ghosts: Close Encounters with Addiction. Toronto: Knopf Canada; 2008.
54. Stamford JA, et al. Regional differences in extracellular ascorbic acid levels in the rat brain determined by high speed cyclic voltammetry. Brain Res. 1984;299(2):289-95.
55. Patak P, et al. Vitamin C is an important cofactor for both adrenal cortex and adrenal medulla. Endocr Res. 2004;30(4):871-5.
56. Nakano K, Suzuki N. Stress-induced change in tissue levels of ascorbic acid and histamine in rats. J Nutr. 1984;114(9):1602-8.
57. Stone I. Hypoascorbemia, the genetic disease causing the human requirement for exogenous ascorbic acid. Perspect Biol Med. 1966;10(1):133-4.
58. Stone I. The natural history of ascorbic acid in the evolution of the mammals and primates and its significance for present-day man. J Orthomol Psychiatry. 1972;1(2):82-9.
59. Conney AH, et al. Metabolic interactions between L-ascorbic acid and drugs. Ann N Y Acad Sci. 1961;92(1):115-27.
60. Lykkesfeldt J, Tveden-Nyborg P. The pharmacokinetics of vitamin C. Nutrients. 2019;11(10).
61. Carr AC, McCall C. The role of vitamin C in the treatment of pain: new insights. J Transl Med. 2017;15(1):1-14.
62. Prigge ST, et al. New insights into copper monooxygenases and peptide amidation: structure, mechanism and function. Cell Mol Life Sci. 2000;57(8-9):1236-59.
63. Merkler DJ. C-Terminal amidated peptides: production by the in vitro enzymatic amidation of glycine-extended peptides and the importance of the amide to bioactivity. Enzyme Microb Technol. 1994;16(6):450-6.
64. Giusti-Paiva A, Domingues V. Centrally administered ascorbic acid induces antidiuresis, natriuresis and neurohypophyseal hormone release in rats. Neuro Endocrinol Lett. 2010;31(1):97-91.
65. Carpenter KJ. The discovery of vitamin C. Ann Nutr Metab. 2012;61(3):259-64.
66. Pearson JF, et al. Vitamin C status correlates with markers of metabolic and cognitive health in 50-year-olds: findings of the CHALICE cohort study. Nutrients. 2017;9(8).
67. Libby AF SI. The hypoascorbemia – kwashiorkor approach to drug addiction therapy: a pilot study. Australas Nurses J. 1978;7(6):4-13.
68. Khanzode SD, et al. Oxidative damage and major depression: the potential antioxidant action of selective serotonin-re-uptake inhibitors. Redox Rep. 2003;8(6):365-70.
69. Nazrul Islam SK, et al. Nutritional status of drug addicts undergoing detoxification: prevalence of malnutrition and influence of illicit drugs and lifestyle. Br J Nutr. 2002;88(5):507-13.
70. Nazrul Islam S, et al. Serum vitamin E, C and A status of the drug addicts undergoing detoxification: influence of drug habit, sexual practice and lifestyle factors. Eur J Clin Nutr. 2001;55(11):1022-7.
71. Ross LJ, et al. Prevalence of malnutrition and nutritional risk factors in patients undergoing alcohol and drug treatment. Nutrition. 2012;28(7-8):738-43.
72. Bueno L, Fioramonti J. Action of opiates on gastrointestinal function. Baillieres Clin Gastroenterol. 1988;2(1):123-39.
73. Hornig D. Distribution of ascorbic acid, metabolites and analogues in man and animals. Ann N Y Acad Sci. 1975;258(1):103-18.

[This article by Dr. Erica Zelfand was first published at Allergy Research Group and is reposted here with permission.]