5 HTP

• Mood regulation
• Sleep quality improvement
• Stress resilience

• Appetite regulation
• Migraine prevention
• Fibromyalgia symptom reduction
• Anxiety reduction
• Potential antioxidant properties

5-Hydroxytryptophan (5-HTP) exerts its biological effects primarily through its role as the immediate precursor to serotonin (5-hydroxytryptamine, 5-HT), a key neurotransmitter involved in mood regulation, sleep, appetite, pain perception, and various other physiological processes. Unlike tryptophan, which is the natural dietary precursor to serotonin but requires conversion to 5-HTP via the rate-limiting enzyme tryptophan hydroxylase (TPH), 5-HTP bypasses this rate-limiting step in serotonin synthesis. This allows 5-HTP to more efficiently increase central nervous system serotonin levels. After oral administration, 5-HTP is rapidly absorbed from the gastrointestinal tract and, crucially, can cross the blood-brain barrier without requiring a transport molecule.

Once in the central nervous system, 5-HTP is converted to serotonin by the enzyme aromatic L-amino acid decarboxylase (AADC), with pyridoxal-5′-phosphate (vitamin B6) serving as a cofactor. This conversion occurs both in peripheral tissues and in the brain. The resulting increase in central serotonin levels is believed to be responsible for 5-HTP’s effects on mood, anxiety, sleep, and appetite. In the brain, serotonin acts on multiple receptor subtypes (5-HT1 through 5-HT7), each mediating different physiological and psychological effects.

For instance, activation of 5-HT1A receptors is associated with anxiolytic effects, while 5-HT2A and 5-HT2C receptors are involved in mood regulation and appetite control. Some serotonin is further metabolized to melatonin, particularly in the pineal gland, which may contribute to 5-HTP’s effects on sleep regulation. In the gastrointestinal tract, where approximately 90% of the body’s serotonin is produced and stored, 5-HTP can increase serotonin levels, potentially affecting gut motility and secretion. This may explain some of the gastrointestinal side effects associated with 5-HTP supplementation, as well as its potential benefits for certain functional gastrointestinal disorders.

Beyond its role in serotonin synthesis, 5-HTP has been shown to possess antioxidant properties, potentially scavenging free radicals and reducing oxidative stress. This may contribute to its neuroprotective effects and potential benefits in conditions characterized by increased oxidative damage. Additionally, 5-HTP may modulate inflammatory pathways, with studies suggesting it can suppress the expression of pro-inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) through effects on the mitogen-activated protein kinase (MAPK) pathway. When administered with carbidopa, a peripheral decarboxylase inhibitor that prevents the conversion of 5-HTP to serotonin outside the brain, the central effects of 5-HTP are enhanced while peripheral side effects are reduced.

This combination is sometimes used in clinical settings to maximize the therapeutic benefits of 5-HTP while minimizing adverse effects.

The optimal dosage of 5-HTP varies depending on the specific condition being addressed, individual response, and tolerance to side effects. Generally, a gradual introduction is recommended, starting with 50 mg once or twice daily and slowly increasing to the target dose over 2-4 weeks to minimize potential gastrointestinal side effects. For most applications, daily doses range from 100-300 mg, typically divided into 2-3 doses throughout the day. Higher doses (300-600 mg daily) have been used in clinical studies for specific conditions like depression and fibromyalgia, but such doses should only be used under medical supervision due to increased risk of side effects.

Taking 5-HTP with food may reduce gastrointestinal side effects, while taking it on an empty stomach may enhance absorption for some individuals. For sleep-related issues, taking the full daily dose or a larger portion of it approximately 30-60 minutes before bedtime is often recommended.

