• How To Increase Serotonin Levels With Supplements

           Is  L-Tryptophan safe ? Is 5 HTP safe?  L-tryptophan vs 5 HTP

           Other  Supplements & Vitamins

  • How To Increase Serotonin Levels -Other Natural Ways

  • How To Increase Serotonin With Drugs, ECT, rTMS

  • Why antidepressants aren’t effective in the majority of people treated for depression? Some thoughts

  1.  How To Increase Serotonin Levels With Supplements . Is L tryptophan safe ? Is 5 HTP safe ? L tryptophan vs 5 HTP- which one is better ? Other Supplements that Increase Serotonin

Serotonin deficiency should be treated to avoid symptoms of serotonin deficiency, which I described in details here.

Both L tryptophan and 5 HTP are precursors of serotonin and can boost the levels of this neurotransmitter. The question is- which one is the best and the safest?

 

                               TRYPTOPHAN

                           /                  |           \

                         /                    |              \

             Proteins             5 HTP         KYNURENINE

                                               |                      |

                                               |                      |          

                              SEROTONIN           Niacin (vitamin B3)

                                 /           |

                              /            N acetyl serotonin

                           /                 |

                     5 HIIA           MELATONIN

 

Many health professionals recommend l tryptophan- for correcting serotonin deficiency associated with depression, fibromyalgia, migraines or persistent nightmares. In some countries, l tryptophan is also available by prescription from medical doctors, for those who prefer a natural alternative to antidepressants. In some countries 5 HTP is a prescription drug. Some doctors will combine l tryptophan with 5 HTP supposedly for better results.

The questions- whether is l tryptophan safe and whether 5 HTP is safe are two great questions.

These are my top  reasons why I don’t recommend l tryptophan : 

Note: there are no issues eating tryptophan rich foods, the problems below can occur when taking l tryptophan supplement:

  • Most of the tryptophan ingested will not convert into serotonin but will follow the kynurenine pathway. The kynurenine pathway malfunctions in multiple sclerosis, other neurodegenerative conditions, depression and cancer, causing immune system activation, accumulation of potentially neurotoxic compounds [2],[1]. 

  • Tryptophan is carcinogenic- may play a role in bladder cancer and possibly liver cancer [3], and other cancers.

 Technical: Excess intake tryptophan (as could happen when you supplement), combined with B 6 deficiency (B 6 is a cofactor in the kyurenate pathways) leads to accumulation of toxic compounds that are involved in the development of cancer [4].

My note : when it comes to increased risk of cancer, I do believe tryptophan is safer than antidepressants (according to preclinical studies 63.6% of antidepressants were linked with carcinogenicity [5]).

  • Tryptophan requires more work (2 steps) to be converted into serotonin ((tryptophan→ 5 HTP→ serotonin), and the conversion to serotonin involves TPH enzymes that limit the production of serotonin. Meanwhile, 5 HTP converts directly into serotonin, without rate limiting enzymes in this process.

  • Higher levels of tryptophan had been associated with increased risk of insulin resistance/diabetes, high triglycerides levels and high blood pressure [6].

  • In order to reach the brain, tryptophan has to cross the blood brain barrier (BBB), and other amino acids compete with tryptophan to get into the brain. Just an example, l tryptophan shares the same transport mechanism with the amino acids valine, leucine, and isoleucine.

  • Tryptophan supplements had been banned by FDA in 1989 for almost a decade because thousands of people got sick and some died due a condition called eosinophilia-myalgia syndrome. Some believe that the problem was a bacterial contamination of the supplement.  Others suggest that high doses of tryptophan were responsible for these complications because high doses of tryptophan metabolites block the breakdown of histamine. I covered in this article the detrimental effects of excess histamine.

So what do you think, is L tryptophan safe?

Next question- Is 5 HTP safe ?

It seems to be a better, safer choice  than l tryptophan.

  • 5 HTP converts to serotonin (while tryptophan metabolism involves 3 pathways, leading to 1.the production of serotonin, 2.niacin through kynurenine pathway and also 3.converts into proteins)

  • 5 HTP is not associated with cancer, diabetes, high triglycerides or high blood pressure

  • 5 HTP does not follow the kynurenine pathway, thus will not aggravate inflammation and autoimmunity.

  • Unlike l tryptophan, 5 HTP converts directly into serotonin and does not compete with amino acids to cross blood brain barrier and reach the brain.

To answer the question :  l tryptophan vs 5 HTP, which one is better ? To me, 5 HTP is the clear winner.

