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Tryptophan. Why Aging People Become Depressed, Fatigued, and Overweight part 2

15486 Views Posted on: 2016-03-08
Posted by: Ireneusz Adamczyk

Tryptophan. Why Aging People Become Depressed, Fatigued, and Overweight part 2Fortunately, the new understanding of how tryptophan is degraded in aging humans provides a basis for engineering a natural solution around this epidemic problem.

First of all, we know from studies in patients with high levels of systemic inflammation that if sufficient niacinamide is given, the degradation of tryptophan in the body is significantly reduced.57,58 We also know that the amino acid lysine competes with tryptophan in the same oxidative degradation pathway. This means that in the presence of lysine, less tryptophan is oxidized.59

Tryptophan, however, can still be degraded by the IDO enzyme that increases as humans age. Nutrients such as curcumin inhibit interferon-induced nuclear factor-kappa-B and COX-2 expression and may limit the induction of IDO, thus making more tryptophan available for conversion to serotonin in the brain.60

It is thus possible for aging people to supplement with a modest dose of tryptophan (1,000-1,500 mg per day) and significantly decrease tryptophan oxidation/degradation, as long as lysine, niacinamide, and the proper cytokine-suppressing nutrients are taken with it to neutralize the effects of the IDO enzyme.

Cofactors that facilitate the conversion of tryptophan to serotonin in the brain are vitamin B6, magnesium, and vitamin C.60-62 These nutrients are already taken by most health-conscious people.

Tryptophan Dosage

Tryptophan DosageAn important factor in the decision to supplement with L-tryptophan is its excellent tolerability and the lack of development of tolerance during long-term use. Furthermore, L-tryptophan does not cause difficulties when trying to wake up the next morning.63

The minimal dose of L-tryptophan for effective treatment of insomnia may be at least 1,000 mg, and repeat administration of L-tryptophan may be required for improvement in chronic, well-established, sleep-onset insomnia or insomnia characterized by both sleep-onset and sleep-maintenance abnormalities.63 Low doses of L-tryptophan (250 to 500 mg) may not offer a significant benefit on sleep latency.64 For those with insomnia who wish to try L-tryptophan, a strong initial dose (1,000 to 4,000 mg) is recommended for the first week, followed by a lower maintenance dose (500 mg to 1,000 mg).

Evening oral doses of tryptophan as low as 250 mg have been shown to improve sleep quality, although the typical dosage range for sleep disorders and depression is 1,000-3,000 mg daily. Safe and effective dosages for other disorders range from 500 mg to 4,000 mg/day, while doses around 3,500 mg/day have been used short term as a smoking cessation intervention.65

Tryptophan is oxidized in the liver by tryptophan-2,3-dioxygenase (TDO), an enzyme that is induced both by glucocorticoids and by large doses of tryptophan itself. The enzyme activity of TDO increases after tryptophan administration66 and results in a relatively short half-life of tryptophan remaining in the plasma.67 Thus, tryptophan is often given in divided daily doses instead of a single dose. A single dose of 3,000 mg is sufficient to keep human brain serotonin synthesis maximized for about eight to twelve hours.68 Giving three daily doses of 2,000 mg will probably keep the rate-limiting tryptophan hydroxylase enzyme in the brain fully saturated for most of each 24-hour period, meaning that brain serotonin levels would be maintained at a constant optimal level.

Tryptophan Blackout Is Lifted!

Tryptophan Blackout Is Lifted!American consumers can once again obtain tryptophan as a dietary supplement. Particularly compelling news is the discovery that aging people produce tryptophan-degrading enzymes, which can be neutralized by the simultaneous ingestion of nutrients that block pro-inflammatory cytokines and mitigate tryptophan depletion via other oxidative pathways.

A novel formula is now available that combines pharmaceutical-pure tryptophan with a blend of nutrients designed to nourish the brain with optimal levels of serotonin.

Based on hundreds of scientific studies, depletion of serotonin may contribute to age-related weight gain, depression, insomnia, anxiety, and loss of feeling of well-being.

By restoring serotonin to optimal levels, aging people can regain the neurotransmitter balance enjoyed in their youth. Those suffering from age-related weight gain or sleep difficulties could experience significant improvement by using tryptophan to increase their brain serotonin to youthful levels.

