21 replies to this topic

[luv2increase]

I have been thinking lately that L-tryptophan and 5-HTP are potentially bad for cognition.

Pronounced cognitive deficits following an intravenous L-tryptophan challenge in first-degree relatives of bipolar patients compared to healthy controls.
Sobczak S, Honig A, Schmitt JA, Riedel WJ.

Brain and Behavior Institute, Department of Psychiatry and Neuropsychology, Universiteit Maastricht, The Netherlands.

Cognitive impairment has repeatedly been described in bipolar disorders (BD). Serotonin (5-hydroxytryptophan; 5-HT) is possibly involved in these cognitive processes, more particularly in executive functions, learning, memory, and attention. The aim of this study was to investigate serotonergic vulnerability and its relation to cognitive functioning in healthy first-degree relatives of BD patients. We investigated the effects of an intravenous (i.v.) tryptophan (Trp) challenge and placebo on cognitive performance in 30 healthy first-degree relatives of bipolar patients (FH) and 15 matched controls in a double-blind crossover design. A distinction was made between relatives of type I BD patients (FH I) and type II BD patients (FH II). Performances on planning, memory, attention, and psychomotor tasks were assessed 3 h after Trp infusion. After Trp, planning and attention were impaired in FH subjects but not in controls. Independent of Trp, FH subjects showed cognitive deficits on memory, focused and divided attention, and psychomotor performance. FH I subjects showed more pronounced cognitive impairments then FH II and controls. In all groups, Trp impaired memory and psychomotor performance significantly. In conclusions, cognitive deficits in FH following Trp may reflect a central 5-HT vulnerability in frontal brain areas. Independent of Trp, cognitive deficits in FH provide evidence for a trait marker for BD.

PMID: 12655316 [PubMed - indexed for MEDLINE]

And this from Wikipedia (oh ya)

Kynurenic acid (KYNA) is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiologic and neuropathologic processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.

Kynurenic acid was discovered in 1853 by the German chemist Justus von Liebig in dog urine.[1]

It is formed from L-kynurenine in a reaction catalyzed by the enzyme kynurenine—oxoglutarate transaminase.
Contents
[hide]

* 1 Mechanism of action
* 2 Role in disease
* 3 See also
* 4 References
* 5 External links

Mechanism of action

KYNA was found to act on three receptors:

* As a noncompetitive antagonist at glycine site of the NMDA receptor.
* As an antagonist of α7 nicotinic acetylcholine receptor. This action is contrary to another tryptophan metabolite, 5-hydroxyindoleacetic acid.[2]
* As a ligand for G protein-coupled receptor GPR35.[3]

Role in disease

High levels of kynurenic acid have been identified in patients suffering from tick-borne encephalitis, schizophrenia and HIV-related illnesses. In all these situations increased levels were associated with confusion and psychotic symptoms. Kynurenic acid acts in the brain as a glycine-site NMDAr antagonist, key in glutamatergic neurotransmission system, which is thought to be involved in the pathophysiology and pathogenesis of schizophrenia.

A kynurenic acid hypothesis of schizophrenia has been proposed in 2007,[4][5] based on its action on midbrain dopamine activity and NMDArs, thus linking dopamine hypothesis of schizophrenia with the glutamate hypothesis of the disease.

High levels of kynurenic acid have been identified in human urine in certain metabolic disorders, such as marked pyridoxine deficiency and deficiency/absence of kynureninase.

Simply put, the more of the tryptophan metabolite kynurenic acid floating around in your body the more antagonism on the a7 nicotinic acetylcholine receptor, glycine site of the NMDA receptor, and enhanced risk of certain metabolic disorders.

I remember when I used to take 5-HTP, it would make me feel good yet dumb at the same time with a negatively affected memory and thinking capabilities. It all makes sense now. I also eat a natural turkey sandwich daily which I feel droggy afterwards due to the l-tryptophan. Maybe it isn't the increase of serotonin that makes you feel dumb but the increase in its metabolite kynurenic acid????? I believe so.

Edited by luv2increase, 30 July 2008 - 05:42 PM.

[jojobiz]

very interesting...i really like 5-HTP myself. i hope this isn't true...anybody else experience a dumbing down of the cognitive abilites? i only take 5-HTP at bedtime so i can't really tell if it's slowing my mind down.

Edited by jojobiz, 03 August 2008 - 09:21 AM.