5 HTP  Benefits

5 HTP does cross the blood brain barrier and boost brain serotonin levels.

Studies found it effective in managing depression, sleeping problems, including sleep terrors in children [7] , fibromyalgia [8] ,[9] , chronic headaches and migraines [10], and mood disorders. In a randomized controlled trial, the antidepressant effects of 5 HTP were achieved within 2 weeks, and had comparable effects with the antidepressant fluoxetine [11]

5 HTP is a clinically effective serotonin precursor. Is well absorbed in supplement form, and 70% of 5 HTP will end up in blood stream. Crosses easily the blood brain barrier and effectively increases serotonin synthesis in the brain, which would be beneficial for treating serotonin deficiency. In the central nervous system, serotonin is involved in the regulation of the sleep, depression, anxiety, decrease aggression and appetite. It also controls the body temperature, sexual behavior and pain sensation [12]. 

Although there aren’t many studies looking at the benefits of 5 HTP (the supplement) for all these conditions, we know that the supplement 5 HTP does increase serotonin in the brain. Therefore, we would expect to see a wide range of benefits from boosting serotonin in the brain. To get a more details and benefits of serotonin in the brain, the gut and entire body, read this article.

5 -HTP and the gut health: again, there aren’t studies in this field using 5 HTP in particular. However, the role of serotonin in the gut is well-established. Serotonin plays key role in gastrointestinal motility, how sensitive we are to pain, the gut immune function and blood flow. Drugs targeting serotonin receptors 5-HT3 and 5-HT4 are currently used to treat digestive symptoms associated with IBS (serotonin playing a key role in this condition). [13], [14] For digestive system, I see 5 HTP working mostly in cases associated with serotonin deficiency in the GI tract associated with  constipation, bloating and stomach upset.

5 htp for weight loss: quite a few studies looked into the benefits of 5 HTP for weight loss. 5 HTP reduces the appetite and carbohydrate intake [19], increased sensation of satiety [20] , leading to significant weight loss in obese individuals [21] ,[22]. Some researchers considered using 5 HTP plus chromium (chromium promotes fat loss more than muscle loss during weight loss) and green tea extract for optimal benefits [23]. I think the addition of chromium is very smart.

 While 5 HTP is safe, there are some issues you should be aware of. Concerns about 5 HTP : it should not be taken with antidepressants (SSRI, SNDRIs) or other drugs that boost serotonin levels, as there is risk of serotonin syndrome

Peak X contaminant had been found in the past in 5 HTP supplements. Stay safe and look for a brand that had been tested and guarantees a peak x free 5 HTP. There are quite a few peak x free 5 HTP supplements available, but most of them have rice flour and other non medicinal ingredients I do not like. An exception I found is 5 HTP from Solgar brand (free of x peak, Gluten, wheat, dairy, soy, yeast, sugar, artificial colors and flavors) In addition of 100 mg 5 HTP mg it also includes magnesium, 5 p 5 and Valerian extract. I am sure you can find other brands, too- just look at the label and verify with the company if they really are peak x free 5 HTP supplements. 

5 HTP should not be used long term, as it may reduce the ability of your own brain and gut to make serotonin. You can use in cycles (i e 2-3 months), preferably in combination with a dopamine/norepi precursor L-tyrosine and the cofactors (vitamins). Supplementing with 5 HTP alone causes dopamine and norepi deficiency [24].

Other compounds that should be used in combination to 5 HTP (to correct serotonin deficiency) :

  • Vitamin B 6 is needed for the conversion of 5 HTP (or tryptophan) into serotonin to facilitate conversion of either 5-HTP or tryptophan into serotonin.P-5-P, is the bio active form of B6 

  • Magnesium [25]

  • Vitamins B3(niacin)

  • B12 (methyl B12)

  • Folic acid  [26] are involved in the synthesis of serotonin (folic alone has antidepressant qualities)

  • SAMe has the ability to boost the production of serotonin and increase serotonin levels in the brain. SAMe alone is used in the treatment of depression.

  • Vitamin C is involved in the synthesis of dopamine and serotonin [27]

  • Vitamin D and omega 3 [28]

  • Zinc [29]

  • Coenzyme Q10. There is some evidence that coenzyme q10 helps raise both dopamine and serotonin levels [30], [31]. This could be one of the reasons why coenzyme q10 had been found to treat depression and fatigue associated with MS (a double-blinded, placebo-controlled trial using 500 mg/day CoQ10) [32].

     

I didn’t look at the research. However, in theory, you could raise serotonin levels  also by supplementing with melatonin, as the brain will not need to convert serotonin to melatonin as this will provided in supplement form. In the same fashion, if you choose to use l tryptophan, would be wise to supplement with the end product -niacin (vitamin B3). Since you get this vitamin in supplement form, tryptophan could be more used in the 5 HTP-serotonin-melatonin pathway and to create more proteins rather than follow kyurenine pathway. 

