Depression and anxiety affect women at nearly twice the rate of men worldwide. While many factors contribute including social, psychological, and environmental influences, biological factors plays a critical role. One area of research that sheds light on these differences is serotonin synthesis in the brain. Serotonin is a key neurotransmitter involved in mood, stress regulation, and emotional well-being. Interestingly, studies have shown that men synthesize serotonin in the brain at a 52% higher rate than women. This biological difference may partly explain why women are more vulnerable to mood disorders.
Serotonin is widely known as the “feel-good” chemical, but its functions go far beyond mood regulation. In the brain, serotonin supports:
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Regulation of mood and emotional stability
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Stress response and resilience
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Sleep and circadian rhythm
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Appetite and energy balance
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Cognitive processes such as memory and learning
Although about 90% of serotonin is produced in the gut, this serotonin cannot cross the blood–brain barrier. The brain relies on its own serotonin production, synthesized from the amino acid tryptophan through the enzyme tryptophan hydroxylase (TPH2). This means that central serotonin levels are determined largely by local synthesis within the brain.
Groundbreaking research using positron emission tomography (PET) has revealed striking differences in serotonin synthesis between men and women. A landmark study led by Nishizawa et al. (1997) found that healthy males had a 52% higher mean rate of serotonin synthesis in the brain compared to healthy females.
It is important to clarify what this finding means. Women do not have “52% less serotonin” overall. Instead, the rate of production which is how quickly the brain makes serotonin, is slower in women. This difference in synthesis could leave women more vulnerable to fluctuations in serotonin during periods of stress or hormonal change.
Serotonin is continuously synthesized, released, and recycled in the brain. When synthesis is slower, serotonin reserves may be more easily depleted under stress or during periods of high demand.
Research suggests that women with slower synthesis may experience:
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Rapid depletion of serotonin during stress → increasing susceptibility to depressive episodes.
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Reduced resilience in maintaining mood stability when challenged by external or internal stressors.
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Different response to antidepressant medications (such as SSRIs), which target serotonin pathways.
This helps explain why women often report higher rates of stress-induced mood changes and why treatment responses can differ by sex.
The stress response relies heavily on serotonin signalling. Chronic stress depletes serotonin reserves more quickly, and when synthesis is slower, this depletion can be more profound.
Animal and human studies suggest that:
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Women may have greater sensitivity to serotonin depletion under stress.
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Stress-induced decreases in serotonin can impair neurogenesis in the hippocampus, a brain region critical for memory and mood regulation.
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This may contribute to a higher risk of recurrent depressive episodes in women compared to men.
Supplementation that can increase serotonin synthesis
While genetics, hormones, and stress play large roles in serotonin balance, certain nutrients and supplements may help support serotonin synthesis within the brain. It is important to note that supplementation is not a replacement for medical treatment of mood disorders, but these compounds have been studied for their potential to influence brain serotonin levels:
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5-HTP (5-Hydroxytryptophan)
5-HTP is a direct precursor to serotonin and readily crosses the blood–brain barrier. Once in the brain, it is converted into serotonin by the enzyme aromatic L-amino acid decarboxylase. Some clinical studies have shown benefits of 5-HTP supplementation for mood support, though results vary, and long-term safety data is limited. -
L-Tryptophan
L-tryptophan is the essential amino acid from which 5-HTP and serotonin are ultimately derived. It crosses the blood–brain barrier via the LAT1 transporter, but competes with other large neutral amino acids (LNAAs) such as leucine, isoleucine, and valine. Pairing tryptophan intake with carbohydrates can reduce this competition by shifting LNAAs into muscle tissue, potentially improving brain uptake of tryptophan. -
Magnesium L-Threonate
Magnesium is a cofactor in many enzymatic processes related to neurotransmitter synthesis and receptor function. Magnesium L-threonate is a form of magnesium that crosses the blood–brain barrier more effectively than other forms. By increasing magnesium levels in the brain, it may help support the enzymes involved in serotonin production and improve stress resilience. -
SAMe (S-Adenosylmethionine)
SAMe is a naturally occurring compound that serves as a methyl donor in numerous biochemical reactions. Within the brain, it contributes to the synthesis and regulation of neurotransmitters including serotonin, dopamine, and norepinephrine. Although the exact mechanism of transport across the blood–brain barrier is not fully understood, SAMe supplementation has been studied for its mood-supporting properties, particularly in mild to moderate depression.
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About the author:
Hi, I’m Abinaa, a fourth-year naturopathic medical student at the Canadian College of Naturopathic Medicine with a deep-rooted passion for natural healing, inspired by my South Asian upbringing. Through this blog, I hope to share my journey, explore topics in holistic health and wellness, and offer simple, thoughtful insights that support a more balanced and mindful way of living.