[abelard lindsay]

I take L-Tryptophan now and then when I am feeling depressed and haven't noticed any significant cognitive impairment. In fact, it often helps subtly in terms of motivation and creativity. I think that they were giving it intravenously probably affected the patients more than anything. I do know people who get very sleepy when they take L-Tryptophan. Doesn't really happen to me though. L-Tryptophan is present in many foods and even in baby formula.

Here's some studies to balance out the thread.

Rats subjected to extended L-tryptophan restriction during early postnatal stage exhibit anxious-depressive features and structural changes.
Zhang L, Guadarrama L, Corona-Morales AA, Vega-Gonzalez A, Rocha L, Escobar A.

Department Physiology, Faculty of Medicine, University of Mexico, Mexico City.

Serotonin transmission dysfunction has been suggested to play an important role in depression and anxiety. This study reports the results of a series of experiments in which rats were subjected to extended maize-based tortilla diets during early postnatal stages. This diet contains only approximately 20% of the L-tryptophan in normal diets of laboratory rodents. Compared with controls, experimental rats displayed a significant increase of immobility counts in the forced swimming test and exhibited anxiety-like behavior in the elevated plus maze test after 1 month of diet treatment. Low levels of serotonin contents were found in prefrontal cortex, striatum, hippocampus, and brainstem using high-performance liquid chromatography. Immunocytochemical reactions against 5-Bromo-2'-deoxyuridine revealed a significant decrease in the proliferation rate for the subgranular zone of dentate gyrus. c-Fos expression after the forced swimming test was found reduced in prefrontal cortex, dentate gyrus, CA1, and hilus of hippocampus and amygdala. Moreover, dendrite arbor atrophy and decreased spine density were evident in Golgi-Cox-impregnated CA1 pyramidal neurons. Abnormal dendrite swelling in dentate gyrus granule cells was also observed. These findings indicate an involvement of hyposerotoninergia in emotional disturbance produced by L-tryptophan restriction during critical developmental stages and suggest that neuroplasticity changes might underlie these changes.
PMID: 16783166 [PubMed - indexed for MEDLINE

Tryptophan supplementation induces a positive bias in the processing of emotional material in healthy female volunteers.
Murphy SE, Longhitano C, Ayres RE, Cowen PJ, Harmer CJ.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK.

RATIONALE: The serotonin precursor L-tryptophan (TRP) is available as a nutritional supplement and is licensed as an antidepressant in a number of countries. However, evidence of its efficacy as the primary treatment for depression is limited, and the direct action of TRP on the symptoms of depression and anxiety has not been well-characterised. OBJECTIVES: The present study assessed whether TRP induces cognitive changes opposite to the negative biases found in depression and characteristic of those induced by serotonergic antidepressants in healthy volunteers. MATERIALS AND METHODS: Thirty eight healthy volunteers were randomised to receive 14 days double-blind intervention with TRP (1 g 3x a day) or placebo. On the final day, emotional processing was assessed using four tasks: facial expression recognition, emotion-potentiated startle, attentional probe and emotional categorisation and memory. RESULTS: TRP increased the recognition of happy facial expressions and decreased the recognition of disgusted facial expressions in female, but not male, volunteers. TRP also reduced attentional vigilance towards negative words and decreased baseline startle responsivity in the females. CONCLUSIONS: These findings provide evidence that TRP supplementation in women induces a positive bias in the processing of emotional material that is reminiscent of the actions of serotonergic antidepressants. This highlights a key role for serotonin in emotional processing and lends support to the use of TRP as a nutritional supplement in people with mild depression or for prevention in those at risk. Future studies are needed to clarify the effect of tryptophan on these measures in men.

PMID: 16767422 [PubMed - indexed for MEDLINE

[stuartes]

I am quite sure this Turkey / Tryptophan has risen to the level of an urban myth. Any search will show that you do not get enough Tryp in a turkey sandwich or Thanksgiving Dinner to make you sleepy or dumb you down. To the contrary it takes some work to get a large dose past the BB barrier. I am certain that there is a range of tolerance but a gram of pharmaceutical grade Tryp, taken with necessary co-factors and without a drop of protein could be taken several times a day without turning you into a zombie. To the contrary if indicated for you it will produce a very positive effect.

[Galantamine]

As someone may have mentioned before, serotonin will impair working memory if greatly elevated.