5-Hydroxytryptophan (5-HTP) demonstrates excellent bioavailability after oral administration, with approximately 70% of an ingested dose being absorbed from the gastrointestinal tract. Unlike its precursor tryptophan, 5-HTP does not require a transport molecule to cross the blood-brain barrier, allowing for more efficient entry into the central nervous system. After oral administration, plasma levels of 5-HTP peak within 1-2 hours, with a plasma half-life of approximately 4-6 hours. The conversion of 5-HTP to serotonin begins rapidly, with measurable increases in central nervous system serotonin levels occurring within 30-90 minutes after ingestion.

However, a significant portion of orally administered 5-HTP is decarboxylated to serotonin in peripheral tissues before reaching the brain, particularly in the enterochromaffin cells of the intestinal mucosa. This peripheral conversion may contribute to gastrointestinal side effects and reduce the amount of 5-HTP available for central serotonin synthesis. The bioavailability of 5-HTP may be influenced by various factors, including gastrointestinal pH, the presence of food, concurrent medications, and individual variations in metabolic enzymes.

Enteric-coated formulations protect 5-HTP from degradation in the stomach and may reduce gastrointestinal side effects, Co-administration with carbidopa (a peripheral decarboxylase inhibitor) prevents peripheral conversion to serotonin, increasing the amount of 5-HTP that reaches the brain, Taking 5-HTP on an empty stomach may enhance absorption for some individuals, though others may experience fewer gastrointestinal side effects when taking it with food, Vitamin B6 supplementation may enhance the conversion of 5-HTP to serotonin, as pyridoxal-5′-phosphate (the active form of B6) is a necessary cofactor for the decarboxylase enzyme, Extended-release or time-release formulations provide more sustained delivery and may reduce side effects associated with rapid increases in serotonin levels, Liposomal delivery systems may enhance absorption and bioavailability by protecting 5-HTP from degradation and facilitating cellular uptake, Avoiding high-protein meals when taking 5-HTP may reduce competition for absorption with other amino acids

For mood disorders such as depression and anxiety, dividing the daily dose into 2-3 administrations throughout the day helps maintain more consistent serotonin levels. Taking 5-HTP with meals may reduce gastrointestinal side effects, though absorption may be slightly decreased due to competition with dietary amino acids. For sleep enhancement, taking 5-HTP approximately 30-60 minutes before bedtime allows peak levels to coincide with the desired sleep onset. For appetite suppression and weight management, taking 5-HTP 30 minutes before meals may maximize its effects on satiety.

When using 5-HTP for migraine prevention, consistent timing of doses throughout the day is more important than specific timing relative to meals or activities. For individuals experiencing nausea or other gastrointestinal side effects, starting with a lower dose taken with food and gradually increasing the dose can improve tolerance. When co-administered with carbidopa to enhance central nervous system effects, timing should be consistent with the pharmacokinetics of both compounds, typically 30-60 minutes before meals. For individuals taking multiple supplements or medications, separating 5-HTP administration from other serotonergic compounds by at least 2 hours may reduce the risk of serotonin syndrome.

Safety Rating

2

Side Effects

• Gastrointestinal disturbances (nausea, vomiting, diarrhea, abdominal pain)
• Headache
• Drowsiness or sedation
• Dizziness
• Vivid dreams or nightmares
• Muscle problems (twitching, cramping, or stiffness)
• Anxiety or agitation (particularly at higher doses)
• Potential cardiac effects (palpitations, irregular heartbeat) in sensitive individuals
• Serotonin syndrome (when combined with other serotonergic substances)

Contraindications

• Concurrent use of antidepressants (SSRIs, SNRIs, MAOIs, tricyclics)
• Concurrent use of other serotonergic medications (triptans, certain pain medications, certain anti-nausea medications)
• Down syndrome (may cause seizures)
• History of serotonin syndrome
• Pregnancy and breastfeeding (insufficient safety data)
• Scheduled surgery (may interact with anesthetics and other perioperative medications)
• Severe liver or kidney disease
• History of eosinophilia-myalgia syndrome
• Carcinoid syndrome (may worsen symptoms)

