Sunday, 26 February 2017

Secondary Monoamine Neurotransmitter Disorders in Autism – Treatment with 5-HTP and levodopa/carbidopa?

This post is about monoamine neurotransmitter disorders in Autism, that are usually a down-stream consequence of other miscellaneous dysfunctions, which makes them “secondary” dysfunctions.

There was a post on this blog way back in 2013 on catecholamines:

Classical monoamine is a broader term and encompasses:-

       ·          Classical Tryptamines:

Drugs used to increase or reduce the effect of monoamines are sometimes used to treat patients with psychiatric disorders, including depression, anxiety, and schizophrenia.

This blog does go on rather ad nauseam about histamine, so today it will skip over it.  It does not cause autism, but it certainly can make it much worse in some people.

Tryptophan is a precursor to the neurotransmitters serotonin and melatonin.  For years it has been known that odd things are going on in some people with autism regarding tryptophan, serotonin and indeed melatonin. This research does not really lead you anywhere.

Other than being converted to serotonin and melatonin, tryptophan has the potential to be converted in the gut into some very good things and some bad ones; this all depends on what bacteria are present. People lucky enough to have Clostridium sporogenes will produce a super potent, but apparently very safe, antioxidant called 3-Indolepropionic acid (IPA), which is seen as an Alzheimer’s  therapy.  To be effective you would need a constant supply of IPA, and that is exactly what you get from the right bacteria living in your gut.

Some people with autism have high levels of serotonin in their blood and so do their parent(s). It is known that in the brain many people with autism have low levels of serotonin.  Various mechanisms have been proposed to explain this using the body’s feedback loops, including mother to child.

Many people with autism take 5-HTP which is an  intermediate in the synthesis of both serotonin and melatonin from tryptophan.

Serotonin itself does not cross the blood brain barrier (BBB).

Too much serotonin in your brain has a negative effect and so taking too much 5-HTP supplement produces negative effects.

Many people take melatonin at small doses for sleep. At larger doses it has many other beneficial effects that range from resolving GI problems to reducing oxidative stress in mitochondria. 

Of the Catecholamines, it is dopamine that gets the most attention in neuro-psychiatric disorders and schizophrenia in particular.

There is a dopamine hypothesis for schizophrenia, but there is also a glutamate hypothesis of schizophrenia. 

If you read the research, it is actually ADHD that has the strongest connection to dopamine.  When you look closer still, you will see that even that connection is quite weak.

The conclusion is that ADHD, just like autism and schizophrenia is usually multigenic, meaning that numerous little things went awry, rather than one single dysfunction.

Tourette's syndrome and related tic disorders may be associated with either too much dopamine or overly sensitive dopamine receptors. 

It is fair to say that secondary monoamine neurotransmitter disorders can occur in autism, ADHD and indeed schizophrenia.

There is a long list of primary monoamine neurotransmitter disorders and much is known about them.

Monoamine Neurotransmitter Disorders  

I found an excellent paper that tells you pretty much all you could want to know about monoamine neurotransmitter disorders.  It also has nice graphics to explain what is going on.

Most people with autism are unlikely to have a primary disorder, but if they did, treating it should have a big impact on them.

BH4 =tetrahydrobiopterin. TH-D=tyrosine hydroxylase deficiency. AADC-D=aromatic L-amino acid decarboxylase deficiency. DTDS=dopamine transporter deficiency syndrome. PLP-DE=pyridoxal-phosphate-dependent epilepsy. P-DE=pyridoxine-dependent epilepsy. AD GTPCH-D=autosomal dominant GTP cyclohydrolase 1 deficiency. SR-D=sepiapterin reductase deficiency. AR GTPCH-D=autosomal recessive GTP cyclohydrolase 1 deficiency. PTPS-D=6-pyruvoyltetrahydropterin synthase deficiency. DHPR-D=dihydropteridine reductase deficiency. HIE=hypoxic ischaemic encephalopathy. PKAN=pantothenate kinase associated neurodegeneration. DNRD=dopa non-responsive dystonia. PKD=paroxysmal kinesogenic dyskinesia.

People with a secondary disorder would typically be identified by testing their spinal fluid for the metabolites of the monoamine.  So for serotonin you measure  5-HIAA (5-hydroxyindoleacetic acid) and for dopamine you measure  HVA (homovanillic acid).

