Dr. Jaquel Patterson, ND, Dr. Elizabeth Sutherland, ND, and Dr. Devin Miles, ND

 

Integrating Natural Therapies into Psychiatric Treatment

It is estimated that more than one in five adults in the United States live with a diagnosable mental illness.1

Despite the high prevalence of mental health issues, engagement with treatment is suboptimal. Only about 50% of patients adhere to their pharmacological treatment plan, even though lack of adherence can lead to increased symptom severity, hospitalization, and relapse.2 One of the primary reasons patients give for discontinuing drug protocols, especially regimens for clinical depression, are adverse effects like weight gain, sexual dysfunction, and emotional blunting.3

A growing research base consisting of both clinical trials and systematic reviews indicates that certain botanical medicines and other natural compounds may optimize neurotransmitter balance in patients with anxiety, depression, attention deficit, and memory loss, by, among other mechanisms, supporting serotonergic, dopaminergic, GABAergic, and HPA (hypothalamic-pituitary-adrenal) axis regulation. These natural compounds target distinct neurochemical systems to support calm focus, emotional resilience, and sustained cognitive performance. They also have a lower side effect profile than conventional pharmacotherapy, making them promising adjunctive or alternative options in the management of mental health conditions.

Core Neurotransmitters to Address in Mental Health

Cortisol

Cortisol plays a central role in mediating the physiological and psychological effects of stress. Long-term cortisol dysregulation contributes to cognitive function decline, mood destabilization, and increased vulnerability to psychiatric conditions such as bipolar disorder and major depressive disorder. Chronic cortisol exposure often leads to atrophy in areas of the brain, such as the hippocampus and amygdala, that are sensitive to stress. These structural changes can have a negative impact on executive function, memory, and the fear response.4

Disturbances in cortisol regulation affect multiple physiological systems. For example, excess cortisol production, HPA axis dysregulation, and neuroinflammation in the central nervous system have been found to contribute to the progression of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s.5

Serotonin

Serotonin is a key neurotransmitter involved in mood regulation, emotional well-being, and appetite satiety. Serotonin is also a precursor to melatonin and therefore plays a role in the sleep-wake cycle and possibly pain perception.6 Serotonin receptor agonists such as triptans are used to treat migraine and vascular headaches by promoting vasoconstriction of intracranial blood vessels.7

Antidepressant drugs that bind to the 5-HT3 receptor commonly cause nausea and vomiting for the first few weeks of use.8

Increased levels of serotonin resulting from SSRI use can impair platelet aggregation and heighten the risk of bleeding, particularly in the upper gastrointestinal tract or intracranially.9

Dopamine

Dopamine supports motor control, cognitive function, and emotional balance by regulating motivation, focus, and reward-driven behaviors. It influences how people experience pleasure and satisfaction. Altered signaling of dopamine is implicated in neurodegenerative disorders such as Parkinson’s disease, and in mental health conditions such as addiction and schizophrenia.10 Dopamine dysregulation is also associated with attention-deficit/hyperactivity disorder (ADHD).11

Clinical Application of Natural Neurotransmitter Support

The clinical value of natural neurotransmitter support becomes even clearer when the relevant botanicals and other compounds are combined for targeted effect. The following table illustrates key formulations for common mental health issues.

 

Indications	Clinical Combination	Mechanism
Anxiety, chronic stress, insomnia	L-theanine, Magnolia, Skullcap, Kanna	Increases serotonin and GABA, calms the central nervous system
Moderate depression, anxiety, insomnia, migraines, appetite, idiopathic constipation	Griffonia, 5-HTP, Kanna	Enhances serotonin significantly, supports gut motility
Age-related mild depression, anxiety, low motivation, poor cognitive focus	Kola nut, St. John’s Wort, Agmatine, Mucuna, Griffonia	Enhances serotonin and dopamine
Parkinson’s symptoms, low motivation, cognitive decline, lack of focus	Mucuna, Magnolia, Lycopodium	Enhances L-dopa significantly thereby supporting neuroprotection, motor control, cognitive function, and emotional balance