Other Natural Supplements (Herbs)

  • St John’s Wort (Hypericum perforatum) works in a similar way with antidepressants, as a natural serotonin reuptake inhibitor. According to a double-blind, randomized trial, patients treated with St John’s Wort extract WS(®) 5570 not only showed a reduction in depression severity score but also had greater response and remission rates compared with patients treated with the antidepressant paroxetine [33]. Another randomized controlled study found that St John’s Wort extract STW 3 is not inferior to the antidepressant sertraline and that it is a well-tolerated drug for the treatment of moderate depression. (daily dose used in this study 612 mg of hypericum extract) [34]. A 3rd randomized controlled trial found St John’s Wort to be as effective as the antidepressant fluoxetine, and provides a great alternative to synthetic antidepressants [35]. The conclusion of a 2017 meta analysis (a review of 27 clinical trials) is the following : “For patients with mild-to-moderate depression, St John’s wort has comparable efficacy and safety when compared to SSRIs” [36]. St John’s Wort can also help treat  OCD [42]. Some symptoms of PMS [43] , menopausal symptoms (when combined with black cohosh). It also has anti inflammatory, antibacterial effects [44].

          Warnings : Can interact with many meds. It is safer  than prescription antidepressants and does not cause sexual dysfunctions. Most common side effects are mild  i.e.stomach upset, skin rashes, fatigue, restlessness. Overall, this supplement can be beneficial to treat  serotonin deficiency if you don’t take prescriptions pills (there are too many drug herb interactions) [46], but rather use it as an alternative to prescription meds.

  • Medical Cannabis: The antidepressant and anti-anxiety effects of cannabis may be partially explained due to the fact that cannabinoids improve serotonin and dopamine levels through direct and indirect mechanisms [47].

  • Rhodiola Rosea: Rhodiola appears to increase serotonin levels in the brain, promote the formation of new brain cells and help repair the injured cells (at least in animal studies) [48]. In human studies, rhodiola seems to be a better alternative than antidepressant sertraline (when looking at the risk/benefits ratio, based on  a randomized placebo controlled study). Overall, it shows to be effective for mild to moderate depression [49]. Rhodiola should not be taken with antidepressants [50] . Other benefits of rhodiola : decreases inflammation, modulates the immune system, is neuroprotective, fights cognitive decline, improves estrogen levels (thus helpful during menopause as well), and has some anti-bacterial and anti-cancer qualities (more details about rhodiola in another article). This supplement should not be used in combination with antidepressants or tryptophan, 5 htp (risk of serotonin syndrome). Rhodiola can be used when you take a break from 5 HTP, for example (I mentioned earlier that 5 HTP should be taken for 2-3 months, followed by a break).

 

  1. How To Increase Serotonin Levels -Other Natural Ways (No Pills Involved) 

Yes, you can manage (mild to moderate) serotonin deficiency without taking any pills.

Positive thoughts promote serotonin synthesis in the brain (specifically in the right anterior cingulate cortex). It appears that it works both ways : good moods can boost the serotonin levels and healthy serotonin levels play a role in positive thoughts.

Sunlight -it is well-established the interaction between bright light and serotonin levels. Tryptophan deficiencies cause depressed moods that can be corrected by exposure to bright light.  We live in a sunlight deprived society. Exposure to sunlight (even during a cloudy day) is beneficial to raise serotonin. The light lamps are successfully used for seasonal affective disorders, PMS, and depression during pregnancy.

Exercise boosts a variety of feel good chemicals, serotonin being just one of them. Mechanism of action: motor activity increases the firing rates of serotonin neurons, leading to increased release and synthesis of serotonin. There is also a raise in the brain of tryptophan that persists after exercise [51]. Exercise also modulates the tryptophan/ kynurenine pathway, decreasing the levels of kynurenine in the brain (which had been involved in depression)[52]

Yoga can increase the levels of  GABA, dopamine and serotonin [53].

Cognitive behavior therapy (CBT) is effective for depression, and one of its mechanism of action seem to derive from its ability to influence serotonin pathways [54].

PEMF – I mentioned in my other article about using PEMF for MS, based on the concept that  neurological deficit in MS is mostly derived from  serotonin deficiency and not the actual brain lesions.  A number of studies found dramatic and quick improvement of symptoms following magnet therapy (PEMF) There are different PEMF devices but the one that appears to be the most beneficial (and boost serotonin) use a weak magnetic field in the picotesla range.[37], [38], [39], [40], [41].

