5-HTP

5-Hydroxytryptophan is an intermediate stage in the endogenous conversion of the amino acid L-tryptophan into the neurotransmitter serotonin. L-tryptophan is first converted to 5-HTP by an enzymatic hydroxylation process and then to serotonin by decarboxylation. A limiting step in this serotonin synthesis is apparently the conversion of L-tryptophan to 5-HTP by the enzyme tryptophan hydrolase. Serotonin is mainly synthesised and also stored in the enterochromaffin cells of the intestinal mucosa. A proportion is also stored in platelets, which transport and release serotonin to several peripheral organs.¹ Serotonin plays an important role in the central nervous system (CNS), in the regulation of mood, sleep-wake rhythm, appetite control, stress tolerance and pain perception. The activity of tryptophan hydroxylase can be impaired by factors such as insulin resistance, stress, magnesium or vitamin B6 deficiency, which limits endogenous 5-HTP synthesis and subsequent serotonin synthesis.² In the mouse model, acute and chronic stress reduced the activity of tryptophan hydroxylase and thus affected the serotonergic system.³ Serotonin cannot cross the blood-brain barrier, whereas 5-HTP is easily able to do so even without an active carrier. Moreover, 5-HTP can be converted to serotonin without biochemical feedback inhibition; the only factor required is the enzyme aromatic L-amino acid decarboxylase (AADC).⁴ Direct intake of 5-HTP leads to enzyme-independent normalisation of serotonin levels. Approximately 70 % of the orally ingested 5-HTP is absorbed and and can pass the blood-brain barrier. Thus, this is an effective way to increase serotonin synthesis in the CNS.⁵ In the pineal gland, the sleep hormone melatonin can be synthesised from serotonin in the further course. A reduced serotonin level is closely related to psychological changes such as depressive moods, anxiety and panic states or aggression. It directly influences the sleep-wake rhythm, appetite control and pain perception.⁶ The therapeutic use of 5-HTP in this indication framework is well documented and verified by practical experience.
 

A disorder in serotonin synthesis can lead to depressive moods, mood swings and psychological changes. Depressed patients show a 50 % reduction in serotonin levels in serum and several reports indicate that the plasma tryptophan concentration of severely depressed patients is significantly lower than that of healthy persons or persons suffering only from mild depression symptoms. Human studies showed that the reduction of serotonin synthesis by deprivation of tryptophan in the brain can lead to depression within a short time. High-dose tryptophan has therefore been tested for its effect as an antidepressant, but is no longer commonly used due to its side-effect profile. In contrast, the use of 5-HTP as a natural therapy alternative for depressive moods and depressions finds high approval - especially due to its low side effect potential. Substitution with 5-HTP achieves an antidepressant effect by increasing the availability of serotonin in the synaptic cleft.^7,9 A systematic evaluation of clinical studies conducted proves the efficiency and safety of the use of 5-HTP as a natural antidepressant.¹⁰ The use of 5-HTP makes it possible to bypass the limiting step in serotonin synthesis: the conversion of L-tryptophan into 5-HTP by tryptophan hydroxylase. The suitability of 5-HTP as a natural antidepressant has already been confirmed by several studies. The best results of 5-HTP were observed in patients with endogenous, senile and agitated depression. A comparative study with 60 depressed patients who received 5-HTP or the serotonin reuptake inhibitor (SRI) fluoxetine confirmed the equivalence of the amino acid and the drug. A 2-week dosage of 150 mg 5-HTP daily was already effective. Over the 8-week study period, the effect stood up to comparison with the common antidepressant fluoxetine.⁷ 5-HTP also has a positive effect on anxiety and panic disorders. Thus, a 5-HTP-containing Griffonia simplicifolia extract attenuated anxiety in rats. The effect was attributed to the 5-HTP in the extract, which can cross the blood-brain barrier and increase serotonin levels in the brain. A number of psychiatric disorders are attributed to irregularities in the serotonergic system; in particular, the development of obsessive-compulsive disorder, panic disorder, depression and anxiety involves the depletion of serotonin in the CNS. Consequently, the increase in synaptic serotonin alleviates symptoms of depression, but also those of anxiety disorders.⁸ For more than 30 years, 5-HTP has been successful in clinical use. Not only is this substance effective against depression, it has also been used to effectively treat conditions such as fibromyalgia, insomnia, chronic headaches or binge-eating disorder associated with obesity.⁷ Dysphoria, the cardinal leading symptom of premenstrual and menopausal mood swings, is also positively influenced by serotonin-increasing substances. In the clinical test, a direct relation was shown between mood and the 5-HTP content in the brain of premenstrual women.¹¹ 
 