 

Agmatine

Agmatine is an endogenous derivative of the amino acid L-arginine. It has demonstrated neuroprotective properties in experimental studies.12 It has also been shown to produce antidepressant-like effects by activating AMPA receptors and mTOR signaling,13 which are the mechanisms thought to underlie the effects of fast-acting antidepressive agents such as ketamine.14 Oral ingestion of 2–3 mg/day of agmatine over 6–8 weeks induced remission of depressive symptoms without any side effects in three subjects diagnosed with major depressive disorder.15

Griffonia (Griffonia simplicifolia)

Griffonia seeds contain high amounts of the amino acid 5-hydroxytryptophan (5-HTP), which is a precursor to serotonin.16 Griffonia has been shown to be clinically effective in improving depression,17,18 anxiety,16 and stress.19 It has also been shown to work well with magnesium for motion sickness.20

In a double-blind randomized controlled trial of 70 patients with their first depressive episode, 5-HTP demonstrated nearly equal reduction in scores on the Hamilton Rating Scale for Depression (HAM-D) compared to fluoxetine after two weeks of treatment and continuing through eight weeks of treatment.21 5-HTP also helps to normalize GI motility and supports enteric epithelial integrity.22

Monitor any patients taking Griffonia along with SSRIs, SNRIs, MAOIs, and other serotonergic medications. Other drug interactions include carbidopa, potentially at higher 5-HTP doses,23 and the risk of serotonin syndrome if combined with serotonergic medications. A potential side effect of 5-HTP is gastrointestinal discomfort at higher doses.24

Kanna (Sceletium tortuosum)

Kanna is a succulent plant native to South Africa with a long history of traditional use for mood enhancement.25 To date, clinical research for Kanna is exploratory and focused on healthy subjects, but a mounting evidence base supports its use for improving symptoms of anxiety,26,27 depression,28 and deficits in attention and memory.29 The beneficial effects of Kanna are attributed to its high polyphenol and alkaloid content.30 It has also been shown to have a positive safety profile.31

Magnolia (Magnolia officinalis)

Magnolia helps regulate neuronal function, reduce neurotoxicity, suppress apoptosis, and decrease neuroinflammation.32 The polyphenol compounds in magnolia, magnolol and honokiol, protect nerve cells and brain microvascular endothelial cells, thereby potentially mitigating neuroinflammation and mental health issues such as anxiety and depression.32

Magnolia bark extract is not well-absorbed, so is optimally delivered using a liposomal phospholipid matrix designed to enhance the gastrointestinal absorption and bioavailability of lipophilic magnolia polyphenols, including magnolol and honokiol. Black pepper can also optimize bioavailability.

Magnolia has been shown to attenuate inflammatory responses and oxidative stress.33 Magnolol and honokiol have also demonstrated positive allosteric modulation of GABA-A receptors, thus providing an anxiolytic effect.34 In a double-blind, placebo-controlled trial, a magnolia–phellodendron blend reduced salivary cortisol levels in stressed adults within 2–4 weeks. The treatment group also reported lower levels of stress, anger, confusion, and fatigue, as well as improved mood and vigor.35

Mucuna (Mucuna pruriens)

Mucuna helps modulate dopaminergic, serotonergic, and noradrenergic systems. It contains L-dopa, the precursor to dopamine, a neurotransmitter that supports motivation, mood, and neuroprotection.36 Mucuna has been shown to improve Parkinson’s disease, which is primarily managed pharmacologically with L-dopa medications.37

Side effects may include nausea and dizziness at higher doses38 and potential changes in blood pressure.39 It is important to monitor if Mucuna is taken along with dopamine agonists,40 MAOIs, antipsychotics, or antidepressant medications.