Drug Interactions

• Serotonergic antidepressants (SSRIs, SNRIs, MAOIs, tricyclics) – risk of serotonin syndrome
• Triptans (migraine medications) – increased risk of serotonin syndrome
• Carbidopa (Parkinson’s medication) – may increase central effects of 5-HTP
• Tramadol and other opioid pain medications – increased risk of serotonin syndrome
• Dextromethorphan (cough suppressant) – increased risk of serotonin syndrome
• St. John’s Wort and other serotonergic herbs – additive effects, increased risk of serotonin syndrome
• Anti-nausea medications (ondansetron, granisetron) – potential for serotonin syndrome
• Sedatives and CNS depressants – may enhance sedative effects
• Medications metabolized by CYP450 enzymes – theoretical interactions, clinical significance unclear

Upper Limit

No official upper limit has been established by regulatory authorities. Clinical studies have used doses up to 600 mg daily, but side effects increase significantly at higher doses. Most experts recommend not exceeding 300 mg daily without medical supervision. For long-term use (beyond 12 weeks), lower maintenance doses (100-200 mg daily) are generally recommended. The risk of serotonin syndrome increases with higher doses, particularly when combined with other serotonergic substances. There is limited data on the safety of 5-HTP use beyond 1-2 years. Individuals with a history of gastrointestinal issues, cardiovascular conditions, or psychiatric disorders should use lower doses and increase gradually under medical supervision.

In the United States, 5-HTP is regulated as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994. As such, it is not subject to the same pre-market approval process as pharmaceutical drugs. Manufacturers are permitted to market 5-HTP without demonstrating safety or efficacy to the FDA, though they are responsible for ensuring their products are safe and properly labeled. The FDA has not approved 5-HTP for the treatment of any medical condition, and manufacturers are prohibited from making specific disease claims (such as ‘treats depression’ or ‘cures insomnia’).

However, structure/function claims (such as ‘supports healthy mood’ or ‘promotes restful sleep’) are permitted when accompanied by the standard disclaimer that the statements have not been evaluated by the FDA and that the product is not intended to diagnose, treat, cure, or prevent any disease. The FDA has issued warning letters to some companies marketing 5-HTP with drug claims or unsubstantiated health claims. Following the eosinophilia-myalgia syndrome (EMS) outbreak associated with contaminated L-tryptophan in 1989, the FDA temporarily restricted tryptophan supplements but did not impose similar restrictions on 5-HTP, despite some concerns about potential similar contaminants. The FDA has not established a recommended daily intake or upper limit for 5-HTP consumption.

Eu: In the European Union, regulatory status varies by country. In some EU countries, 5-HTP is available as a prescription medication for depression and other conditions, while in others it is regulated as a food supplement. The European Food Safety Authority (EFSA) has not approved any health claims for 5-HTP under the Nutrition and Health Claims Regulation. In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) has approved 5-HTP as a prescription drug for depression under certain brand names.

Canada: Health Canada regulates 5-HTP as a natural health product (NHP). It has been issued a Natural Product Number (NPN) and is approved for use in helping to promote healthy mood balance, helping to reduce the symptoms of fibromyalgia, and as a sleep aid. Products containing 5-HTP must meet specific quality, safety, and efficacy requirements to be legally sold in Canada.

Australia: The Therapeutic Goods Administration (TGA) in Australia regulates 5-HTP as a complementary medicine. It is included in the Australian Register of Therapeutic Goods (ARTG) and can be sold as a listed medicine for various indications related to mood support and sleep, provided it meets quality and safety standards.

Uk: In the United Kingdom, 5-HTP is regulated as a food supplement and is widely available without prescription. The Medicines and Healthcare products Regulatory Agency (MHRA) has not classified it as a medicinal product, though this could change if specific medicinal claims are made.

Japan: In Japan, 5-HTP is not approved as a pharmaceutical or recognized as a food with functional claims. It exists in a regulatory gray area and is not widely available as a supplement.

