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Name: L-tryptophan, Tryptophan
Goes well with: Amino acids, Vitamin B complex
Number of scientific references: 41
Level of Evidence: Level II What is this?
Note: L-tryptophan metabolism is disturbed in alcoholism and may contribute to serotonin deficiency. Low tryptophan levels may increase, depression, anxiety or aggression in individuals with alcohol addiction, especially if patients have mutations in genes required for tryptophan metabolism.
Two studies have reported that supplementation with tryptophan can reduce depressive symptoms in alcoholism.
Not much is known about the safety of L-tryptophan treatment in patients with alcohol addiction and comorbid mental health issues. Further research is required to learn more about L-tryptophan supplements for reducing alcohol intake and addiction treatment.
Alcohol dependence is influenced by both genetic and environmental factors. Serotonin is a chemical in our brain that is linked to our optimal mood, pain regulation and it also assists our brain cells to communicate with each other.
Abnormalities in the serotonergic system can increase the risk of developing alcohol addiction.
Now, tryptophan is an amino acid that serves as a raw material for serotonin synthesis, and it is used as a dietary supplement for reducing depressive symptoms. It is metabolised by enzyme tryptophan hydroxylase.
Tryptophan hydroxylase 2 is a rate-limiting enzyme (regulates the rate of the reaction) involved in serotonin synthesis, and mutations in TPH2 gene linked with this enzyme has been associated with reduced serotonin and mood disorders.
Some research studies (not all) suggest that mutations in TPH2 gene may increase the risk of alcoholism.
Individuals who develop alcohol addiction at an early age have disturbed brain chemistry and more severe symptoms than late-onset alcoholism patients. Mutations in the tryptophan hydroxylase gene could be associated with age of onset of alcoholism.
A recent study published in Neuroscience Letters, 2015 reveals that different genetic variants of TPH2 gene may be associated with different psychological traits such as:
- rs1843809 gene variant was associated with depressive and aggressive traits and social anxiety in abstinent individuals
- rs4290270 gene variant was associated with depressive and anxiety traits
- rs4570625 gene variant was associated with aggressive traits
There is mixed evidence on increased suicide risk in alcoholism and its link with mutations in TPH2 gene.
What we gather from here is that disturbances in the serotonergic system and the genes linked with it can affect the psychological status of patients with alcoholism. So, would it be valid to supplement with serotonin precursor tryptophan to compensate for these mutations?
Few studies show that tryptophan supplementation helps reduce depressive symptoms and alcohol withdrawal symptoms in patients with alcohol addiction. But tryptophan metabolism is disturbed at every stage of alcoholism. There is insufficient data to confirm whether L-tryptophan supplements are useful and effective for treating alcohol addiction
How does alcohol consumption affect tryptophan metabolism?
Image Credit: Jeon, S.W. & Kim, Yong-Ku. (2015). Kynurenine and serotonin pathways of tryptophan metabolism: The etiology and pathogenesis of depression.
Tryptophan metabolism provides raw materials for various biochemical reactions, but two major pathways are:
- Serotonin synthesis
- Kynurenine pathway
A small amount of tryptophan is available for serotonin synthesis while most is metabolised through the kynurenine pathway.
In the kynurenine pathway, enzymes Tryptophan 2,3-dioxygenase (TDO, in the liver) and Indoleamine 2,3-dioxygenase (IDO, in organs other than liver) breakdown tryptophan to produce kynurenine and related metabolites.
Excessive production of these metabolites has been linked to depressive symptoms, and they are neurotoxic as well.
The enzyme IDO is activated as a result of immune response and by inflammatory agents. The kynurenine to tryptophan ratio is indicative of IDO activity and tryptophan degradation. This ratio is increased in depressive disorder.
Alcohol-induced liver damage impairs TDO activity resulting in altered levels of tryptophan and kynurenine.
Table of Contents
- 1 How does alcohol consumption affect tryptophan metabolism?
- 2 Can L-tryptophan help reduce alcohol cravings and binge drinking?
- 3 Can L-tryptophan supplements help treat alcoholism?
- 4 Dosage of L-Tryptophan or 5-HTP For Alcoholism
- 5 Precautions with L-Tryptophan or 5-HTP Use
- 6 Conclusion
Tryptophan metabolism is disturbed during all stages of alcoholism: during chronic alcohol intake, alcohol withdrawal and abstinence.
Tryptophan levels are reduced in chronic alcoholism
Consumption of a poor diet, especially in disadvantaged populations contributes to tryptophan deficiency.
An animal study indicates that alcohol consumption can worsen serotonin dysfunction which may be pre-existing in alcoholic individuals (as a result of genetic mutations).