L-Theanine

The amino acid L-theanine increases alpha-brain waves,41 thereby promoting relaxation while maintaining alertness. It can help stabilize mood by elevating central GABA, dopamine, and serotonin levels.42 L-theanine helps reduce symptoms of stress, depression, anxiety, and sleep disturbance,43 as well as supporting cognitive function and attention.44

In a double-blind placebo-controlled trial of 95 patients diagnosed with Obsessive Compulsive Disorder (OCD), the combination of L-theanine and fluvoxamine led to significant improvement in obsession scores compared to fluvoxamine plus placebo.45

St. John’s Wort (Hypericum perforatum)

St. John’s Wort improves serotonin levels. Hyperforin, a principal constituent of St. John’s Wort, has been shown to inhibit serotonin uptake.46 It also potently inhibits the uptake of dopamine, noradrenaline, GABA, and L-glutamate, which may all contribute to the antidepressive properties of St. John’s Wort.47

Adverse effects from taking St. John’s Wort may include gastrointestinal symptoms48 and, rarely, photosensitivity. It is important to monitor the intake of St. John’s Wort if taken along with SSRI medications.

Clinical Take Aways

Issues relating to mental health are a common complaint in the clinical setting. Patients may present with, for example, mild to moderate depression, stress and anxiety, low motivation, or poor concentration, often with concomitant sleep problems. Pharmacological options for these conditions usually have significant adverse effects, which can discourage patient adherence to treatment regimens. A growing research base supports the safety and efficacy of botanical medicines and other natural compounds to address neurotransmitter imbalance. Used individually, these components can be important allies for improving mental health, but expert combinations of specific herbs and amino acids can provide a considerably more targeted and effective approach, allowing your patients additional therapeutic options for addressing their mental health and well-being.

Author Bios & Social Media

Dr. Jaquel Patterson, ND is a nationally recognized leader in naturopathic and functional medicine, a sought-after speaker, three-time Amazon bestselling author, and Forbes contributor. She is the founder and owner of Fairfield Family Health, a successful multidisciplinary medical practice based in Connecticut that serves patients throughout the country. She has over 16 years of clinical experience specializing in integrative psychiatry, Lyme disease, autoimmune conditions, complex chronic illness, and environmental medicine. She is a clinician partner for Restorative Formulations, serves on several scientific and medical advisory boards, and completed a fellowship in functional medicine for psychiatry with Psychiatry Redefined.

Dr. Elizabeth (Liz) Sutherland, ND began her undergraduate degree at the University of Cambridge in Classics and finished it at Tufts University with a BS in Biopsychology. She earned her doctorate in naturopathic medicine (ND) from National University of Natural Medicine (NUNM), in Portland, OR, after which she completed post-doctoral research fellowships at the Kaiser Permanente Northwest (KPNW) Center for Health Research and the University of Arizona College of Medicine. Dr. Sutherland has served as co-investigator on a number of NIH-funded studies and is primary author or co-author on multiple peer-reviewed publications. Currently, Dr. Sutherland serves as a Restorative Formulations Medical Writer and editor in chief of the Journal of Restorative Medicine.

Dr. Devin Miles, ND provides integrative and natural approaches to kidney function, cardiovascular health, digestion, autoimmunity, and prevention. She graduated from Sonoran University of Health Sciences in Arizona. Dr. Miles has also launched an online course sharing natural support for kidney and blood pressure health. She is a medical writer and has written for traditional, integrative, naturopathic, and functional medicine sources.

