Other Therapies for Bipolar Disorder – Serotonin Precursors

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Serotonin precursors are compounds used in the production of serotonin, dopamine, and norepinephrine, brain chemicals responsible for mood. A subset of people with bipolar disorder will respond to serotonin precursor treatment, but this intervention is still considered experimental. Both 5-hydorxytryptophan (5-HTP) and S-adenosyl-L-methionine (SAMe, pronounced "Sammy") are serotonin precursors that can be used in the treatment of bipolar disorder.

5-HTP is a compound made from the amino acid (protein) tryptophan and is primarily found in the brain. 5-HTP is one of the basic building blocks for serotonin, one of the neurotransmitters (brain chemical) responsible for mood regulation. Individuals who experience depression have reduced levels of serotonin in their brains.


Serotonin itself can be manufactured in the laboratory, but when taken as a supplement, it cannot reach the brain (it does not have the ability to cross from general blood circulation into brain circulation, because of a selective membrane that only allows certain chemicals into the brain). 5-HTP came into use in an effort to find a natural way to increase brain serotonin levels. Multiple research studies have demonstrated 5-HTP's ability to increase serotonin levels when taken as a supplement.

SAMe is a compound produced by the liver and used throughout the body in a chemical process called methylation. Methylation, essential to many chemical reactions in the body, is one of the last steps in the production of the brain chemicals serotonin, dopamine and norepinephrine (which regulate mood).

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Because there are no foods that have high SAMe levels, our bodies must make this substance. Our liver usually creates SAMe from the amino acid (protein) methionine, which is found in many foods. Interestingly, supplementing with methionine does not work as well as supplementing with SAMe, because creating SAMe takes multiple steps and requires many co-factors (other nutrients, such as vitamin B12, folate and others) to ensure that the process is successful.

While the use of SAMe in your body is diverse (it participates in over 35 biochemical processes), the process of interest in bipolar disorder is the creation of the brain chemicals mentioned above (dopamine, serotonin and norepinephrine). SAMe slows the breakdown of these brain chemicals, allowing them to work longer. In addition, SAMe speeds production of the receptors which receive these neurotransmitters. The presence of additional receptors allows the neurotransmitters that are present to work more effectively. Some research suggests that SAMe may also make the existing receptors more responsive (better able to receive messages from neurotransmitters). All of these functions combine to create increased levels of neurotransmitters, which can decrease the symptoms of bipolar disorder.

Both 5-HTP and SAMe have a few research studies to support their use as treatment for bipolar disorder. However, no one should use either supplement without consulting with a health care professional because both of these compounds may induce a manic state. They can also interfere with the functioning of standard antidepressant medications and lithium (commonly used to treat bipolar disorder). Again, the use of these supplements should not be attempted without the support of a qualified health care professional.

Safety and Dosing for 5-HTP

A typical dose of 5-HTP is between 150-300 mg a day. 5-HTP should not be used with any other antidepressant medication due to the risk of a rare condition called serotonin syndrome (or serotonin toxicity) that produces mental confusion, agitation, headache, shivering, sweating, hypertension (high blood pressure), tachycardia (fast heart rate), and other symptoms. As mentioned above, 5-HTP may also interfere with lithium.

Side Effects of 5-HTP

  • Agitation
  • Drowsiness
  • Flushing
  • Headache
  • Mild stomach upset
  • Tachycardia (fast heart rate)

There is a small risk of developing liver toxicity when using 5-HTP. L-tryptophan, a closely related chemical, was pulled from shelves in 1989 when it was associated with liver failure in a few people taking the supplement. While it appears that 5-HTP does not have this problem, it is best to check with your health practitioner before starting any new medication, especially if you currently have (or have a history of) liver problems.

Any substance that increases serotonin carries with it the risk of causing a manic episode. Consult your health care provider before taking 5-HTP.

Safety and Dosing for SAMe

Dosing is typically between 800mg/day and 1600mg/day for SAMe.

Side Effects of SAMe

  • Stomach upset

SAMe is very safe at recommended dosages. Because it is essentially a protein, it has no real side effects other than gastrointestinal upset (see box) and the possibility of causing mania in people with bipolar disorder. Supplementing with SAMe should not be undertaken without the support of your health care provider.

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