5-HTP Is Helpful for Mitochondrial Biogenesis

Because the metaphor is so apt, mitochondria are often referred to as the "powerhouses" that generate energy, optimize cellular function and regulate the survival of neurons, especially under stress. Then a recent study uncovered more.

Teams of researchers based at Tata Institute of Fundamental Research (TIFR) in Mumbai, India, found that the neurotransmitter serotonin, known in scientific circles as 5-HT, is a significant player in the creation of new mitochondria in neurons, a process called mitochondrial biogenesis.

The process simultaneously enhances mitochondrial function while increasing cellular respiration and ATP, the energy currency of the cell. ATP is described in one study as both a neurotransmitter and neuromodulator.¹ It involves the serotonin-2A (or 5-HT2A) receptor via "master regulators" of mitochondrial biogenesis, SIRT1 and PGC-1α.

According to the study,² published in Proceedings of the National Academy of Sciences of the United States of America (PNAS), 5-HT reduces cellular reactive oxygen species, boosts antioxidant enzymes, enhances mitochondrial function and "exerts potent neuroprotective action in neurons challenged with stress, an effect that requires SIRT1." EurekAlert explains further that 5-HT:

"Uncovers an unprecedented role for serotonin in energy production in neurons directly impacting how neurons handle stress. Mitochondrial function in neurons is vital in determining how neurons cope with stress and the trajectory of aging."³

Lead scientists Vidita Vaidya and Ullas Kolthur-Seetharam from TIFR and clinical researcher Ashok Vaidya wrote that after they identified 5-HT2A as the "key determinant" for the effects of the mitochondria by 5-HT, their next task was to point out the specific signaling pathways bringing about those effects.

While those pathways remained elusive, the researchers did note previously unknown evidence that 5-HT is an upstream regulator of SIRT1, which the authors of a previous study published in Cell⁴ observed is involved in numerous metabolic processes in many tissues. For instance, in a mouse model, SIRT1 reduced the production of Aβ amyloid peptides, the plaques often found in the brains of Alzheimer's patients. In addition:

"Our findings raise the tantalizing possibility of a reciprocal relationship between 5-HT and SIRT1 in the brain. Given the role of 5-HT in facilitating stress adaptation, this suggests the possibility that 5-HT could serve as a vital intermediary in enhancing stress adaptation of neurons through recruitment of the SIRT1–PGC-1α axis to enhance mitochondrial biogenesis and function, thus endowing neurons with enhanced capacity to buffer stress."⁵

The Efficacy of 5-HTP

An amino acid your body produces naturally and uses to produce serotonin, 5-HTP is the hydroxylated form of tryptophan. The supplements are made from the seeds of an African plant known as Griffonia simplicifolia and aren't derived from foods.⁶

In 2012, the journal Neuropsychiatric Disease and Treatment published a study⁷ that described L-5-hydroxytryptophan (5-HTP) as the immediate precursor of serotonin. (The term "precursor" in chemistry describes a compound that participates in a chemical reaction that forms another substance.) One of the interesting comparisons is that 5-HTP freely crosses the blood–brain barrier, while serotonin does not.⁸

This study noted the popularity of 5-HTP for cases of depression, as well as attention-deficit hyperactivity disorder (ADHD), Parkinson's and other maladies, but also asserted that some of the claims are "exaggerated and inaccurate," with efficacy only in combination with other compounds.

The key to the efficacy of 5-HTP for depression and anxiety, many experts say, may involve individual levels of serotonin or a lack thereof. While serotonin is a neurotransmitter with a central role in regulating mood, there's not a lot of clinical evidence that it's effective for anxiety. However, one study notes:

"Anxiety-like behavior is regulated primarily by 5-HT1A and 5-HT2C receptors, among others, but the 5-HT2C receptor regulates not only anxiety but also reward processing, locomotion, appetite, and energy balance."⁹

Medical News Today notes two challenges in the claim that 5-HTP helps depression. First, a number of studies were conducted without the use of placebos,¹⁰ which some contend compromises their findings. Second, it doesn't generally last long in the body because it's too rapidly absorbed and eliminated; however, "If researchers could find a way to make 5-HTP last longer in the body, it may show more promise as a depression treatment."¹¹

An Australian review analyzed 5-HTP to see if it was more effective than a placebo for anxiety. It was, indeed, deemed better than placebos, although the researchers concluded more studies are needed.¹² That said, there's evidence that there are other areas where 5-HTP shines, some of which may hearken back to the new discovery of mitochondrial biogenesis.