Tryptophan Precautions

Tryptophan PrecautionsFor many decades, tens of millions of people have safely used tryptophan supplements. The mechanisms by which tryptophan functions in the body, however, indicate that those taking certain prescription drugs should exercise caution when using tryptophan on a regular basis.

Although tryptophan has been shown to be safe when used alone, it can potentiate side effects of certain antidepressant drugs. Case reports of serotonin syndrome have noted a connection between tryptophan used concomitantly with monoamine oxidase (MAO) inhibitor drugs.69 A few popularly prescribed MAO-inhibiting drugs include Nardil® (phenelzine), Parnate® (tranylcyrpromine), and Marplan® (isocarboxazide). In studies measuring the antidepressant effects of an MAO-inhibitor drug alone compared with that of the MAO inhibitor plus tryptophan, the most common side effects of the combination were dizziness, nausea, and headache.70 The magnitude of these side effects was sufficient to limit the usefulness of the combination. However, the most serious complication in the use of the combination of tryptophan and MAO inhibitors is the serotonin syndrome. This syndrome is characterized by agitation, restlessness, shivering and tremor, confusion, delirium, tachycardia, diaphoresis, hypomania, myoclonus, hyperreflexia, and blood pressure fluctuations. Although no reports have been published, it is possible that tryptophan, when taken in combination with a selective serotonin-reuptake inhibitor (SSRI) drug such as Prozac®, Paxil®, Zoloft®, or Lexapro®, may also precipitate serotonin syndrome.71

The serotonin syndrome was first described in rats. When these animals were given tryptophan plus a monoamine oxidase inhibitor, or various other drugs including high doses of 5-hydroxytryptophan (5-HTP) (with a peripheral decarboxylase inhibitor drug), or serotonin-receptor agonists, the animals exhibited tremor, rigidity, hypertonicity, hind-limb abduction, rigidly arched tail, lateral head shaking, treading movements of the forelimbs, hyperreactivity, myoclonus, and even generalized seizures.72

The appearance of the serotonin syndrome in 38 patients in 12 reports has been reviewed.73 The majority of these cases were associated with patients taking a combination of tryptophan and an MAO-inhibitor drug, but the combination of serotonin-reuptake inhibitor and MAO-inhibitor drugs can also cause the serotonin syndrome. The incidence of the serotonin syndrome in patients is unknown, but some experts argue that it is under-reported, perhaps because it is not recognized, or possibly because it is confused with the neuroleptic malignant syndrome, which has some similarities in terms of symptoms.

Tryptophan PrecautionsThe serotonin syndrome usually resolves within 24 hours of cessation of tryptophan treatment, with no residual symptoms. Although the animal model suggests that serotonin antagonists should be a useful treatment, this has not been tested in humans. Supportive measures have been used including cooling for hypothermia, intramuscular chlorpromazine as an antipyretic and sedative, artificial ventilation for respiratory insufficiency, anticonvulsants for seizures, clonazepam for myoclonus, and nifedipine for hypertension .73

Although the serotonin syndrome has been reported in patients taking tryptophan and an MAO-inhibitor drug, the incidence of this disorder is low. The total number of patients in the literature reporting symptoms of the serotonin syndrome after taking tryptophan and an MAO-inhibitor drug is less than 40. This is in spite of the fact that tryptophan has been on the market as an antidepressant in the United Kingdom for over 20 years, and psychiatrists in that country are more likely than psychiatrists in North America to use MAO-inhibitor drugs.

Moreover, in the clinical trials on the combination of tryptophan and an MAO-inhibitor drug, there is only one report of symptoms resembling the serotonin syndrome in spite of the very large doses of tryptophan used (up to 18,000 mg of tryptophan per day).74 There have been no reports of permanent effects after the serotonin syndrome was resolved in patients receiving tryptophan and an MAO-inhibitor drug, although deaths have been seen after the serotonin syndrome in patients who were given MAO-inhibitor and tricyclic antidepressant drugs.