Figure 2: The monoamine neurotransmitter biosynthesis pathway BH4 is synthesized in four enzymatic steps from GTP. BH4 is a necessary cofactor for TrpH and TH, the rate limiting enzymes in monoamine synthesis. Tryptophan is converted to 5-HTP by TrpH. Tyrosine is converted to L-dopa by TH. The conversion of 5-HTP to serotonin and of L-dopa to dopamine is catalyzed by AADC and its cofactor PLP.  When BH4 acts as a cofactor for TH and TrpH, it is converted to PCBD, which in turn is converted to BH4 (in the BH4 regeneration pathway) by a two-step process involving PCD and DHPR. After synthesis, uptake of monoamine neurotransmitters into the synaptic secretory vesicles requires the vesicular monoamine transporter VMAT (not shown).⁶ After synaptic transmission, serotonin and dopamine are metabolised through similar pathways, which involve MAO enzymes and COMT. Presynaptic reuptake of the monoamines is facilitated by DAT and SERT (not shown).⁷ Metabolic pathway of BH4 synthesis is shown in light blue, monoamine synthesis in light green, monoamine catabolism in dark blue, and BH4 regeneration in red. The biogenic amines are illustrated in light green circles and the cofactors (BH4 and PLP) are represented by light blue circles. Enzymes in the monoamine neurotransmitter pathway are underlined. GTPCH=GTP cyclohydrolase 1. H₂NP₃=dihydroneopterin triphosphate. PTPS=6-pyruvoyltetrahydropterin synthase. 6-PTP=6-pyruvoyltetrahydropterin. AR=aldose reductase. SP=sepiapterin. SR=sepiapterin reductase. BH4 =tetrahydrobiopterin. TrpH=tryptophan hydroxylase. TH=tyrosine hydroxylase. DHPR=dihydropteridine reductase. PCBD=tetrahydrobiopterin-α-carbinolamine. PCD=pterin-4αcarbinolamine dehydratase. qBH₂=(quinonoid) dihydrobiopterin. 5-HTP=5-hydroxytryptophan. L-dopa=levodihydroxyphenylalanine. COMT=catechol-O-methyltransferase. 3-OMD=3-ortho-methyldopa. VLA=vanillactic acid. AADC=aromatic L-amino acid decarboxylase. PLP=pyridoxal phosphate. DBH=dopamine β hydroxylase. PNMT=phenylethanolamine N-methyltransferase. MAO=monoamine oxidase. AD=aldehyde dehydrogenase. 3-MT=3-methoxytyramine. DOPAC=3,4-dihydroxyphenylacetic acid. 5-HIAA=5-hydroxyindoleacetic acid. HVA=homovanillic acid. MHPG=3-methoxy-4-hydroxylphenylglycol. VMA=vanillylmandelic acid.

The paper is very clear about what to:-

Secondary neurotransmitter disorders

Neurotransmitters abnormalities indicative of dopamine or serotonin depletion are becoming increasingly recognized as secondary phenomena in several neurological disorders. Concentrations of HVA and 5-HIAA in CSF in such patients are mostly within the range deemed abnormal for primary neurotransmitter disorders, but generally do not reach the lowest levels.

A secondary reduction in HVA is reported in perinatal asphyxia, disorders of folate metabolism, phenyl ketonuria, Lesch-Nyhan disease, mitochondrial disorders, epilepsy (and infantile spasms), opsoclonus-myoclonus, pontocerebellar hypoplasia, leukodystrophies, Rett’s syndrome, and some neuropsychiatric disorders.  Many patients who have no specific diagnosis but who present with neuromuscular or dystonic symptoms have low HVA concentrations in CSF, which suggests dopaminergic depletion. These patients also often present with dyskinesia, tremor, and eye-movement disorders similar to those seen in many of the primary monoamine neurotransmitter disorders. Cortical atrophy is associated with low levels of 5-HIAA in CSF. Low concentrations of HVA and 5-HIAA have been reported in patients with type 2 pontocerebellar hypoplasia and in a syndrome that involves spontaneous periodic hypothermia and hyperhidrosis.  Whether the latter syndrome is a primary or secondary neurotransmitter disorder is still unclear because the underlying cause is unknown. Patients with neonatal disease onset who have severe motor deficits and abnormalities on brain MRI seem particularly vulnerable to secondary reductions in HVA production. Such disruption of normal brain function is likely to impair biogenic monoamine synthesis, and the resultant neurotransmitter deficiencies in critical periods of neurodevelopment are thought to prevent development of certain brain functions. The possibility of treating such patients with levodopa, 5-hydroxytryptophan, or both should be considered, therefore, to improve brain maturation and neurological outcome.