[luv2increase]

I am quite sure this Turkey / Tryptophan has risen to the level of an urban myth. Any search will show that you do not get enough Tryp in a turkey sandwich or Thanksgiving Dinner to make you sleepy or dumb you down. To the contrary it takes some work to get a large dose past the BB barrier. I am certain that there is a range of tolerance but a gram of pharmaceutical grade Tryp, taken with necessary co-factors and without a drop of protein could be taken several times a day without turning you into a zombie. To the contrary if indicated for you it will produce a very positive effect.

Ok forget the turkey sandwich and focus on the tryptophan and 5-htp then.

[kenj]

No problems with 5-HTP, IME. It may be symptoms of other neurotransmitters being low. Years back I got that 'dumb' feeling as well, but when I started ACh supplements and other things, 5-HTP only relaxes now and improves mood slightly, - no fatigue or confusion.

EDIT: In fact I suspect it improves my memory.

Edited by kenj, 05 August 2008 - 02:05 PM.

[Nate-2004]

Possibly relevant to the original post. I found this in a review of BulkSupplements L-Tryptophan:

 

Have been taking L-Tryptophan for a while now, after experimenting with several different herbs and pharmaceuticals. Tryptophan is by far the most effective for my sleep maintenance issues, it puts me to sleep and keeps me asleep. Started with about 4g, for about a week, then 1g after that. Important to note, that if your body is fighting inflammation, try mixing the powder tryptophan to a tbsp of collagen in some warm water, this will help it pass the blood-brain barrier without competing with certain cytokines cause by inflammation, learned this trick from a biochemist names Steve Fowkes. If after taking tryptophan, you feel a litte "off" the next morning, most likely the culprit is your body producing inflammation cytokines, which compete with L-Tryptophan and the bi-product is toxins in your brain. I tried and boy does it work! Give it 15-20 min for the collagen protein bind with the tryptophan before drinking it. The mix will "cheat" and dodge the cytokines and go straight to your brain and knock you out! Your will wake up feeling refreshed the next day. I add a tablespoon of raw honey and tart cherry juice concentrate (for its anti-inflammatory properties). I sleep between 7 and 8 hours every night now, my back pain is gone as well! Try it, it works...

 

Edited by Nate-2004, 03 September 2016 - 04:10 PM.

[gamesguru]

Mostly you want to antagonize the serotonin receptors.  But a mild sustained release can have a similar effect by modulating autoreceptors on the presynapse, particularly 5-HT1A... this is the mechanism of SSRIs as well as saffron, and bacopa which blocks the 5-HT6 receptor^{[1], [2], [3]} (the 6 receptor is particularly relevant in cognitive studies, but also, you might not expect, in social functioning too):

The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment.
de Bruin NM1, van Loevezijn A2, Wicke KM3, de Haan M2, Venhorst J2, Lange JH2 (2016)

In the present study, our aim was to investigate whether the novel highly selective 5-hydroxytryptamine6 (5-HT6) receptor antagonist SLV can ameliorate impairments in cognition and social interaction with potential relevance for both schizophrenia and Alzheimer's disease (AD). SLV sub-chronically - treated Wistar rats reared in isolation showed significantly enhanced prepulse inhibition (PPI) and object recognition performance when compared to vehicle - treated rats. In the isolated rats, also a significant reduction in expression of hippocampal neural cell adhesion molecule polysialylation (NCAM-PSA) was found which was ameliorated following treatment with SLV (30mg/kg). The social engagement deficit in rats exposed in utero (on gestational day 12.5) to valproic acid (VPA) was reversed by treatment with SLV (30mg/kg). SLV (20 and 30mg/kg, p.o.) fully reversed MK-801 - induced deficits in the ORT and also scopolamine - induced deficits in both the Object Recognition Task (ORT) and Object Location Task (OLT) in Wistar rats. In addition, a combination of sub-optimal doses of SLV and donepezil attenuated scopolamine-induced ORT deficits. Furthermore, SLV (10mg/kg, p.o.) reversed spontaneous alternation deficits in the T-maze induced by MK-801 administration in Swiss mice and in aged C57Bl/6J mice. SLV additionally improved T-Maze spatial learning and passive avoidance learning in Sprague-Dawley rats with amyoid-beta (Aβ) injections into the hippocampus. In contrast, no benefits were found with SLV or the tested reference compounds (donepezil and RVT-101) on cognitive performance of 12months old Tg2576 mice. Also, in the social recognition task, an absence of cognitive enhancing properties was observed with SLV on "normal forgetting" in Wistar rats. Finally, analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) frequency recorded from pyramidal cells revealed a reduction in the presence of 1μM of SLV. In conclusion, SLV was investigated in several rodent animal models and found to be effective at a least effective dose (LED) of 20mg/kg and 10mg/kg (p.o.) in the rat and the mouse, respectively.