5-HTP in Studies for Alleviating Several Disorders

Studies show a deficiency in 5-HTP is associated with depression, weight gain, anxiety, sleep disorders and other problems. On the other hand, increasing your 5-HTP intake has been noted for its ability to counterbalance all of them. In studies, it's been found to be beneficial for the following:

• Weight loss — As if bent on making your weight loss journey fail, losing weight produces hormones that make you feel hungry, which so often leads to failure.^13,14 However, 5-HTP may be able to counteract these hunger-inducing hormones, suppress your appetite and help you lose weight.¹⁵

One study showed that after taking 5-HTP or a placebo for five weeks, 20 people with diabetes on the 5-HTP ate about 435 fewer calories than the other group; 5-HTP also inhibited calorie intake from carbs, which also helped control their blood sugar.¹⁶ In addition, animal studies showed 5-HTP may reduce overeating due to stress or depression.^17,18

• Fibromyalgia and migraine pain — One study showed 5-HTP decreased pain perception in mice.¹⁹ In cases of fibromyalgia, causing overall weakness, bone and muscle pain, low serotonin has been suggested as the cause. One study recommends 5-HTP to improve pain from this cause, along with improving sleep, as well as depression and anxiety.²⁰ In another, 50 patients using it were "significantly improved."²¹

While the cause is still under debate, some scientists believe migraines stem from low levels of serotonin.²² One study notes, "The serotonergic (serotonin, 5-HT) system from the brainstem raphe nucleus has been most convincingly implicated in migraine pathophysiology."²³

Another involved 124 people with migraines who reported significant improvement after treatment with 5-HTP for six months, including decreases in migraine intensity and duration in 71% of the patients.²⁴

• Insomnia — Because 5-HTP makes serotonin, and serotonin can be converted to melatonin, this supplement is also used for sleeplessness and works by increasing your body's melatonin production.

Combining 5-HTP with GABA was found to reduce falling-asleep time from an average of 32.3 minutes to 19.1 minutes in 18 patients with sleep disorders, as well as increasing sleep time and improving sleep quality.²⁵

In another study, patients with parasomnia and/or DOA (disorders with arousals), characterized by unusual or abnormal behavior such as night terrors or sleepwalking, were advised that 5-HTP might be a beneficial treatment option.²⁶

Side Effects and Dosages of 5-HTP

If you've ever wondered what the term "dose dependent" means when it comes to supplements, not to mention drugs, it's that backing off or increasing your dose can impact both how it works and the side effects.²⁷ Having said that, the dose of 5-HTP you take will depend on your reason for taking it. For example:

• Weight management — One study with obese patients showed that taking 250 milligrams (mg) 30 minutes before eating a meal helped reduce their calorie consumption, mostly in the form of reduced carbohydrate intake.²⁸
• Mood enhancement — Psychology Today reports that 5-HTP may help with depression and anxiety when taken at 50 to 100 mg doses three times per day with meals, but it may take at least a week to notice beneficial effects. However, to avoid adverse effects, you may want to start a lower dose, such as 25 mg per day, and gradually increase it over a period of weeks, this article says.²⁹
• Fibromyalgia symptom relief — University of Michigan Medicine reports that taking 100 mg, three per day with meals, may have a beneficial effect.³⁰ A double-blind, placebo-controlled study reported significant improvements with 5-HTP supplementation and minimal side effects.³¹
• Migraines — Studies show that taking 100 to 200 mg, two to three times per day with meals for two to three weeks to notice a beneficial effect.^32,33
• Improved sleep — Since 5-HTP is naturally converted to serotonin, taking 200 mg before bedtime may work for those who don't respond to L-Tryptophan as a supplement.^34,35

If you're considering taking 5-HTP for any of these conditions or something else, it's also important to consult with a health care practitioner first, to make sure you're taking a dosage that's right for you, and that this supplement won't interfere with any other medications you may be on.

Some drugs cause increased serotonin production, so combining some drugs with 5-HTP may cause dangerous levels and lead to serotonin syndrome, which can be life threatening.³⁶ Certain cough medicines, antidepressants and prescription pain relievers are on this list. Similarly, if you take a sleep-promoting medication, including Ativan, Ambien or Klonopin, taking 5-HTP, which causes sleepiness, may be problematic.

Additionally, some research says taking 5-HTP may increase serotonin, but deplete the amounts of other neurotransmitters, including dopamine and norepinephrine, which could worsen some medical conditions, especially when taken long term. Some of these include ADHD, anxiety, depression, obesity, Parkinson's and seasonal affective disorder (SAD syndrome).

As for side effects, some individuals have reported nausea, vomiting, diarrhea, dizziness and stomach pain after taking 5-HTP supplements. You can minimize the potential of negative side effects by starting with smaller doses and increasing them gradually, if needed. As mentioned, because of the possibility of negative interactions with other medications, talk to your doctor or pharmacist before taking 5-HTP supplements.

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