3. How To Increase Serotonin Levels With Drugs, ECT and rTMS

Different kind of reuptake inhibitors will target different neurotransmitters. For serotonin, doctors use SSRIs (Selective serotonin reuptake inhibitors) and SNRIs (Serotonin and norepinephrine reuptake inhibitors), although serotonin levels can be influenced by another classes of drugs- for example Serotonin antagonist and reuptake inhibitor (SARIs) and the older classes of antidepressants: Tricyclic antidepressants (TCAs) and Monoamine oxidase inhibitors (MAOIs)

SRIs are the most commonly used and include: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and the newer drugs that work like SSRIs by affecting the serotonin transporter: vilazodone, vortioxetine. Sometimes SSRIs are combined with drugs that treat bipolar or schizophrenia (ie olanzapine, quetiapine, aripiprazole)

SNRIs include duloxetine, venlafaxine, desvenlafaxine ER, levomilnacipran and desvenlafaxine. MS is associated with high rates of depression -with a lifetime prevalence of depression being around 50% [55].  SSRIs are used to manage depression associated with MS, the first two choices being sertraline and paroxetine [56]. My note: of course these two drugs would work if MS is associated with serotonin deficiency , and unlikely to work if depression comes from dopa deficiency. Some studies suggested that SSRIs could help to delay disability associated with MS, however, a study that evaluated almost 4000 participants found no evidence that SSRIs could help to prevent the progression of disability [57].

Some studies evaluate antidepressants for possibly being neuroprotective [58]. However, I see more risks than benefits to use them for this purpose- or generally speaking- for any reason. As you see above, there are plenty of options available. 

 Most common side effects of these drugs include: headaches, weight changes (either loss of gain), nausea, vomiting, bipolar disorder. Sexual dysfunction is very common as well -SSRIs diminish sexual interest, desire, performance, satisfaction, or all four. Taken during pregnancy, antidepressants during the second and third trimester increase the risk of autistic spectrum disease in babies [59] .Emotional flatness, forgetfulness, drowsiness, sleeping problems (they typically reduce the quantity, but reduce the quality of sleep), tremors and other neurological symptoms, abnormal heart rhythm. For more details/side effects check Drug.com

One major side effect  you may not be aware :  Serious risk of cancer. Preclinical trials conducted for FDA reveal the following :

63.6% of antidepressants were linked with carcinogenicity, specifically: mirtazapine, sertraline, paroxetine, citalopram, escitalopram, duloxetine and bupropion; 90% of antipsychotics (except clozapine) were linked with carcinogenicity [60]. The risk of cancer was also confirmed in  human trials [61] , although some studies found weak association [62] , or yielded mixed results [63] .One study found that women with history of breast cancer who took certain antidepressants were more likely to experience cancer return [64]. And the risk of breast and ovarian cancer in relation with antidepressants: Based on a review of 61 studies, the scientists found an association (the highest risk coming from SSRIs use) between antidepressants and risk of breast and ovarian. The authors also noted that “ Industry affiliations were significantly associated with negative conclusions regarding cancer risk” [65]. This shouldn’t be a surprise.

Another thing you should know: 9 antidepressants: amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine are currently on the FDA watch list due to serious side effects [74]- some off them could be off the market in the future. 

Back to the question: is l tryptophan safe ? it may not be so safe compared with 5 HTP or other supplements that boost serotonin, but I believe is safer than prescription meds.

ECT (Electroconvulsive therapy) improves/activates serotonin and dopamine pathways [66]. It looks that the serotonin boost is significant, as a case of serotonin syndrome was reported after the first session of ECT in a person who was taking serotonin boosting antidepressants.

rTMS (Repetitive transcranial magnetic stimulation) shows similar efficacy to SSRIs in a meta analysis [67], [68] it is possible to work by boosting serotonin levels.

 You may wonder why I mention ECT rTMS in this article. Here is a personal thought : in a case of severe depression (for example- with suicidal thoughts), my first choice would be ECT (which is more effective than rTMS). For mild to moderate depression, there are plenty of natural supplements available, as well as exercise, psychotherapy and light/sunlight therapy, PEMF, rTMS. In both cases, antidepressants are not on my list.

4. Why antidepressants aren’t effective for the majority of people treated for depression ?

I think antidepressants would be more effective if the treatment would be individualized. If you look from neurotransmitter perspective, depression is mostly caused by serotonin, dopamine and norepi deficiencies, yet drugs that target serotonin are used for everyone, as a first line therapy. Since 5 HTP depletes the levels of dopa and norepi, I suspect SSRIs would cause the same issues. Giving an SSRI to someone who has dopamine deficiency would not help, but actually aggravate the depression. I wrote about symptoms of dopamine deficiency, norepinephrine deficiency and serotonin deficiency, and they clearly have different symptoms.

Other reasons why antidepressants don’t work would be the fact that inflammation [73], sugar metabolism [70], the gut microbiome and gut brain axis [71] aren’t addressed in the treatment for depression, yet are key factors that play a key role in depression. Does it make sense?

 

Good to know in case you are on interferon beta : Interferon beta affects negatively tryptophan metabolism [69]. You may need extra support for healthy levels of serotonin, melatonin, and niacin.