When you look at autism specifically it is usually 5-HIAA and not HVA that is disturbed.  

Now for two papers by one of our reader Roger’s favourite researchers, Vincent Ramaekers. Ramaekers is one of the specialists for central folate deficiency and even better is a researcher/clinician who replies to my emails. 


Patients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF).


We sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis.


The known heterozygous p.Gly56Ala mutation in the SLC6A4 gene was equally found in the ASD and control populations. Using a genetic candidate gene approach, we identified, in 8 patients of a cohort of 248 with ASD, a high prevalence (3.2%) of three novel heterozygous non-synonymous mutations within the SLC29A4 plasma membrane monoamine transporter (PMAT) gene, c.86A > G (p.Asp29Gly) in two patients, c.412G > A (p.Ala138Thr) in five patients, and c.978 T > G (p.Asp326Glu) in one patient. Genome analysis of unaffected parents confirmed that these PMAT mutations were not de novo but inherited mutations.

Expression of mutations PMAT-p.Ala138Thr and p.Asp326Glu in cellulae revealed significant reduced transport uptake activity towards a variety of substrates including serotonin, dopamine, and 1-methyl-4-phenylpyridinium (MPP+), while mutation p.Asp29Gly had reduced transport activity only towards MPP+. At least two ASD subjects with either the PMAT-Ala138Thr or the PMAT-Asp326Glu mutation with altered serotonin transport activity had, besides low 5HIAA in CSF, elevated serotonin levels in blood and platelets. Moreover, whole exome sequencing revealed additional alterations in these two ASD patients in mainly serotonin-homeostasis genes compared to their non-affected family members.


Our findings link mutations in SLC29A4 to the ASD population although not invariably to low brain serotonin. PMAT dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis. Exome sequencing of serotonin homeostasis genes in two families illustrated more insight in aberrant serotonin signaling in ASD.

In this context, we found that isolated low brain serotonin concentration, as reflected by the 5HIAA in the CSF, is associated with PDD-NOS and the functional (heterozygous) c.167G > C (p.G56A) mutation of the serotonin re-uptake transporter gene (SERT/SCL6A4) combined with a homozygous long (L/L) SERT gene-linked polymorphic promoter (5-HTTLPR) region [21]. Moreover, daily treatment with serotonin precursor 5-hydroxytryptophan and aromatic amino acid decarboxylase (AADC) inhibitor carbidopaled to clinical improvements and normalization of the 5HIAA levels in the CSF and urine, indicating that the brain serotonin turnover was normalized [22]. In an attempt to gain some insight into the brain serotonin physiology and underlying mechanisms of abnormal brain metabolism, we report in patients with ASD and low brain 5HIAA mutations in the serotonin transporter SCL29A4, an observation that may provide some bases for improving the application of various therapeutic tools.

Whole blood serotonin and platelet serotonin content are increased in about 25 to 30% of the ASD population and their first-degree relatives. Because the fetal blood–brain barrier during pregnancy is not yet fully formed, the fetal brain will be exposed to high serotonin levels, leading through a negative-feedback mechanism to a loss of serotonin neurons and a limited outgrowth of their terminals. This hypothesis has been confirmed by rat studies using the serotonin agonist 5-methoxytryptamine between gestational days 12 until postnatal day 20 [42].