 

• Based on findings from animal models, we hypothesize that lithium downregulates the presynaptic 5-HT1A receptor, upregulates the postsynaptic 5-HT1A receptor, and upregulates 5-HTT^[1]
• Asenapine shows a unique breadth of action at these sites, with potential effects at clinical doses at 5HT1A, 1B, 2A, 2C, 6 and 7 receptors. Antagonism at alpha2 adrenoceptors may also be involved^[2]
• ... reserpine-induced rise in axon terminal 5-HTP accumulation is dependent on intact (5-HT) neuronal impulse flow, which may or may not involve a transient impairment of somatodendritic 5-HT release and, in turn, autoreceptor tone^[3]

[Nate-2004]

What is SLV?

 

 

[gamesguru]

synthetic serotonin antagonist (not to be confused with Ibipinabant, or SLV319.. a CB1 antagonist).

you're gonna see lab synths soon, and sick monkeys self-medicating.

Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties.
Rauly-Lestienne I1, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Cussac D. (2007)

5-HT(7) receptors are present in thalamus and limbic structures, and a possible role of these receptors in the pathology of schizophrenia has been evoked. In this study, we examined binding affinity and agonist/antagonist/inverse agonist properties at these receptors of a large series of antipsychotics, i.e., typical, atypical, and third generation compounds preferentially targeting D(2) and 5-HT(1A) sites. Adenylyl cyclase (AC) activity was measured in HEK293 cells stably expressing the human (h) 5-HT(7a) receptor isoform. 5-HT and 5-CT increased cyclic adenosine monophosphate level by about 20-fold whereas (+)-8-OH-DPAT, the antidyskinetic agent sarizotan, and the novel antipsychotic compound bifeprunox exhibited partial agonist properties at h5-HT(7a) receptors stimulating AC. Other compounds antagonized 5-HT-induced AC activity with pK (B) values which correlated with their pK (i) as determined by competition binding vs [(3)H]5-CT. The selective 5-HT(7) receptor ligand, SB269970, was the most potent antagonist. For antipsychotic compounds, the following rank order of antagonism potency (pK (B)) was ziprasidone > tiospirone > SSR181507 > or = clozapine > or = olanzapine > SLV-314 > SLV-313 > or = aripiprazole > or = chlorpromazine > nemonapride > haloperidol. Interestingly, pretreatment of HEK293-h5-HT(7a) cells with forskolin enhanced basal AC activity and revealed inverse agonist properties for both typical and atypical antipsychotics as well as for aripiprazole. In contrast, other novel antipsychotics exhibited diverse 5-HT(7a) properties; SLV-313 and SLV-314 behaved as quasi-neutral antagonists, SSR181507 acted as an inverse agonist, and bifeprunox as a partial agonist, as mentioned above. In conclusion, the differential properties of third generation antipsychotics at 5-HT(7) receptors may influence their antipsychotic profile.

[jroseland]

I've used powdered 5-HTP a handful of times and can confirm that it's not helpful for cognition. I would not exactly call it an anti-Nootropic but I wouldn't but it in the same category as real cognitive enhancers.

[Nate-2004]

It's good for recovering from molly and for times with depression. 

 

I was wrong above about tryptophan, so was the review I quoted. Tryptophan needs to be coupled with any anti-inflammatory compound that inhibits TNF-α or IL-6, these send tryptophan on a pathway that does not lead to serotonin or melatonin. 

 

See this video for more details:

 

[jack black]

WOW, what an old thread! I partially agree with the OP, but IMHO, the mechanism he posted is wrong.

It's not KYNA, but 5HT that does it via various 5HT receptors that are known to increase anxiety and that's bad for memory.

[Jiminy Glick]

Tryptophan works great for sleep so now I don't use Benadryl which is extremely bad for cognition. Tryptophan is an essential amino acid, I don't see how it can be bad for you, except maybe in large doses. 

Edited by Jiminy Glick, 05 August 2017 - 03:20 AM.

[gamesguru]

how do you know it's good for recovering from molly?  because it's often purported for antioxidative properties?  might as well eat carrots.  because of serotonin boosting properties (which may be quite detrimental in a depleted state)?  might as well eat nuts or turkey.  but people have got along with the dialectic for hundreds of generations, so who am i to cast down on public opinion?