Depressive moods are usually causally related to sleep disorders. Numerous experiments have demonstrated the relationship between sleep and serotonin. A reduced serotonin level probably also leads to reduced melatonin levels during the night hours.^{12, 13} As a neurotransmitter, serotonin plays a significant role in the circadian rhythm. It inhibits or stimulates various sleep-promoting neurons and thus plays an important role in sleep regulation.¹³ Thus, impaired serotonin neurotransmission appears to be involved not only in depression and anxiety disorders, but also in sleep disorders. By inducing acute tryptophan deficiency, the essential role of serotonin in the sleep-wake rhythm was demonstrated in animal models. Tryptophan deprivation not only severely disturbed sleep phases, the depletion also caused depressive episodes.¹⁴ Exogenous substitution with 5-HTP can therefore normalise disturbed sleep behaviour and promote sleep.
 

There is much evidence to suggest that serotonergic dysfunction also plays a relevant role in the neurobiology of heartbreak. High levels of romantic stress are clinically associated with negative mood states, such as depression, anxiety disorders and obsessive-compulsive tendencies. Both neurotrophins and serotonin are closely associated with romantic attachment. An open-label study from 2010 therefore examined changes in serum BDNF (brain-derived neurotrophic factor) levels and platelet serotonin levels in relation to changes in romantic stress. After 6 weeks of taking a 60 mg Griffonia extract with 12.8 mg 5-HTP, both BDNF and platelet serotonin levels increased significantly. The correlation between improvements in platelet serotonin levels and feelings of heartbreak in patients receiving 5-HTP was significant.¹⁸
 

Serotonin and its precursor 5-HTP play an important role in controlling appetite and eating behaviour and are an effective adjunctive tool in comprehensive obesity treatment. In addition to regulatory mechanisms that control food intake, a number of neurotransmitters and neuropeptides exist that regulate the selective uptake of food components.¹⁹ Serotonin concentration in the brain influences three food components in particular: fatty acids, proteins and carbohydrates. The intake of fatty acids as well as carbohydrates leads to an increase in serotonin production via various interactions and signalling pathways. And conversely, human studies confirmed that tryptophan plays an influence on food or macronutrient cravings. 5-HTP is associated with reduced appetite, early satiety and weight loss. In overweight women, the administration of 5-HTP has already been successful. They ate less food, felt satiety earlier and lost weight after treatment. Normalising the tryptophan level of depressed overweight people through additional supplementation also led to weight loss. A recent placebo-controlled study used functional magnetic resonance imaging (fMRI) to show that responses to food stimuli are strongly dependent on individual brain physiology. The brain areas of participants given either 5-HTP or vitamin C responded differently while observing high-calorie protein-containing or carbohydrate-containing food. 5-HTP supported the activity of brain regions involved in healthy eating behaviours and caused greater control over food consumption. Regions associated with the feeling of satiety were more stimulated after 5-HTP ingestion and the brain preferred high-protein rather than high-carbohydrate foods. Serotonin counteracts the intake of carbohydrates, reduces appetite, increases the feeling of satiety and can thus promote weight loss. Serotonin and its precursor 5-HTP therefore play an important role in controlling appetite and eating behaviour and are an effective adjunctive tool in comprehensive obesity treatment.²⁰
 

5-HTP substitution also shows good results in pain treatment. Chronic headaches, especially migraine attacks, can be directly linked to low serotonin levels, possibly as a result of increased serotonin degradation by the enzyme monoamine oxidase.⁵ In a clinical study, 5-HTP supplementation positively influenced headaches and sleep disorders in school children.^{21, 22} 5-HTP has also been used to successfully prevent chronic headaches, migraine attacks and tension headaches. headaches, migraine attacks and tension headaches.⁵ Serotonin is involved in mediating endogenous pain-inhibiting mechanisms. Decreased serotonin levels have been found in fibromyalgia patients. Other symptoms of fibromyalgia, such as fatigue and cognitive deficits, have also been associated with serotonergic imbalances or serotonin deficiency. The use of SRIs can bring about a lasting improvement in pain. In fibromyalgia and chronic fatigue syndrome, 5-HTP and serotonin also seem to influence the hypothalamic-pituitary-adrenocortical axis. adrenal cortex axis and its stimulation. In this respect, hormonal parameters can also reduce the occurrence of pain.^{23, 24} In a double-blind study, 100 mg of 5-HTP three times a day over a period of 30 days led to a significant reduction in pain intensity in fibromyalgia patients. There was also a reduction in the number of pain-sensitive sites and positive changes in morning stiffness, sleep quality, fatigue and anxiety.²⁵
 