Tryptophan hydroxylase (TPH; EC catalyzes the first rate-limiting step of serotonin biosynthesis by converting l-tryptophan to 5-hydroxytryptophan. Serotonin controls multiple vegetative functions and modulates sensory and alpha-motor neurons at the spinal level. We report on five boys with floppiness in infancy followed by motor delay, development of a hypotonic-ataxic syndrome, learning disability, and short attention span. Cerebrospinal fluid (CSF) analysis showed a 51 to 65% reduction of the serotonin end-metabolite 5-hydroxyindoleacetic acid (5HIAA) compared to age-matched median values. In one out of five patients a low CSF 5-methyltetrahydrofolate (MTHF) was present probably due to the common C677T heterozygous mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. Baseline 24-h urinary excretion showed diminished 5HIAA values, not changing after a single oral load with l-tryptophan (50-70 mg/kg), but normalizing after 5-hydroxytryptophan administration (1 mg/kg). Treatment with 5-hydroxytryptophan (4-6 mg/kg) and carbidopa (0.5-1.0 mg/kg) resulted in clinical amelioration and normalization of 5HIAA levels in CSF and urine. In the patient with additional MTHFR heterozygosity, a heterozygous missense mutation within exon 6 (G529A) of the TPH gene caused an exchange of valine by isoleucine at codon 177 (V177I). This has been interpreted as a rare DNA variant because the pedigree analysis did not provide any genotype-phenotype correlation. In the other four patients the TPH gene analysis was normal. In conclusion, this new neurodevelopmental syndrome responsive to treatment with 5-hydroxytryptophan and carbidopa might result from an overall reduced capacity of serotonin production due to a TPH gene regulatory defect, unknown factors inactivating the TPH enzyme, or selective loss of serotonergic neurons.

Carbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of peripheral levodopa to cross the blood–brain barrier for central nervous system effect.

L-DOPA/levodopa is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. Furthermore, L-DOPA itself mediates neurotrophic factor release by the brain and CNS. As a drug, it is used in the clinical treatment of Parkinson's disease.


Based upon the hypothesis that brain monoamine metabolism is disorganized in some children with an autistic disorder, we tried low dose levodopa therapy (0.5 mg/kg/day) proposed by Segawa, et al. We treated 20 patients with an autistic disorder diagnosed according to DSM-IV, and evaluated the effectiveness. A double blind cross over method was applied in this study because of the small number of patients. Drug effects were observed carefully by the psychologists and pediatric neurologists using an evaluation sheet consisting of twenty items. No significant effectiveness was observed in this study, although four cases (20%) showed some improvement. In conclusion, administration of low dose levodopa to autistic children resulted in no clear clinical improvements of autistic symptoms.

A team led by Wen-Hann Tan,  of the Genetics Program at Children’s, is completing a phase I clinical trial examining the safety and dosing of levodopa, a drug commonly used for Parkinson disease, in patients with Angelman syndrome. The results will inform a planned phase II treatment trial, to be conducted in collaboration with University of California San Francisco, University of California San Diego, Vanderbilt University, Baylor College of Medicine and Greenwood Genetic Center. [For more information on Angelman research and events, check out this Facebook page.]

Research suggests that levodopa may increase the activity of an important brain enzyme known as CaMKII, which is involved in learning and memory, and that may be decreased in Angelman syndrome. In a mouse model of Angelman syndrome, low activity of CaMKII is associated with neurologic defects. Levodopa reverses the chemical modification that underlies decreased CaMKII activity. When this same modification is reversed in mice by genetic means, they show improvement in neurologic deficits, and it’s hoped that levodopa can do the same in humans.

Parkinson's disease

We saw in an earlier post that people with Down Syndrome are prone to early onset Alzheimer’s. In the case of lack of dopamine the risk might be towards Parkinson's disease (PD). 

There was a recent post on PANS/PANDAS/Tourette’s which like PD results from dysfunction in the basal ganglia region of the brain.

The basal ganglia, a group of brain structures innervated by the dopaminergic system, are the most seriously affected brain areas in PD. The main pathological characteristic of PD is cell death in the substantia nigra, where greatly reduced activity of dopamine-secreting cells caused by cell death.

When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus, the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output. Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias.

The drugs used in PD only treat some of the symptoms and are not curative, but do offer effective ways to increase dopamine levels.

High rates of Parkinsonism in adults with autism? Or is it partly drug-induced Parkinsonism

There is a study suggesting high rates of Parkinsonism in adults with autism.  I think some of this is more likely to be drug-induced Parkinsonism, either caused by currently taken drugs, or those taken in earlier years, which is not mentioned in the study. 


While it is now recognized that autism spectrum disorder (ASD) is typically a life-long condition, there exist only a handful of systematic studies on middle-aged and older adults with this condition.