References

1. National Institute of Mental Health. Mental illness. NIMH website. https://www.nimh.nih.gov/health/statistics/mental-illness. Accessed April 23, 2026.
2. Girone N, Cocchi M, Achilli F, Grechi E, Vicentini C, Benatti B, Vismara M, Priori A, Dell’Osso B. Treatment adherence rates across different psychiatric disorders and settings: findings from a large patient cohort. Int Clin Psychopharmacol. 2025 Jul 1;40(4):232-241. doi: 10.1097/YIC.0000000000000557. Epub 2024 May 30. PMID: 38813934.
3. WebMD. Antidepressants: Side effects. WebMD website. https://www.webmd.com/depression/drug-side-effects. Accessed April 23, 2026.
4. George MY, Abdel Mageed SS, Mansour DE, Fawzi SF. The cortisol axis and psychiatric disorders: an updated review. Pharmacol Rep. 2025;77(6):1573-1599. doi:10.1007/s43440-025-00782-x
5. Knezevic E, Nenic K, Milanovic V, Knezevic NN. The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders. Cells. 2023;12(23):2726. Published 2023 Nov 29. doi:10.3390/cells12232726
6. Srinivasan V, Lauterbach EC, Ho KY, Acuña-Castroviejo D, Zakaria R, Brzezinski A. Melatonin in antinociception: its therapeutic applications. Curr Neuropharmacol. 2012;10(2):167-178. doi:10.2174/157015912800604489
7. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Serotonin Receptor Agonists (Triptans) [Updated 2018 Feb 10]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548713/
8. Wen S, Yan Y, Shao J, et al. Comparative gastrointestinal effects of antidepressants for the acute treatment of adults with major depressive disorder: a network and dose-response meta-analysis. Transl Psychiatry. 2025;16(1):34. Published 2025 Nov 25. doi:10.1038/s41398-025-03751-3
9. Edinoff AN, Raveendran K, Colon MA, et al. Selective Serotonin Reuptake Inhibitors and Associated Bleeding Risks: A Narrative and Clinical Review. Health Psychol Res. 2022;10(4):39580. Published 2022 Nov 3. doi:10.52965/001c.39580
10. Speranza L, Miniaci MC, Volpicelli F. The Role of Dopamine in Neurological, Psychiatric, and Metabolic Disorders and Cancer: A Complex Web of Interactions. Biomedicines. 2025;13(2):492. Published 2025 Feb 17. doi:10.3390/biomedicines13020492
11. MacDonald HJ, Kleppe R, Szigetvari PD, Haavik J. The dopamine hypothesis for ADHD: An evaluation of evidence accumulated from human studies and animal models. Front Psychiatry. 2024;15:1492126. Published 2024 Nov 15. doi:10.3389/fpsyt.2024.1492126
12. Wang WP, Iyo AH, Miguel-Hidalgo J, Regunathan S, Zhu MY. Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons. Brain Res. 2006;1084(1):210-216. doi:10.1016/j.brainres.2006.02.024
13. Neis VB, Moretti M, Bettio LE, et al. Agmatine produces antidepressant-like effects by activating AMPA receptors and mTOR signaling. Eur Neuropsychopharmacol. 2016;26(6):959-971. doi:10.1016/j.euroneuro.2016.03.009
14. Valverde AP, Camargo A, Rodrigues ALS. Agmatine as a novel candidate for rapid-onset antidepressant response. World J Psychiatry. 2021;11(11):981-996. Published 2021 Nov 19. doi:10.5498/wjp.v11.i11.981
15. Shopsin B. The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study. Acta Neuropsychiatrica. 2013;25(2):113-118. doi:10.1111/j.1601-5215.2012.00675.x
16. Carnevale G, Di Viesti V, Zavatti M, Zanoli P. Anxiolytic-like effect of Griffonia simplicifolia Baill. seed extract in rats. Phytomedicine. 2011;18(10):848-851. doi:10.1016/j.phymed.2011.01.016
17. Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 1998;3(4):271-280.
18. Muszyńska B, Łojewski M, Rojowski J, Opoka W, Sułkowska-Ziaja K. Natural products of relevance in the prevention and supportive treatment of depression. Psychiatr Pol. 2015;49(3):435-453. doi:10.12740/PP/29367
19. Emanuele E, Bertona M, Minoretti P, Geroldi D. An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress. Neuro Endocrinol Lett. 2010;31(5):663-666.
20. Esposito M, Precenzano F, Sorrentino M, Avolio D, Carotenuto M. A Medical Food Formulation of Griffonia simplicifolia/Magnesium for Childhood Periodic Syndrome Therapy: An Open-Label Study on Motion Sickness. J Med Food. 2015;18(8):916-920. doi:10.1089/jmf.2014.0113
21. Jangid P, Malik P, Singh P, Sharma M, Gulia AK. Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr. 2013;6(1):29-34. doi:10.1016/j.ajp.2012.05.011
22. 22. Israelyan N, Del Colle A, Li Z, et al. Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression. Gastroenterology. 2019;157(2):507-521.e4. doi:10.1053/j.gastro.2019.04.022
23. Smarius LJ, Jacobs GE, Hoeberechts-Lefrandt DH, et al. Pharmacology of rising oral doses of 5-hydroxytryptophan with carbidopa. J Psychopharmacol. 2008;22(4):426-433. doi:10.1177/0269881107082025
24. Jacobsen JPR, Krystal AD, Krishnan KRR, Caron MG. Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale. Trends Pharmacol Sci. 2016;37(11):933-944. doi:10.1016/j.tips.2016.09.001
25. Brendler T, Brinckmann JA, Feiter U, et al. Sceletium for Managing Anxiety, Depression and Cognitive Impairment: A Traditional Herbal Medicine in Modern-Day Regulatory Systems. Curr Neuropharmacol. 2021;19(9):1384-1400. doi:10.2174/1570159X19666210215124737
26. Terburg D, Syal S, Rosenberger L, et al. Acute Effects of Sceletium tortuosum (Zembrin), a Dual 5-HT Reuptake and PDE4 Inhibitor, in the Human Amygdala and its Connection to the Hypothalamus. Neuropsychopharmacol. 2013;38:2708-2716. doi:10.1038/npp.2013.183
27. Manganyi MC, Bezuidenhout CC, Regnier T, Ateba CN. A Chewable Cure “Kanna”: Biological and Pharmaceutical Properties of Sceletium tortuosum. Molecules. 2021;26(9):2557. doi:10.3390/molecules26092557
28. Coetzee DD, López V, Smith C. High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor. J Ethnopharmacol. 2016;177:111-116. doi:10.1016/j.jep.2015.11.034
29. Dimpfel W, Gericke N, Suliman S, Chiegoua Dipah G. Psychophysiological Effects of Zembrin® Using Quantitative EEG Source Density in Combination with Eye-Tracking in 60 Healthy Subjects. A Double-Blind, Randomized, Placebo-Controlled, 3-Armed Study with Parallel Design. Neuroscience and Medicine. 2016;7:114-132.
30. Bennett A, Van Camp A, López V, et al. Sceletium tortuosum may delay chronic disease progression via alkaloid-dependent antioxidant or anti-inflammatory action. J Physiol Biochem. 2018;74:539-547. doi:10.1007/s13105-018-0620-6
31. Nell H, Siebert M, Chellan P, Gericke N. A randomized, double-blind, parallel-group, placebo-controlled trial of Extract Sceletium tortuosum (Zembrin) in healthy adults. J Altern Complement Med. 2013;19(11):898-904. doi:10.1089/acm.2012.0185
32. Zhu S, Liu F, Zhang R, et al. Neuroprotective Potency of Neolignans in Magnolia officinalis Cortex Against Brain Disorders. Front Pharmacol. 2022;13:857449. Published 2022 Jun 16. doi:10.3389/fphar.2022.857449