Tryptophan metabolism is disturbed during alcohol withdrawal
Right before the appearance of alcohol withdrawal symptoms (within 6-9 hours of alcohol cessation), tryptophan levels in the blood are elevated. It is hypothesised that these elevated levels may lead to the formation of toxic metabolites via the kynurenine pathway which cause the behavioural symptoms of alcohol withdrawal syndrome.
Discontinuing alcohol consumption leads to an increase in cortisol or stress hormones which increases the activity of tryptophan 2,3-dioxygenase enzyme (TDO). This enzyme further reduces tryptophan concentration in the brain and reduces serotonin synthesis.
Tryptophan degradation continues during alcohol abstinence
According to the researchers, the reason for this unusual finding could be that transitioning from short to medium period of abstinence could involve stress and induction of high-stress hormone levels.
These stress hormone levels can activate enzyme TDO and breakdown tryptophan to kynurenine resulting in low serotonin levels.
Previously, a study published in Alcoholism, Clinical and Experimental Research, 1988 has confirmed that stress hormone and TDO levels are high even after one month of alcohol cessation.
Surprisingly, researchers from the University of Oslo, Norway came across some unexpected results on tryptophan levels and depression in alcoholism.
169 patients were enrolled in the study. Patients who had high scores of disease severity had higher kynurenine levels and higher kynurenine-tryptophan ratio than those who had lower scores.
Interestingly patients with severe depressive symptoms had higher tryptophan levels and lower kynurenine-tryptophan ratio than those with less severe depressive symptoms. These findings were found only in patients with high alcoholism severity and longer duration of abstinence.
Few reasons for these unexpected findings could be the effect of
- Dietary protein helped sustain tryptophan levels even though the kynurenine pathway is activated.
- Although high kynurenine-tryptophan ratio is frequently observed in depression, some patients with alcoholism and depression may have low ratios.
- High plasma levels of tryptophan may also indicate low uptake of tryptophan in the brain as it has to compete with other amino acids.
- The level to which tryptophan metabolism has been disturbed may differ based on the severity of depression.
Quick Gist: Tryptophan metabolism is disturbed in alcoholism as a result of the removal of tryptophan from the blood and excretion of its metabolites. The level of disturbance may be different in every patient.
Activation of enzymes tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase degrade tryptophan via the kynurenine pathway and cause serotonin deficiency. This can contribute to depressive symptoms and occurrence of symptoms such as seizures during alcohol withdrawal.
The disturbing effect of alcohol on tryptophan metabolism lasts even in alcohol abstinence which could be a result of high-stress hormone levels, alcoholic liver damage or due to the presence of mental health diseases.
Can L-tryptophan help reduce alcohol cravings and binge drinking?
Disturbances in our brain chemistry can affect our drinking habits. Depletion of both neurotransmitters serotonin and dopamine is found to increase the desire to drink in alcohol-dependent individuals.
Theoretically, tryptophan depletion and reduced serotonin synthesis should impact an individual’s desire to consume alcohol but the clinical evidence on this equivocal.
In 1987, Pihl et al. reported that tryptophan levels (increase or decrease) do not affect alcohol intake.
Stress contributes to initiation and relapse of alcoholism, and the neurotransmitter serotonin mediates stress-induced alcohol consumption.
A study published in Behavioural Pharmacology, 2014 examined the effect of stress and dietary tryptophan on alcohol cravings on binge drinkers or non-binge drinkers.
In the first half of the experiment, stress induction significantly increased the desire to drink in binge drinkers rather than non-binge drinkers.
Interestingly in the second half, a tryptophan-rich diet reduced stress-induced alcohol cravings in binge drinkers but increased stress-induced craving in non-binge drinkers.
What this study highlights is that dysfunction of the serotonergic system may present with different symptoms in each based on their binge drinking habits.
Irrespective of its effects on alcohol cravings, low tryptophan levels may impact mood and overall health of patients with alcoholism:
- Altered tryptophan levels may increase impulsivity and aggression in some patients with alcoholism.
- Low tryptophan-amino acid ratio can contribute to depression and anxiety in alcohol-dependent individuals.
- Low tryptophan levels may be linked to alcoholic liver disease, inflammation and immune system dysfunction.
Quick Gist: Depletion of neurotransmitters is found to increase alcohol cravings. However, tryptophan depletion in alcoholism may not necessarily increase the desire to drink. In fact, its effects may differ with each individual.
In binge drinkers, dietary tryptophan may reduce alcohol craving, but in non-binge drinkers, it may increase the desire to drink.