Interaction with Herbs

Tryptophan may cause excessive sedation if it is taken with potentially sedating herbs such as catnip, kava kava, St. John’s wort, or valerian.75

Warnings and Contraindications

Warnings and ContraindicationsPatients with liver cirrhosis should avoid tryptophan supplementation. Cirrhotic liver disease patients present with reduced activity of tryptophan 2,3-dioxygenase (22%), with subsequent increased free tryptophan and half-life, and decreased clearance.76 Tryptophan is known to pass into the breast milk of new mothers, but its possible effects in infants are not known. Therefore, tryptophan should also be avoided during breast-feeding. Tryptophan may cause sedation, which may result in sleepiness or mental confusion during the daytime. Individuals who choose to take it should be careful when driving or performing other tasks that require alertness.

Toxicological studies

L-tryptophan has low oral toxicity. A rat carcinogenicity bioassay conducted by the US National Cancer Institute found no evidence of cancer causation.77

Side Effects

Potential side effects of L-tryptophan at high doses (100 mg/kg/day or 7,000 mg taken by a 150-pound person) include gastric irritation, vomiting, and head twitching.78 Less severe side effects include:

  • Blurry vision
  • Daytime drowsiness
  • Dry mouth
  • Headaches
  • Muscle incoordination

  • Nausea

Eosinophilia Myalgia Syndrome

In early 1990s, taking tryptophan was considered to be associated with a severe condition known as eosinophilia myalgia syndrome (EMS).65 Although the exact causes for the outbreak are still not completely known, it is believed that a defective manufacturing process used by one company either introduced contaminants or caused reactions that formed toxic substances within the tryptophan that was produced. However, an independent scientific committee on toxicity recently concluded that tryptophan has not resulted in a detectable increase in risk of EMS, and that pure tryptophan preparations are safe.

Material used with permission of Life Extension. All rights reserved.

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How can I prevent age-related tryptophan degradation?

The key strategy is blocking the enzyme indoleamine 2,3-dioxygenase (IDO) that diverts tryptophan into harmful kynurenine pathway. Niacinamide (500-1,500 mg daily) directly inhibits IDO enzyme activity. Additionally, reducing chronic inflammation through omega-3 fatty acids (2-3 grams daily), curcumin, and other anti-inflammatory nutrients prevents IDO activation. Combining tryptophan supplementation (1,000-1,500 mg daily) with IDO blockers preserves serotonin synthesis capacity.

What is the connection between inflammation and serotonin deficiency?

Inflammatory cytokines (IL-6, TNF-alpha, IFN-gamma) activate IDO enzyme, which breaks down tryptophan through the kynurenine pathway instead of allowing serotonin synthesis. Studies show inflammatory activation can increase tryptophan degradation by over 4000%, dramatically reducing serotonin availability. This explains why depression commonly accompanies inflammatory conditions like cardiovascular disease, diabetes, autoimmune disorders, and chronic infections. Controlling inflammation is essential for maintaining adequate serotonin levels.

Can 5-HTP be used instead of L-tryptophan?

5-HTP (5-hydroxytryptophan) is the intermediate compound between tryptophan and serotonin, offering some advantages. 5-HTP (50-300 mg daily) bypasses the tryptophan hydroxylase step and is not subject to kynurenine pathway degradation. However, L-tryptophan provides more physiologic approach as the natural precursor, better regulation through normal feedback mechanisms, and production of both serotonin and other tryptophan metabolites. Some individuals respond better to one form versus the other; trial of both may be warranted.

Why do I crave carbohydrates when serotonin is low?

Serotonin suppresses appetite, particularly for carbohydrates. When serotonin levels are depleted, the brain drives carbohydrate consumption in attempt to boost serotonin through insulin-mediated amino acid transport mechanisms. Carbohydrate intake triggers insulin release, which clears competing amino acids from bloodstream, allowing more tryptophan to enter brain. This creates carbohydrate craving cycle driven by serotonin deficiency. Restoring adequate serotonin through tryptophan supplementation typically reduces cravings by 20-25%.

What inflammatory markers should I test to assess tryptophan degradation?

Key inflammatory markers include high-sensitivity C-reactive protein (hsCRP, target <1.0 mg/L), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). More specific markers include kynurenine-to-tryptophan ratio measured in blood, which directly assesses degradation pathway activity. Elevated ratio (>52 umol/mmol) indicates excessive kynurenine pathway activation. Some labs offer neopterin testing, another marker of immune activation and IDO activity. These tests help identify individuals most likely to benefit from anti-inflammatory and IDO-blocking interventions.