Medium

$0.30-$1.50 per day for standard formulations (50-200 mg); $1.00-$3.00 per day for premium or specialized formulations (enteric-coated, time-release, or higher potency)

5-HTP offers moderate value for its cost, with significant variation based on brand, formulation, and dosage. Standard 5-HTP supplements typically cost between $10-$30 for a 30-60 day supply at common therapeutic doses (100-200 mg daily), resulting in a daily cost of approximately $0.30-$1.00. Premium formulations, including enteric-coated, time-release, or higher potency products, typically cost $20-$45 for a similar supply, increasing the daily cost to $0.70-$1.50. Specialized formulations that combine 5-HTP with synergistic ingredients (such as vitamin B6, magnesium, or L-theanine) generally command higher prices, ranging from $25-$60 for a 30-day supply, or $0.80-$2.00 per day.

The cost-effectiveness of 5-HTP must be evaluated in the context of its intended use and compared to alternative treatments. For mood disorders such as depression and anxiety, 5-HTP represents a significantly lower cost option compared to prescription antidepressants, particularly for uninsured individuals. Brand-name SSRIs can cost $200-$500 monthly without insurance, while generic versions typically range from $40-$100 monthly. However, the efficacy of 5-HTP for clinical depression is less well-established than pharmaceutical options.

For sleep enhancement, 5-HTP is moderately cost-effective compared to other natural sleep aids like melatonin (typically less expensive) or valerian root (similarly priced), and substantially less expensive than prescription sleep medications. For fibromyalgia symptom management, the cost-effectiveness of 5-HTP is particularly notable, as effective doses (300-400 mg daily) cost approximately $1.00-$2.00 per day, compared to prescription fibromyalgia medications that can cost $200-$600 monthly. For weight management, the value proposition is less clear, as effects are typically modest and may diminish over time. To maximize cost-efficiency, consumers should consider: 1) Standard formulations over specialized ones for initial trials, as the basic form is sufficient for many users; 2) Bulk purchasing options, which can reduce costs by 20-30%; 3) Subscription services offered by many supplement companies, which typically provide 10-15% discounts; 4) The potential need for complementary supplements (such as vitamin B6) which may increase overall costs but enhance efficacy.

Properly stored 5-HTP supplements typically have a shelf life of 2-3 years from the date of manufacture. However, the actual stability can vary based on formulation, packaging, and storage conditions. Capsules and tablets generally maintain stability longer than powder forms due to reduced exposure to air and moisture. Enteric-coated formulations may have slightly shorter shelf lives due to the potential degradation of the coating material over time.

Liquid formulations typically have the shortest shelf life, usually 1-2 years when properly preserved. The manufacturer’s expiration date should be considered the primary guide for shelf life, though properly stored supplements may retain potency for some time beyond this date. After opening, powder forms should ideally be used within 6-12 months to ensure optimal potency.

Store 5-HTP supplements in a cool, dry place away from direct sunlight and heat sources. Room temperature storage (below 77°F/25°C) is generally adequate, though refrigeration may extend shelf life in hot and humid climates. Keep containers tightly closed to prevent moisture entry, which can accelerate degradation. The original container with desiccant packets is typically optimal for storage.

For powder forms, transfer to an airtight container if the original packaging doesn’t reseal effectively. Amber or opaque containers provide protection from light-induced degradation. Avoid storing in bathroom medicine cabinets or kitchen areas where temperature and humidity fluctuations are common. If refrigerating, ensure the container is sealed to prevent condensation upon removal.

For travel, consider transferring only the amount needed to smaller containers to minimize exposure of the main supply to environmental fluctuations.