Low tryptophan levels may significantly affect the mood of alcohol-dependent individuals and may contribute to anti-social, aggressive and impulsive behaviours. It may also increase depressive and anxiety-like symptoms especially in individuals with mutations in serotonin transporter gene.
Can L-tryptophan supplements help treat alcoholism?
I know you might be overwhelmed (or bored) after reading the geeky aspects of tryptophan metabolism and its impact on alcoholism. So here is the answer to the golden question: can tryptophan supplements help in alcohol addiction?
Most studies conducted to date have studied only the disturbances in tryptophan metabolism and its impact on alcohol withdrawal syndrome, alcohol cravings and mood.
Very few studies have examined whether L-tryptophan or 5-HTP help in alcohol addiction and they have been summarised below.
1.Tryptophan and benserazide combination may cause alcohol aversion
In an animal study, Badawy et al. demonstrated that kynurenine metabolites (3-hydroxykynurenine, 3-HK) derived from tryptophan produce an aversion to alcohol by inhibiting the activity of enzyme aldehyde dehydrogenase.
Aldehyde dehydrogenase is an enzyme that breaks down acetaldehyde, the by-product of alcohol metabolism. Its inhibition leads to accumulation of acetaldehyde in the body, and this causes toxic effects leading to aversion towards alcohol.
Further, the researchers also demonstrated that combination of tryptophan and benserazide could elevate acetaldehyde concentrations in the blood and lead to alcohol aversion.
Benserazide (used in Parkinson’s) inhibits the activity of enzymes which would otherwise break down 3-hydroxykynurenine, 3-HK.
Quick Gist: Production of kynurenine metabolite: 3-hydroxykynurenine helps cause aversion to alcohol.
Researchers have proposed that supplementation of tryptophan with enzyme inhibitor (benserazide) can help manipulate the kynurenine pathway in a way that it causes alcohol aversion and reduces alcohol intake.
2.Dietary supplementation with 5-HTP and other amino acids reduce alcohol withdrawal symptoms
5-hydroxytryptophan is an immediate precursor of serotonin while levodopa is a natural precursor of dopamine.
A study conducted by NIAAA in 1992 revealed that treatment with 5-HTP and carbidopa and levodopa and carbidopa for one year did not affect alcohol abstinence.
This is partially in line with the findings presented by Halladay and colleagues. They demonstrated that simply supplementing with tryptophan is not enough to reduce alcohol intake; its combination with drugs that regulate brain chemicals effectively reduce alcohol intake and ameliorate alcohol withdrawal seizures.
I have not come across any studies that examine the effect of tryptophan supplementation with psychiatric drugs for treating alcoholism.
But one study did examine the effect of supplementing with an amino acid mixture that serves as a raw material for the production of our brain chemicals.
Researchers from J. J. Strossmayer University, Croatia conducted a study wherein they treated alcohol withdrawal symptoms with a food supplement comprising amino acids.
Alcohol abstinence affects our internal reward circuit and causes a disturbance in dopamine and endogenous opioid levels. The food supplement was designed to contain:
- L-amino acids such as L-glutamine and L-5-hydroxytryptophan for dopamine synthesis
- D-phenylalanine for preventing degradation of endogenous opioids
20 patients were enrolled in the study and assigned to an alcohol detoxification program. One group was treated with the food supplement while the other was given placebo for 40 days.
Patients receiving the food supplement experienced a decrease in psychiatric symptoms and increase in immune response. Alcohol abstinence caused stress in the patients, and the food supplement did not affect the stress hormone levels or liver function.
Quick Gist: Simply supplementing with L-tryptophan may not be sufficient for treating alcohol addiction.
Dietary supplementation with an amino acid mixture may help balance the disturbed brain chemistry and reduce alcohol withdrawal symptoms in patients.
3.L-tryptophan may reduce depressive symptoms in alcoholism
They were treated with 3g of L-tryptophan or placebo for four days. After a four-day washout period, the treatments were reversed in both groups. There was a third group that received placebo on all occasions and two other groups that received no treatment.
(The study design is confusing but attempts to eliminate any casual associations in the results.)
Interestingly, all participants reported a decrease in depressive symptoms, but those who received L-tryptophan (in any order) experienced a significant reduction in depressive scores compared to other patients.
Sleep disturbances were not affected by L-tryptophan treatment, and one reason for this was that the participants did not have significant baseline sleep disturbance related symptoms, to begin with.
Researchers from the University of Gottingen, Germany found that tryptophan depletion did not influence alcohol cravings in the participants. However, it did cause a significant increase in depressive symptoms and anxiety.
