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Balanced Amino Acid Supplementation for Depressed Mood

Emerging findings support beneficial effects, though more studies are needed.

Research on 5-HTP for depressed mood

5-hydroxytryptophan (5-HTP) is a naturally occurring amino acid and the essential precursors of serotonin (5-hydroxytryptamine) an important neurotransmitter for mood regulation, memory, learning, and other cognitive functions. Research findings support that 5-HTP begins to have antidepressant effects at doses between 100mg and 300mg/day. More than 15 controlled studies have demonstrated consistent positive effects of 5-HTP in moderate depressed mood (Birdsall 1998). However, most studies on 5-HTP in depressed mood are small and study design problems preclude definitive conclusions. A Cochrane systematic review of 5-HTP and L-tryptophan (a related amino acid) in depressed mood identified 108 studies but analysis of findings was limited to only two studies involving 64 patients that met rigorous inclusion criteria (Shaw 2002). On the basis of those limited findings, the authors concluded that 5-HTP is probably more effective than placebo in depressed mood. The limited antidepressant benefits of 5-HTP, when taken alone, may reflect complex relationships between different neurotransmitters involved in mood regulation and their amino acid precursors. In this blog I examine current thinking on this topic focusing on amino acid balancing as a promising, more holistic, and possibly more effective approach to managing depressed mood.

Olga Larionovas/Shutterstock
Source: Olga Larionovas/Shutterstock

The monoamine depletion theory

According to the monoamine depletion theory, a deficiency of key neurotransmitters in the central nervous system can result from increased metabolism or inadequate synthesis of serotonin and dopamine induced by chronic use of a class of antidepressants called monoamine reuptake inhibitors such as serotonin reuptake inhibitors, tricyclic antidepressants, and antidepressants that inhibit reuptake of both serotonin and norepinephrine (i.e., the serotonin-norepinephrine reuptake inhibitors) (Hinz, Stein and Uncini 2011). According to the theory, when this happens the administration of 5-HTP and l-tyrosine is the only effective way to compensate for the depletion of serotonin and dopamine in the brain. It is important to note that the monoamine depletion theory is controversial and is the subject of ongoing debate among researchers. Proponents of the monoamine depletion theory contend that the problem of depletion of serotonin and dopamine caused by reuptake inhibitors is a serious issue that has been largely overlooked, resulting in ‘placebo relapse,’ loss of efficacy of antidepressants, worsening of depressive mood symptoms, increased risk of suicide and more frequent adverse effects.

The importance of taking neurotransmitter precursors in a balanced way

The neurotransmitters serotonin and dopamine do not cross the blood–brain barrier, hence levels of serotonin and dopamine in the brain depend on specific nutrients in the form of amino acids that are required for their synthesis. 5-hydroxytryptophan (5-HTP) is an essential amino acid precursor of serotonin, and the amino acid l-tyrosine is an essential precursor required for synthesis of dopamine. The amino acids that are necessary for synthesis of serotonin and dopamine sometimes ‘compete’ with each other potentially resulting in an imbalance of serotonin, dopamine or both neurotransmitters.

The synthesis and metabolism of serotonin and dopamine in the brain are regulated by transporter molecules that move these neurotransmitters and their amino acid precursors to the spaces between neurons (i.e., synapses) where neurotransmitter synthesis takes place. Differences in function of transporter molecules between individuals are related to differences in exposure to toxins or other biological substances, trauma, as well as genetic factors that affect postsynaptic neuronal membranes. Hence, dosages of 5-HTP and l-tyrosine needed to achieve optimal balance between serotonin and dopamine may differ substantially between individuals with similar depressive mood symptoms. In cases where neuronal membrane damage is permanent, the rate of synthesis of serotonin, dopamine, or other neurotransmitters may increase or decrease to compensate for the damage.

When serotonin and dopamine amino acid precursors in the form of 5-HTP and l-tyrosine are properly balanced, they are highly effective treatments of depressed mood (Hinz, Stein and Uncini 2010; Kohlstadt and Hinz 2009). In contrast, improperly balanced serotonin and dopamine precursors taken as supplements can lead to diminished effectiveness and increased risk of adverse effects. In some cases, balancing amino acids requires the addition of other amino acids. Optimal neurotransmitter synthesis occurs when serotonin and dopamine precursors are properly balanced. This process is called monoamine transport optimization (MTO). Two researchers, Kohlstadt and Hinz, have developed a detailed protocol for balancing amino acids addressing depressed mood that entails gradually increasing their respective dosages over several days while monitoring levels of their metabolites in the urine (Kohlstadt and Hinz 2009).

In cases where serotonin or dopamine levels are abnormally low due to damage of the post-synaptic neuronal membranes or a nutritional deficiency of amino acid precursors essential for neurotransmitter synthesis, MTO can be used to determine optimal dosages of amino acid supplementation. Optimal effectiveness with minimum adverse effects is achieved not through taking higher doses of amino acids, but through identifying the proper balance of amino acid precursors to achieve optimal ‘balance’ between serotonin and dopamine in a unique individual.

Achieving the optimal balance of 5-HTP and l-tyrosine is an important practical consideration since taking 5-HTP alone or in a dosage that is unbalanced with l-tyrosone may result in depletion of dopamine. As dopamine is the precursor of norepinephrine, which in turn is the precursor of epinephrine, depletion of l-tyrosine may result in reduced synthesis of all 3 neurotransmitters. The cascade depletion effect caused by inadequate or imbalanced amino acid precursors may result in worsening of depressive mood symptoms, increased risk of adverse effects and reduction in synthesis of neurotransmitters that complement one another to achieve optimal mood regulation.

Bottom line

Emerging research findings support that amino acid supplementation may be a safe and effective treatment of depressed mood. To date, most human clinical trials have investigated single amino acids such as 5-HTP or l-tyrosine, and have not examined complex relationships between 5-HTP and l-tyrosine or other amino acids that may play important roles in synthesis of neurotransmitters involved in mood regulation. A balanced approach to amino acid supplementation with 5-HTP and l-tyrosine, the essential precursors of serotonin and dopamine, may provide an important integrative strategy for management of depressed mood. Achieving optimal antidepressant response using this approach involves finding the optimal balance of amino acids. Large placebo-controlled studies conducted by independent researchers are needed to elucidate complex relationships between amino acid precursors and neurotransmitters involved in mood regulation, and to determine practical, safe strategies for amino acid supplementation for management of depressed mood and possibly other psychiatric disorders.


Depressed Mood: The Integrative Mental Health Solution, J. Lake M.D.


About the Author

James Lake, M.D., a clinical assistant professor at the University of Arizona College of Medicine, works to transform mental health care through the evidence-based uses of alternative therapies.