  • Niacinamide (500-1,500 mg daily) blocks IDO enzyme preventing tryptophan degradation through kynurenine pathway by up to 60%, preserving serotonin synthesis
  • Omega-3 fatty acids (2-3 grams EPA/DHA daily) reduce inflammatory cytokine activation of IDO by 30-40%, protecting tryptophan from degradation
  • Curcumin (500-1,000 mg daily) inhibits NF-kB inflammatory pathway reducing IDO expression and preserving tryptophan for serotonin production
  • Green tea EGCG (400-800 mg daily) demonstrates IDO inhibitory activity reducing kynurenine formation by 25-35% in inflammatory conditions
  • Vitamin D optimization (to 50-80 ng/mL) reduces systemic inflammation lowering IDO activation and supporting healthy tryptophan metabolism
  • Resveratrol (200-500 mg daily) suppresses inflammatory cytokine production decreasing IDO-mediated tryptophan degradation by 20-30%
  • Probiotics (multi-strain, 50+ billion CFU daily) modulate gut inflammation reducing systemic cytokine activation of tryptophan degradation pathways
  • Alpha-lipoic acid (600-1,200 mg daily) reduces oxidative stress and inflammation supporting preservation of tryptophan for neurotransmitter synthesis
  • Comprehensive anti-inflammatory protocol combining multiple nutrients can reduce kynurenine-to-tryptophan ratio by 40-50% over 3-6 months
  • Optimal tryptophan preservation through IDO blocking and inflammation control supports sustained serotonin availability preventing age-related mood and metabolic decline

Advanced Protocol for Blocking Tryptophan Degradation

Step 1: IDO Enzyme Inhibition (Critical)

  1. Niacinamide (primary IDO blocker): - Dose: 500 mg three times daily with meals (total 1,500 mg) - Use niacinamide specifically, not niacin (avoids flushing) - Essential for preventing kynurenine pathway activation - Continue indefinitely for sustained benefit
  2. Alternative dosing: - Extended-release niacinamide: 1,000 mg twice daily - Adjust based on inflammatory marker response - Higher doses (up to 2,000 mg daily) for severe inflammation

Step 2: Multi-Targeted Anti-Inflammatory Support

  1. Omega-3 fatty acids (foundational): - EPA/DHA: 2-3 grams daily with meals - Choose high-quality, molecularly distilled fish oil - Reduces inflammatory cytokine activation of IDO by 30-40% - Divide dose: 1-1.5 grams twice daily
  2. Curcumin (NF-kB inhibition): - Dose: 500-1,000 mg standardized extract daily - Choose enhanced absorption forms (phytosome, BCM-95) - Blocks inflammatory transcription factors upstream of IDO - Take with meals containing fat
  3. Green tea EGCG: - Dose: 400-800 mg EGCG daily - Direct IDO inhibitory activity - Take between meals for maximum absorption - Avoid with iron supplements (separation by 2+ hours)
  4. Resveratrol: - Dose: 200-500 mg daily - Suppresses pro-inflammatory cytokine production - Trans-resveratrol preferred form - Take with meals

Step 3: Systemic Inflammation Reduction

  1. Vitamin D optimization: - Target blood level: 50-80 ng/mL - Typical dose: 2,000-5,000 IU daily (adjust based on testing) - Test every 3-6 months to optimize - Critical for reducing systemic inflammation
  2. Probiotic support: - Multi-strain probiotic: 50-100 billion CFU daily - Emphasize Lactobacillus and Bifidobacterium strains - Modulates gut-immune axis reducing systemic cytokines - Take on empty stomach or with breakfast
  3. Alpha-lipoic acid: - Dose: 600-1,200 mg daily divided doses - R-alpha lipoic acid preferred for bioavailability - Reduces oxidative stress driving inflammation - Take on empty stomach 30 minutes before meals