They also observed that supplementation with a tryptophan-rich drink helped maintain plasma tryptophan levels and also lowered anxiety ratings.
Quick Gist: Supplementation with L-tryptophan (3g per day) or tryptophan-rich drink is found to reduce depressive and anxiety symptoms in patients with alcohol addiction. More research is required to corroborate these findings.
Dosage of L-Tryptophan or 5-HTP For Alcoholism
Please consult a health practitioner before taking tryptophan supplements. Not many studies have been conducted on its supplementation in alcoholism. Also, not much is known about the safety of L-tryptophan in other mental health disorders that may coexist with alcohol addiction.
The general dosage of L-tryptophan for depressive disorder and mental health ranges from 3-12g per day and for sleep disturbances doses as low as 250-1000mg per day are proven to be beneficial.
One study has reported a reduction in depressive symptoms in patients with alcoholism after treating with 3g of L-tryptophan per day.
If deficient in B vitamins, you should consider supplementing with them as B complex helps treat many symptoms of alcoholism and improves utilisation of tryptophan.
5-HTP requires one less step to be converted to serotonin than L-tryptophan, but no studies to date have examined the effects of 5-HTP supplementation in patients with alcohol addiction. The general dose of 5-HTP is 50-250 mg per day.
Please start with small doses and increment gradually over weeks to identify a dose that suits you.
High levels of isolated 5-HTP or long-term treatment with it may cause depletion of other neurotransmitters and increase the risk of other side effects. Consider supplementing with other amino acids via diet to minimise such effects.
5-HTP supplements are safe and effective if used for a short period (max three months) and cycled (taking a break from supplements) regularly.
Precautions with L-Tryptophan or 5-HTP Use
The upper safety limit for tryptophan supplementation is 4.5g per day, but high doses have been used in clinical studies.
High dose supplementation with L-tryptophan and 5-HTP can cause gastric side effects such as nausea, vomiting, heartburn, stomach spasms.
In rare cases, it may cause serotonin syndrome (excessively high levels of serotonin) and present with dizziness, tremors or even serious complications such as delirium and coma.
At low doses, oral 5-HTP is found to act as a psychoactive substance and can affect decision making.
To prevent the risk of high serotonin or serotonin syndrome, it is advised not to combine SSRIs or other antidepressants and 5-HTP; however, many studies have found the combination safe.
FDA had banned tryptophan supplements in 1989 due to the presence of contaminants which caused eosinophilic myalgia syndrome. However, that was related to the quality and purity of the supplement, and no such cases have been reported since then.
Avoid 5-HTP in pregnancy and lactation.
High levels of isolated 5-HTP or long-term treatment with it may cause depletion of other neurotransmitters and increase the risk of other side effects.
5-HTP supplements are safe and effective if used for a short period (max three months) and cycled (taking a break from supplements) regularly.
Please consult a health practitioner before taking any supplements.
Poor diet combined with detrimental effects of alcohol consumption leads to tryptophan deficiency in alcohol addiction.
Excessive alcohol intake disturbs tryptophan metabolism and leads to the production of toxic kynurenine metabolites. This reduces the amount of tryptophan available for serotonin synthesis.
No exact relationship between tryptophan depletion induced serotonin synthesis and drinking habits have been established. But disturbances in tryptophan metabolism may adversely affect mood in some patients with alcoholism and cause aggression, anxiety and depression.
It may even contribute to alcohol withdrawal symptoms. Also, the effects of tryptophan levels on alcohol cravings differ with every individual.
The level to which tryptophan metabolism has been disturbed may differ with every patient; thus making it difficult to make any generalisations and to use it as a target for therapy.
Mutations in the tryptophan hydroxylase gene are associated with increased risk of anxiety and depression in alcohol-dependent individuals.
Interestingly, animal studies demonstrate that formation of kynurenine metabolites (3-hydroxykynurenine, 3-HK) cause alcohol aversion.
Very few studies have investigated the effect of tryptophan supplementation in alcoholism. Dietary supplementation with the amino acid mixture is found to reduce alcohol withdrawal symptoms. L-tryptophan (3g per day) reduces depressive symptoms in patients with alcohol dependence.
Based on the research available to date, supplementing with a quality food supplement containing amino acid mixture or a protein powder and (in case you are on the road to recovery) adding amino-acid rich drinks or protein to your diet would be beneficial for supporting recovery from alcohol addiction.
More research in the form of well-designed clinical trials is required to make any conclusions about the use of 5-HTP or L-tryptophan for alcoholism.
We need to learn more about the safety of L-tryptophan supplementation in individuals who have mental health issues in addition to alcohol addiction.