 

it's okay for depression, even schizotypal/blunted symptoms.  at my high school we had, basically, a philosophy class in the morning and i would always make the most annoying broom up your ass type of comments after somebody just got done explaining their opinion.  but on one occasion where i took 300mg of 5-htp prior to class i was really mellow, a fly on the wall, i was really not myself, i even made the class laugh twice

 

it's good for sleep in the same sense gaba is good for anxiety, it's good for about two weeks, which is far more patience than the average internet joe has before he posts and brags about how wonderfully his new regiment is working

[Nate-2004]

how do you know it's good for recovering from molly?  because it's often purported for antioxidative properties?  might as well eat carrots.  because of serotonin boosting properties (which may be quite detrimental in a depleted state)?  might as well eat nuts or turkey.  but people have got along with the dialectic for hundreds of generations, so who am i to cast down on public opinion?

 

it's okay for depression, even schizotypal/blunted symptoms.  at my high school we had, basically, a philosophy class in the morning and i would always make the most annoying broom up your ass type of comments after somebody just got done explaining their opinion.  but on one occasion where i took 300mg of 5-htp prior to class i was really mellow, a fly on the wall, i was really not myself, i even made the class laugh twice

 

it's good for sleep in the same sense gaba is good for anxiety, it's good for about two weeks, which is far more patience than the average internet joe has before he posts and brags about how wonderfully his new regiment is working

 

Because A: I've done it many times and it works consistently compared to my friends who neglect this. When they try my way they see a pretty dramatic difference. B: Molly depletes serotonin due to the increase in reuptake that occurs during the increase in serotonin released. It essentially takes too much and you're left with a deficit at the end. A reuptake inhibitor would be too dangerous so better off just giving your body what it needs to make more. Tryptophan is both a serotonin and melatonin precursor. 5-HTP is a better choice however as it is much closer upstream in terms of being a precursor. For molly recovery you'll want to take tryptophan the day before, then 5-HTP just before, when the night is over, and a few times the following couple of days after that, probably in addition to L-tyrosine, a dopamine precursor. This will essentially remove any bad effects of molly keeping you only with the positive effects, such as the therapeutic effects on social anxiety, anti-PTSD effects, the bonding with friends and the fun experience itself.

 

If you choose to go with tryptophan instead of 5-HTP you'll want to ensure, as I said before, that you take something that inhibits TNF alpha and IL-6 and other inflammatory cytokines. Things like curcumin and fish oil will help with this.

 

Eating nuts is fine, but again, you'll want to make sure you've got anti-inflammatories going.

 

The problem with eating nuts before you go to bed is that eating before bed has a detrimental effect on sleep quality, also tryptophan before bed can backfire as increased serotonin levels tend to cause insomnia, despite it producing melatonin. 

Edited by Nate-2004, 05 August 2017 - 06:34 PM.

[gamesguru]

5-htp can also lead to serotonin insensitivity, cardiac fibrosis, sexual dysfunction, anxiety and increased cortisol signalling.  like gaba, too much of it over an extended period may interfere with sleep.  i suspect if you dive deep enough into the literature you'll find drawbacks for anything.  others will surely appreciate the advice about tryptophan and inflammation, but with my insane diet i'm probably the last man in america who has to worry about inflammation.  you can't seriously listen to a few studies about inflammation, like with tyrosine vs phenylanaline and choline vs GPC, i am tempted to err on the side of mother nature (ie. the lower step in the ladder) unless there is some profoundly disconcerting evidence to the contrary

Edited by gamesguru, 05 August 2017 - 07:11 PM.

[Nate-2004]

I didn't say take it all the time. In fact I'd only take tryptophan about twice a week at most. I haven't even taken it in a while. Who said take things in excess here?

[gamesguru]

I was talking about 5htp, how often are you recommending that.

and unless you follow an absurd diet, i regret that you "take" tryptophan every single day

[GreenWhite]

Is there any way to get Carbidopa without L-Dopa?

 

Are there any natural decarboxylase inhibitors?

 

Edited by GreenWhite, 16 August 2017 - 02:32 PM.

[Nate-2004]

I was talking about 5htp, how often are you recommending that.

and unless you follow an absurd diet, i regret that you "take" tryptophan every single day

 

I rarely take 5-HTP either, usually after a molly experience. I'd take it maybe twice a week at most. It can cause insomnia the same way SSRI's do.