Breakthrough Study: Inflammation Causes Depression
By Robert Schinetsky
Systemic inflammation is linked with multiple disorders, including obesity, type 2 diabetes, cardiovascular disease, Alzheimer’s and Parkinson’s disease. Recently, published research also finds that it may play a role in depression.
Specifically, inflammation may contribute to the development of symptoms of depression and anhedonia – the inability to experience pleasure. This is due, in part, to reduced dopamine availability. Dopamine, as you likely remember, is a vitally important neurotransmitter involved in mood, memory, motivation, reward, motor control, and decision making.
Previous work from the same group of researchers also noted that peripheral inflammatory cytokine-induced reductions in striatal dopamine release, and were reversed by administration of the dopamine precursor, levodopa (L-DOPA).
For the current study, 40 individuals (ages 18-65) with major depressive disorder and elevated CRP (c-reactive protein, a key biomarker of inflammation) took part in a double-blind, randomized, crossover study in which they underwent a functional MRI (fMRI) and behavioral assessments on separate visits separated by a week and received either L-DOPA (250 mg with 25 to 50 mg carbidopa) or placebo. Resting-fMRI and self-reported anhedonia scores (SHAPS) were collected before and after acute L-DOPA or placebo treatment, and task-fMRI and objective motivation were collected post-L-DOPA or placebo ingestion.
At the end of the trial, researchers found that L-DOPA administration led to improvements in functional connectivity only in those individuals that had higher levels of CRP. This improvement in reward circuitry also correlated with reduced symptoms of anhedonia as well. Senior author of the paper, Dr. Jennifer Felger, associate professor of psychiatry and behavioral sciences, Emory School of Medicine, noted that the study’s results suggest that dopamine enhancers may be particularly beneficial for depressed patients with high inflammation levels and functional connectivity in reward circuitry may serve as a meaningful biomarker for the effects of neuroinflammation.
As a powerful dopamine enhancer, L-DOPA is also the most commonly employed means for combatting Parkinson’s disease, and a hallmark sign of Parkinson’s disease is the gradual dying off of dopamine-synthesizing cells.
In fact, Parkinson’s disease is the second most common age-related neurodegenerative disease worldwide. Recent studies indicate that upwards of 90,000 Americans are diagnosed with the disease each year.
While no cure has been found for the disease, a number of other treatments have been studied and utilized to slow the disease’s progression and/or mediate symptoms common to the disease. Still, L-DOPA remains the preferred option among clinicians, for myriad reasons, including that it may be superior to other stimulants and dopamine agonists, even at low doses.
However, some research finds that supplementing with pure L-DOPA may pose its own risks – generating free radicals, damaging dopamine-producing neurons, and inducing apoptosis (cell death).[4,5]
Fortunately, there are some natural options available that offer similar benefits as synthetic L-DOPA as well as neuroprotection. Here are some supplements to increase dopamine...
Mucuna pruriens (aka velvet bean) is plant native to tropical and subtropical regions of the world that has a long history of use as both a cognitive enhancer and aphrodisiac. It is a natural source of L-DOPA (the immediate precursor to dopamine) as well as numerous other phytoactive nutrients, including polyphenols, and antioxidants.[7,8]
Animal studies also suggest that Mucuna pruriens may be superior to pure L-DOPA, potentially due to additional beneficial compounds naturally present in the plant. Smaller studies in humans suggest that Mucuna pruriens extracts offer similar benefits to levodopa alone at the same dose, with a more favorable tolerability profile.
Furthermore, in vitro assays of Mucuna pruriens extract, containing large amounts of phenolic compounds, exhibited high antioxidant and free radical-scavenging activities, indicating that Mucuna pruriens extract is a formidable source of natural antioxidants, which may help stymie the progress of various oxidative stresses.[10,11]
Heralded for its immune support benefits, vitamin C is an essential vitamin that also plays a key role in the body’s recycling of other antioxidants, including vitamin E (alpha-tocopherol), which is found in all biological membranes and is involved in preventing lipid peroxidation by removing peroxyl radicals.
Additionally, vitamin C bolsters antioxidant defense capacity, cognitive function and neuroprotection. More specifically, the vitamin aids cognitive health, performance, and longevity by maintaining integrity and function of several processes in the central nervous system (CNS), including:
- Neuronal differentiation and maturation
- Myelin formation (myelin is a protective membrane – “covering” – that surrounds nerve cell axons (the “wires” of the nervous system) to insulate them and increase the rate that electrical impulses pass along the axon).
- Modulation of neurotransmitters
Vitamin C also acts as a cofactor in the synthesis of various neurotransmitters, especially the catecholamines – dopamine and norepinephrine.
Furthermore, a 2020 systematic review in BMC Psychiatry concluded that “vitamin C deficiency is related to adverse mood and cognitive effects … Vitamin C replacement is inexpensive and easy to deliver.”