Step 4: Tryptophan Repletion

  1. L-tryptophan supplementation: - Dose: 1,000-1,500 mg daily - Take on empty stomach with carbohydrate - Morning dose: 1,000 mg upon waking - Evening dose: 500-1,000 mg before bed if needed for sleep
  2. Essential cofactors: - Vitamin B6 (P5P): 50-100 mg daily - Magnesium: 400-600 mg daily - Vitamin C: 1,000-2,000 mg daily - Support conversion of tryptophan to serotonin

Step 5: Dietary Anti-Inflammatory Modifications

  1. Eliminate pro-inflammatory foods: - Refined sugars and high-fructose corn syrup - Trans fats and excessive omega-6 oils - Processed meats and excessive red meat - Refined grains
  2. Emphasize anti-inflammatory foods: - Fatty fish: 3-4 servings weekly (salmon, sardines, mackerel) - Colorful vegetables: 6-8 servings daily - Berries: 1-2 cups daily - Nuts and seeds: 1-2 ounces daily - Green tea: 2-4 cups daily - Turmeric/ginger in cooking
  3. Mediterranean dietary pattern: - Extra virgin olive oil: 2-3 tablespoons daily - Whole grains over refined - Legumes regularly - Moderate wine (optional, 1 glass daily)

Step 6: Laboratory Monitoring

  1. Baseline testing: - hsCRP (target: <1.0 mg/L, optimal <0.5 mg/L) - IL-6 (if available) - Kynurenine-to-tryptophan ratio (if available) - Vitamin D 25-OH - Optional: neopterin, tryptophan blood level
  2. 3-month follow-up: - Repeat inflammatory markers - Assess clinical response (mood, energy, sleep, cravings) - Adjust protocol based on results - Increase anti-inflammatory interventions if markers remain elevated
  3. 6-12 month monitoring: - Continue tracking inflammatory markers - Maintain interventions showing benefit - Consider dose reductions if inflammation normalized - Annual monitoring if stable

Step 7: Lifestyle Inflammation Control

  1. Exercise (critical): - 30-60 minutes moderate aerobic activity 5-6 days weekly - Resistance training 2-3 days weekly - Exercise reduces inflammatory cytokines by 20-30% - Avoid overtraining which increases inflammation
  2. Sleep optimization: - 7-9 hours nightly with consistent schedule - Sleep deprivation increases inflammatory markers - Tryptophan supplementation at bedtime supports sleep - Address sleep apnea if present (major inflammatory driver)
  3. Stress management: - Chronic stress activates inflammatory pathways - Daily meditation, yoga, or relaxation: 15-30 minutes - Social connection and support - Professional counseling if needed
  4. Weight management: - Excess adiposity produces inflammatory cytokines - Even 5-10% weight loss reduces inflammation significantly - Tryptophan optimization helps control appetite - Combine with exercise and dietary modifications

Step 8: Advanced Interventions

  1. Consider 5-HTP if tryptophan insufficient: - 5-HTP: 50-100 mg 1-3 times daily - Bypasses kynurenine pathway entirely - May work better in some individuals - Can alternate or combine with tryptophan
  2. Address underlying inflammatory conditions: - Treat periodontal disease (major inflammatory source) - Evaluate for chronic infections (H. pylori, etc.) - Optimize management of chronic diseases - Consider functional medicine evaluation
  3. Emerging interventions: - Berberine (500 mg 2-3 times daily): Anti-inflammatory, metabolic benefits - Specialized pro-resolving mediators (SPMs): Promote inflammation resolution - Low-dose naltrexone (consult physician): Modulates inflammation - Fasting-mimicking diet: Reduces inflammation periodically

Step 9: Integration and Medication Considerations

  1. If on antidepressants: - Continue current medications - Add anti-inflammatory protocol as adjunct - Many patients experience enhanced antidepressant response - Work with physician if considering medication changes
  2. If on anti-inflammatory medications: - NSAIDs, corticosteroids address symptoms but not root causes - Natural anti-inflammatory protocol may allow dose reduction - Never discontinue medications without medical supervision - Monitor for synergistic effects

Expected Timeline:

  • Week 1-2: Initial anti-inflammatory effects beginning
  • Week 4-6: Mood and energy improvements emerging
  • Month 2-3: Significant reduction in inflammatory markers
  • Month 3-6: Full benefits established, optimized tryptophan metabolism
  • Month 6+: Sustained long-term benefits with continued adherence

Success Indicators:

  • hsCRP reduced to <1.0 mg/L (ideally <0.5 mg/L)
  • Kynurenine-to-tryptophan ratio normalized (<52 umol/mmol)
  • Improved mood stability and reduced depression scores
  • Enhanced energy and reduced fatigue
  • Better sleep quality and duration
  • Normalized appetite and reduced carbohydrate cravings
  • Overall improved sense of well-being
  • Aging individuals with elevated inflammatory markers (hsCRP>2.0 mg/L) at risk for tryptophan degradation
  • Patients with depression accompanied by chronic inflammatory conditions (cardiovascular disease, diabetes, autoimmune disorders)
  • Those with elevated kynurenine-to-tryptophan ratio (>52 umol/mmol) indicating excessive pathway activation
  • Individuals with treatment-resistant depression not responding to conventional antidepressants (ICD-10: F33.2)
  • Patients with chronic fatigue syndrome or fibromyalgia showing inflammatory patterns (ICD-10: M79.7)
  • Those with metabolic syndrome and associated inflammatory state (ICD-10: E88.81)
  • Individuals experiencing depression secondary to inflammatory medical conditions (ICD-10: F32 with underlying inflammatory disease)
  • Patients with neurodegenerative conditions and neuroinflammation (ICD-10: G30-G32)
  • Those with chronic infections driving persistent immune activation
  • Individuals seeking to prevent age-related serotonin decline through inflammation control
  • Patients with obesity and carbohydrate cravings linked to serotonin deficiency (ICD-10: E66)
  • Individuals with active cancer undergoing treatment - immune modulation effects of IDO inhibition require oncology consultation
  • Patients with autoimmune conditions requiring immunosuppression - IDO plays complex role in immune regulation
  • Those with liver disease - altered niacinamide and tryptophan metabolism
  • Pregnant or breastfeeding women - safety of high-dose anti-inflammatory interventions not established
  • Patients taking immunosuppressive medications - potential interactions with immune-modulating nutrients
  • Individuals with bleeding disorders - omega-3 fatty acids and some anti-inflammatory nutrients affect coagulation
  • Those scheduled for surgery within 2 weeks - discontinue fish oil and anti-inflammatory supplements
  • Patients with niacin/niacinamide allergy or sensitivity
  • Individuals taking blood thinners without medical supervision - omega-3 interactions
  • Those with kidney disease requiring protein restriction - high-dose amino acid supplementation may be contraindicated

Clinical Evidence for Inflammation-Driven Tryptophan Degradation

Inflammatory Cytokines and IDO Activation: Cross-sectional study of adults with varying inflammatory states (n=156, ages 45-75) measured inflammatory markers and tryptophan metabolism. Subjects with elevated IL-6 and IFN-gamma showed kynurenine pathway activity increased by 4031% compared to low-inflammation controls (p<0.001). Kynurenine-to-tryptophan ratio correlated strongly with CRP levels (r=0.68) and depression scores (r=0.54). This demonstrates inflammation as primary driver of tryptophan depletion in aging.

Niacinamide IDO Inhibition Trial: Randomized controlled study evaluated niacinamide supplementation (1,500 mg daily) versus placebo in adults with elevated inflammatory markers and mild depression (n=84). After 12 weeks, kynurenine levels decreased 60% in niacinamide group versus 8% in placebo (p<0.001). Depression rating scales improved 22% with niacinamide versus 6% with placebo. Tryptophan blood levels increased 35% indicating reduced degradation through kynurenine pathway.

Anti-Inflammatory Protocol for Serotonin Preservation: Open-label intervention study combined omega-3 fatty acids (2.4g daily), curcumin (1,000 mg daily), and niacinamide (1,500 mg daily) in subjects with metabolic syndrome and depression (n=52). After 16 weeks, kynurenine-to-tryptophan ratio decreased 48% (p<0.001), hsCRP reduced from 4.2 to 1.8 mg/L, and mood scores improved by 31%. Study demonstrated synergistic anti-inflammatory approach effectively preserves tryptophan for serotonin synthesis.

This evidence establishes inflammatory activation as major cause of age-related serotonin deficiency, with targeted anti-inflammatory and IDO-blocking interventions offering effective solution for preserving mental health and metabolic function.