¹ Nakamura, K., Hasegawa, H. 2009. Production and Peripheral Roles of 5-HTP, a Precursor of Serotonin. Int J Tryptophan Res. 2:37–43.
² Gröber, U. 2011. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung. Wissenschaftliche Verlagsgesellschaft Stuttgart.
³ Browne, C. A. et al. 2011. Differential stress-induced alterations in tryptophan hydroxylase activity and serotonin turnover in two inbred mouse strains. Neuropharmacology. 60(4):683–91
⁴ Hinz, M. et al. 2012. 5-HTP efficacy and contraindications. Neuropsychiatr Dis Treat. 8:323–8.
⁵ Birdsall, T. C. 1998. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 3(4):271–80.
⁶ Gröber, U. 2002. Orthomolekulare Medizin. Ein Leitfaden für Apotheker und Ärzte. Stuttgart (Wiss. Verlag-Ges.).
⁷ Jangid, P. et al. 2013. Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr. 6(1):29–34.
⁸ Carnevale, G. et al. 2011. Anxiolytic-like effect of Griffonia simplicifolia Baill. seed extract in rats. Phytomedicine. 18(10):848–51.
⁹ Niestroj, I. 2000. Praxis der Orthomolekularen Medizin. Physiologische Grundlagen. Therapie mit Mikro-Nährstoffen. Stuttgart (Georg Thieme Verlag).
¹⁰ Shaw, K. A. et al. 2002. Tryptophan and 5-Hydroxytryptophan for depression. Cochrane Database of Systematic Reviews.
¹¹ Eriksson, O. et al. 2006. Mood changes correlate to changes in brain serotonin precursor trapping in women with premenstrual dysphoria. Psychiatry Research: Neuroimaging 146 (2): 107–116. doi:10.1016/j.pscychresns.2005.02.012.
¹² Balogh, A. 2001. Drug for the treatment of sleep disorders – review. Zeitschrift für ärztliche Fortbildung und Qualitätssicherung. 95(1):11-6.
¹³ Rancillac, A. 2016. Serotonin and sleep-promoting neurons. Oncotarget. 7(48):78222–3.
¹⁴ NakamaruOgiso, E. et al. 2012. Novel biochemical manipulation of brain serotonin reveals a role of serotonin in the circadian rhythm of sleep–wake cycles. Eur J Neurosci. 35(11):1762–70.
¹⁵ Yonkers, K. A. et al. 2008. Premenstrual syndrome. Lancet. 371(9619):1200–10.
¹⁶ Eriksson, O. et al. 2006. Mood changes correlate to changes in brain serotonin precursor trapping in women with premenstrual dysphoria. Psychiatry Res. 146(2):107–16.
¹⁷ Esposito, M. et al. 2015. A Medical Food Formulation of Griffonia simplicifolia/Magnesium for Childhood Periodic Syndrome Therapy: An Open-Label Study on Motion Sickness. J Med Food. doi: 10.1089/jmf.2014.0113.
¹⁸ Emanuele, E. et al. 2010. An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress. Neuro Endocrinol Lett. 31(5):663–6.
¹⁹ Halford, J. et al. 2005. Serotonin (5-HT) Drugs: Effects on Appetite Expression and Use for the Treatment of Obesity. Current Drug Targets. 6(2):201–213. doi:10.2174/1389450053174550.
²⁰ Ioannou, S., Williams, A. L. 2016. Preliminary fMRI findings concerning the influence of 5HTP on food selection. Brain Behav. 7(1):e00594.
²¹ DeGiorgis, D. et al. 1987. Headache in association with sleep disorders in children: a psychodiagnostic valuation and controlled clinical study – L-5-HTP versus placebo. Drugs Exp Clin Res. 13(7):425-33.
²² Bruni O. et al. 2004. L-5-Hydroxytryptophan treatment of sleep terrors in children. Eur J Pediatr. 163(7):402-7. 
²³ Neeck, G., Crofford, L. J. 2000. Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. Rheum Dis Clin North Am. 26(4):989–1002.
²⁴ Welsch, P. et al. 2018. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database Syst Rev. 2: CD010292.
²⁵ Caruso, I. et al. 1990. Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. J. Int Med Res. 18(3):201–9.
²⁶ Hahn, A. et al. 2005. Ernährung. Physiologische Grundlagen, Prävention, Therapie. Stuttgart (Wiss. Verlag-Ges.).
²⁷ Almeida, O. P. et al. 2010. B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Ann Neurol. 68(4):503–10.

References Interactions
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.'
Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.