Previous research also indicates that vitamin C supplementation may combat oxidative stress induced by L-DOPA administration. For the study, healthy mice were divided into four groups, and all animals, except those in the control group, received two injections of L-DOPA, followed by benserazide, a compound that increases the amount of L-DOPA crossing the blood-brain barrier and thus converting into dopamine.
Two of the four study groups were pre-treated with injections of vitamin C or rose oil before they were treated with L-DOPA and benserazide.
Scientists then assessed the oxidative stress levels of the animals. Compared to the control group, mice treated with antioxidants + L-DOPA had significantly lower levels of oxidative stress compared to those receiving only L-DOPA.
Vitamin C (1000mg) has been shown to increase “absorption” (how focused an individual feels) during work or study as well as mental vitality and attentional focus.
Monoamine oxidase B is an enzyme that metabolizes (degrades) dopamine and other catecholamines. MAO-B inhibitors are substances that limit the actions of MAO-B, thus increasing the longevity of catecholamines in the body and their associated effects.
A number of dietary supplements possess MAO-B inhibiting activity and are often combined with dopamine precursors to enhance energy, focus, motivation, and performance. As an added bonus, some research suggests that MAO inhibition may slow down the aging process via reduction of oxidative stress.
Mucuna pruriens extract has been found to offer mild MAO inhibition. Another naturally occuring compound with MAO-inhibiting properties is garcinol.
Found in Garcinia indica, a plant historically used for its antioxidant and anti-inflammatory properties, garcinol is a unique molecule that not only sustains dopamine levels but also offers anticholinesterase benefits (cholinesterase is the enzyme that breaks down acetylcholine – the learning neurotransmitter), inhibits neuroinflammation and combats L-DOPA dyskinesia.[19,20,23] Dyskinesia can result from prolonged L-DOPA administration. It’s characterized by erratic, writhing (“dance-like”) movements of the face, arms, or lower body, but they may also cause rapid jerking or slow and extended muscle spasms.
Research notes that garcinol may combat L-DOPA-induced dyskinesia as well as offer MAO-inhibitory potential on par to other known MAO-B inhibitors. Researchers note these effects are due, in part, to garinol’s antioxidant, anti-inflammatory and catechol-o-methyltransferase (COMT)-inhibitory potential. As a result, garcinol may offer neuroprotection.[18,22]
Low-grade, systemic inflammation is a considerable threat for individuals, both old and young. Lifestyle factors (diet, exercise, sleep, stress management, and body composition) all play a role in inflammation. Additional nutrients may also help limit free radical activity and oxidative stress, supporting energy, focus, productivity, health, and longevity.
© Published by Advanced Research Media, Inc. 2023
© Reprinted with permission from Advanced Research Media, Inc.
- Bekhbat, M., Li, Z., Mehta, N.D. et al. Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study. Mol Psychiatry 27, 4113-4121 (2022). https://doi.org/10.1038/s41380-022-01715-3
- Felger JC, Hernandez CR, Miller AH. Levodopa reverses cytokine-induced reductions in striatal dopamine release. Int J Neuropsychopharmacol. 2015;18:1-5.
- Willis, A.W., Roberts, E., Beck, J.C. et al. Incidence of Parkinson disease in North America. npj Parkinsons Dis. 8, 170 (2022). https://doi.org/10.1038/s41531-022-00410-y
- Romagnolo A, Merola A, Artusi CA, Rizzone MG, Zibetti M, Lopiano L. Levodopa-induced neuropathy: A systematic review. Mov Disord Clin Pract. 2019;6(2):96-103.
- Gandhi KR, Saadabadi A. Levodopa (L-Dopa) [Updated 2022 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482140/
- Lampariello LR, Cortelazzo A, Guerranti R, Sticozzi C, Valacchi G. The Magic Velvet Bean of Mucuna pruriens. J Tradit Complement Med. 2012 Oct;2(4):331-9. doi: 10.1016/s2225-4110(16)30119-5. PMID: 24716148; PMCID: PMC3942911.
- Hussian, G. and Manyam, B.V. (1997), Mucuna pruriens proves more effective than L-DOPA in Parkinson's disease animal model. Phytother. Res., 11: 419-423. https://doi.org/10.1002/(SICI)1099-1573(199709)11:6<419::AID-PTR120>3.0.CO;2-Q
- Cilia, R., Laguna, J., Cassani, E., Cereda, E., Pozzi, N. G., Isaias, I. U., Contin, M., Barichella, M., & Pezzoli, G. (2017). Mucuna pruriens in Parkinson disease: A double-blind, randomized, controlled, crossover study. Neurology, 89(5), 432 LP-438. https://doi.org/10.1212/WNL.0000000000004175
- Rutherford BR, Slifstein M, Chen C, Abi-Dargham A, Brown PJ, Wall MW, Vanegas-Arroyave N, Stern Y, Bailey V, Valente E, Roose SP. Effects of L-DOPA Monotherapy on Psychomotor Speed and [11C]. Raclopride Binding in High-Risk Older Adults With Depression. Biol Psychiatry. 2019 Aug 1;86(3):221-229. doi: 10.1016/j.biopsych.2019.04.007. Epub 2019 Apr 15. Retraction in: Biol Psychiatry. 2023 Feb 15;93(4):382. PMID: 31178096; PMCID: PMC6641997.