33. Chuang DY, Chan MH, Zong Y, et al. Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells. J Neuroinflammation. 2013;10:15. Published 2013 Jan 29. doi:10.1186/1742-2094-10-15
34. Alexeev M, Grosenbaugh DK, Mott DD, Fisher JL. The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA(A) receptors. Neuropharmacology. 2012;62(8):2507-2514. doi:10.1016/j.neuropharm.2012.03.002
35. Talbott SM, Talbott JA, Pugh M. Effect of Magnolia officinalis and Phellodendron amurense (Relora®) on cortisol and psychological mood state in moderately stressed subjects. J Int Soc Sports Nutr. 2013;10(1):37. Published 2013 Aug 7. doi:10.1186/1550-2783-10-37
36. Mata-Bermudez A, Diaz-Ruiz A, Silva-García LR, et al. Mucuna pruriens, a Possible Treatment for Depressive Disorders. Neurol Int. 2024;16(6):1509-1527. Published 2024 Nov 16. doi:10.3390/neurolint16060112
37. Hammoud F, Ismail A, Zaher R, El Majzoub R, Abou-Abbas L. Mucuna pruriens Treatment for Parkinson Disease: A Systematic Review of Clinical Trials. Parkinsons Dis. 2025;2025:1319419. Published 2025 Aug 18. doi:10.1155/padi/1319419
38. Hammoud F, Ismail A, Zaher R, El Majzoub R, Abou-Abbas L. Mucuna pruriens Treatment for Parkinson Disease: A Systematic Review of Clinical Trials. Parkinsons Dis. 2025;2025:1319419. Published 2025 Aug 18. doi:10.1155/padi/1319419
39. Earl T, Jridi A, Thulin PC, et al. Effect of levodopa on postural blood pressure changes in Parkinson disease: a randomized crossover study. Clin Auton Res. 2024;34(1):117-124. doi:10.1007/s10286-024-01024-5
40. Contin M, Lopane G, Passini A, Poli F, Iannello C, Guarino M. Mucuna pruriens in Parkinson Disease: A Kinetic-Dynamic Comparison With Levodopa Standard Formulations. Clin Neuropharmacol. 2015;38(5):201-203. doi:10.1097/WNF.0000000000000098
41. Dashwood R, Visioli F. l-theanine: From tea leaf to trending supplement – does the science match the hype for brain health and relaxation? Nutr Res. 2025;134:39-48. doi:10.1016/j.nutres.2024.12.008
42. Moshfeghinia R, Sanaei E, Mostafavi S, Assadian K, Sanaei A, Ayano G. The effects of L-theanine supplementation on the outcomes of patients with mental disorders: a systematic review. BMC Psychiatry. 2024;24(1):886. Published 2024 Dec 4. doi:10.1186/s12888-024-06285-y
43. Hidese S, Ogawa S, Ota M, et al. Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial. Nutrients. 2019;11(10):2362. Published 2019 Oct 3. doi:10.3390/nu11102362
44. Anas Sohail A, Ortiz F, Varghese T, et al. The Cognitive-Enhancing Outcomes of Caffeine and L-theanine: A Systematic Review. Cureus. 2021;13(12):e20828. Published 2021 Dec 30. doi:10.7759/cureus.20828
45. Nematizadeh M, Ghorbanzadeh H, Moghaddam HS, et al. L-theanine combination therapy with fluvoxamine in moderate-to-severe obsessive-compulsive disorder: A placebo-controlled, double-blind, randomized trial. Psychiatry Clin Neurosci. 2023;77(9):478-485. doi:10.1111/pcn.13565
46. Singer A, Wonnemann M, Müller WE. Hyperforin, a major antidepressant constituent of St. John’s Wort, inhibits serotonin uptake by elevating free intracellular Na+1. J Pharmacol Exp Ther. 1999;290(3):1363-1368.
47. Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci. 1998;63(6):499-510. doi:10.1016/s0024-3205(98)00299-9
48. Ernst E, Rand JI, Barnes J, Stevinson C. Adverse effects profile of the herbal antidepressant St. John’s wort (Hypericum perforatum L.). Eur J Clin Pharmacol. 1998;54(8):589-594. doi:10.1007/s002280050519