Exposure to oxygen (leads to oxidation, particularly in powder forms), Exposure to light, especially UV light (accelerates degradation), High temperatures (accelerate chemical breakdown), Moisture (promotes hydrolysis and potential microbial growth), pH extremes (5-HTP is most stable at slightly acidic to neutral pH), Presence of certain metal ions (can catalyze oxidation reactions), Enzymatic degradation (particularly in liquid formulations without preservatives), Mechanical stress (excessive shaking or grinding of tablets can affect stability)

Synthesis Methods

Natural Sources

Quality Considerations

Unlike many traditional herbal remedies with centuries of documented use, 5-hydroxytryptophan (5-HTP) has a relatively recent history as a therapeutic agent, emerging primarily through scientific discovery rather than traditional medicine systems. The seeds of Griffonia simplicifolia, the primary natural source of 5-HTP, have been used in traditional West African medicine for centuries, though not specifically for their 5-HTP content. Traditional uses included treatments for diarrhea, vomiting, and as an aphrodisiac, though these applications were not directly related to the serotonergic effects now associated with 5-HTP. The scientific understanding of 5-HTP began to develop in the mid-20th century with advances in neurochemistry and the identification of serotonin as a neurotransmitter.

In 1951, serotonin (5-hydroxytryptamine or 5-HT) was first identified in the mammalian brain, leading to research into its precursors and metabolic pathways. By the late 1950s, researchers had established the metabolic pathway from tryptophan to 5-HTP to serotonin, with the recognition that 5-HTP could cross the blood-brain barrier while serotonin could not. The first clinical applications of 5-HTP emerged in the 1960s and early 1970s, primarily in European countries, where it was investigated as a treatment for depression. Early studies by researchers such as Angst, Woggon, and Schoepf (1977) and Takahashi et al.

(1975) explored its antidepressant effects, often finding comparable efficacy to standard tricyclic antidepressants of the era but with fewer side effects. In the 1970s and 1980s, research expanded to include other conditions affected by serotonergic function, including anxiety disorders, insomnia, and headaches. The work of van Praag and other researchers during this period established much of our current understanding of 5-HTP’s clinical applications. The commercial availability of 5-HTP as a dietary supplement began in the 1980s, primarily in Europe, with wider global distribution following in the 1990s.

However, its adoption was temporarily affected by the eosinophilia-myalgia syndrome (EMS) outbreak associated with contaminated L-tryptophan supplements in 1989. While this outbreak was specifically linked to contaminants in tryptophan produced by a single manufacturer using genetically engineered bacteria, it raised concerns about amino acid supplements in general, including 5-HTP. In the late 1990s and early 2000s, interest in 5-HTP as a natural alternative to pharmaceutical antidepressants grew substantially, particularly as awareness of the side effects of selective serotonin reuptake inhibitors (SSRIs) increased. The publication of influential reviews, such as Birdsall’s 1998 paper ‘5-Hydroxytryptophan: A Clinically-Effective Serotonin Precursor,’ helped establish 5-HTP’s place in complementary and alternative medicine.

Today, 5-HTP is widely used as a dietary supplement for mood support, sleep enhancement, and appetite regulation. Its usage continues to grow as interest in natural approaches to mental health increases, though it remains less commonly prescribed by conventional medical practitioners than pharmaceutical alternatives, particularly in the United States. In some European countries, however, 5-HTP is available as a prescription medication for depression and other conditions.

Shaw K, Turner J, Del Mar C. Are tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysis. Aust N Z J Psychiatry. 2002;36(4):488-491. (Found insufficient evidence to determine efficacy in depression due to small number of studies and methodological issues), Javelle F, Lampit A, Bloch W, Häussermann P, Johnson SL, Zimmer P. Effects of 5-hydroxytryptophan on distinct types of depression: a systematic review and meta-analysis. Nutr Rev. 2020;78(1):77-88. (Found limited evidence for efficacy in depression, with methodological limitations in existing studies)

5-HTP for treatment-resistant depression in combination with SSRIs, Comparison of 5-HTP and melatonin for sleep quality improvement, 5-HTP for anxiety symptoms in perimenopausal women, Effects of 5-HTP supplementation on gut microbiome composition, 5-HTP for emotional eating and weight management