- Dhanasekaran M, Tharakan B, Manyam BV. Antiparkinson drug - Mucuna pruriens shows antioxidant and metal chelating activity. Phytother Res. 2008 Jan;22(1):6-11. doi: 10.1002/ptr.2109. PMID: 18064727.
- Rajeshwar, Y., Kumar, G. P. S., Gupta, M., & Mazumder, U. K. (2005). Studies on in vitro antioxidant activities of methanol extract of Mucuna pruriens (fabaceae) seeds. European Bulletin of Drug Research, 13(1), 31-39.
- Figueroa-Méndez R., Rivas-Arancibia S. Vitamin C in Health and Disease: Its Role in the Metabolism of Cells and Redox State in the Brain. Front. Physiol. 2015;23:397. doi: 10.3389/fphys.2015.00397.
- Kocot J, Luchowska-Kocot D, Kiełczykowska M, Musik I, Kurzepa J. Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders? Nutrients. 2017 Jun 27;9(7):659. doi: 10.3390/nu9070659. PMID: 28654017; PMCID: PMC5537779.
- Plevin, D., Galletly, C. The neuropsychiatric effects of vitamin C deficiency: a systematic review. BMC Psychiatry 20, 315 (2020). https://doi.org/10.1186/s12888-020-02730-w
- Nikolova, G., Karamalakova, Y., & Gadjeva, V. (2019). Reducing oxidative toxicity of L-dopa in combination with two different antioxidants: an essential oil isolated from Rosa Damascena Mill., and vitamin C. Toxicology Reports, 6, 267–271. https://doi.org/https://doi.org/10.1016/j.toxrep.2019.03.006
- Sim, M., Hong, S., Jung, S. et al. Vitamin C supplementation promotes mental vitality in healthy young adults: results from a cross-sectional analysis and a randomized, double-blind, placebo-controlled trial. Eur J Nutr 61, 447-459 (2022). https://doi.org/10.1007/s00394-021-02656-3
- YILDIZ, O., KARAHALIL, F., CAN, Z., SAHIN, H. and KOLAYLI, S. 2013. Total monoamine oxidase (MAO) inhibition by chestnut honey, pollen and propolis. J. Enzyme Inhibition Med. Chem. 29, 690-694
- Mazumder MK, Paul R, Phukan BC, Dutta A, Chakrabarty J, Bhattacharya P, Borah A. Garcinol, an effective monoamine oxidase-B inhibitor for the treatment of Parkinson's disease. Med Hypotheses. 2018 Aug;117:54-58. doi: 10.1016/j.mehy.2018.06.009. Epub 2018 Jun 8. PMID: 30077198.
- Fuchs, R., McLaughlin, R. Garcinol: A Magic Bullet of Amnesia for Maladaptive Memories? Neuropsychopharmacol 42, 581-583 (2017). https://doi.org/10.1038/npp.2016.165
- Chetia Phukan B, Dutta A, Deb S, Saikia R, Mazumder MK, Paul R, Bhattacharya P, Sandhir R, Borah A. Garcinol blocks motor behavioural deficits by providing dopaminergic neuroprotection in MPTP mouse model of Parkinson's disease: involvement of anti-inflammatory response. Exp Brain Res. 2022 Jan;240(1):113-122. doi: 10.1007/s00221-021-06237-y. Epub 2021 Oct 11. PMID: 34633467.
- Pandey S, Srivanitchapoom P. Levodopa-induced Dyskinesia: Clinical Features, Pathophysiology, and Medical Management. Ann Indian Acad Neurol. 2017 Jul-Sep;20(3):190-198. doi: 10.4103/aian.AIAN_239_17. PMID: 28904447; PMCID: PMC5586110.
- Deb S, Phukan BC, Mazumder MK, Dutta A, Paul R, Bhattacharya P, Sandhir R, Borah A. Garcinol, a multifaceted sword for the treatment of Parkinson's disease. Neurochem Int. 2019 Sep;128:50-57. doi: 10.1016/j.neuint.2019.04.004. Epub 2019 Apr 12. PMID: 30986504.
- Kopytko P, Piotrowska K, Janisiak J, Tarnowski M. Garcinol-A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug. Int J Mol Sci. 2021 Mar 11;22(6):2828. doi: 10.3390/ijms22062828. PMID: 33799504; PMCID: PMC8001519.