We first performed a structured examination of parkinsonian motor signs in a hypothesis-generating, pilot study (study I) of 19 adults with ASD over 49 years of age. Observing high rates of parkinsonism in those off atypical neuroleptics (2/12, 17 %) in comparison to published population rates for Parkinson’s disease and parkinsonism, we examined a second sample of 37 adults with ASD, over 39 years of age, using a structured neurological assessment for parkinsonism.
Twelve of the 37 subjects (32 %) met the diagnostic criteria for parkinsonism; however, of these, 29 subjects were on atypical neuroleptics, complicating interpretation of the findings. Two of eight (25 %) subjects not taking atypical neuroleptic medications met the criteria for parkinsonism. Combining subjects who were not currently taking atypical neuroleptic medications, across both studies, we conservatively classified 4/20 (20 %) with parkinsonism.
We find a high frequency of parkinsonism among ASD individuals older than 39 years. If high rates of parkinsonism and potentially Parkinson’s disease are confirmed in subsequent studies of ASD, this observation has important implications for understanding the neurobiology of autism and treatment of manifestations in older adults. Given the prevalence of autism in school-age children, the recognition of its life-long natural history, and the recognition of the aging of western societies, these findings also support the importance of further systematic study of other aspects of older adults with autism.

Drug induced Parkinsonism

Any drug that blocks the action of dopamine (referred to as a dopamine antagonist) is likely to cause parkinsonism. Drugs used to treat schizophrenia and other psychotic disorders such as behaviour disturbances in people with dementia, known as neuroleptic drugs, are possibly the major cause of drug-induced parkinsonism worldwide. Parkinsonism can occur from the use of any of the various classes of neuroleptics.
The atypical neuroleptics – clozapine (Clozaril) and quetiapine (Seroquel), and to a lesser extent olanzapine (Zyprexa) and risperidone (Risperdal) – appear to have a lower incidence of extrapyramidal side effects, including parkinsonism. These drugs are generally best avoided by people with Parkinson’s, although some may be used by specialists to treat symptoms such as hallucinations occurring with Parkinson’s.
For people with Parkinson’s, anti-sickness drugs such as domperidone (Motilium) or ondansetron (Zofran) are the drugs of choice for nausea and vomiting.
As well as neuroleptics, some other drugs can cause drug-induced parkinsonism. These include some medications for dizziness and nausea such as prochlorperazine (Stemetil); and metoclopromide (Maxalon), which is used to stop sickness and in the treatment of indigestion.
Calcium channel blocking drugs used to treat high blood pressure, abnormal heart rhythm, angina pectoris, panic attacks, manic depression and migraine may occasionally cause drug-induced parkinsonism. Calcium channel blocking drugs are, however, widely used to treat angina and high blood pressure, and it is important to note that most common agents in clinical use probably do not have this side effect. These drugs should never be stopped abruptly without discussion with your doctor.
A number of other agents have been reported to cause drug-induced parkinsonism, but clear proof of cause and effect is often lacking. Amiodarone, used to treat heart problems, causes tremor and some people have been reported to develop Parkinson’s-like symptoms. Sodium valproate, used to treat epilepsy, and lithium, used in depression, both commonly cause tremor which may be mistaken for Parkinson’s.

Dopamine Receptors vs Dopamine as Dysfunctions 

We saw in great detail with the neurotransmitter GABA that the autism dysfunctions are usually related to the function and make-up of the neurotransmitter receptors, rather than the amount of GABA itself. Targeting these dysfunctions does indeed deliver results for many people with autism and Asperger’s.

Potentially this might be the case with dopamine, but it looks much less likely.

I did look at the following paper which seeks to link the genes of dopamine receptors (DRD1, DRD2, DRD3, DRD4, DRD5), dopamine-synthesizing enzyme DDC, dopamine transporter (DAT) and dopamine-catabolizing enzymes COMT and MAO to the several hundred known autism genes.

Using bioinformatics, in some they found a link and in others they did not.

The graphic below looks nice, but I am not sure it tells us much useful.  To me it looks much better to go direct to the autism gene and then see how to selectively modulate it. I do not think you can assume that the associated dopamine gene/receptor is the unifying problem across dysfunctional autism genes.  It would be great if it was.  

Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis.

Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca2+ signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.

Fig. 3. Reconstruction of biomolecular pathways related to dopaminergic genes associated with ASD (also see Fig. 2 and Table 2 for details). Known biological interactions between protein products of various genes are shown as complexes or denoted by arrows (sharp – activation, dull – inhibition). Proteins encoded by genes associated with ASD are marked with red (other colors are used here for illustration purposes only, to better distinguish visually between multiple different proteins within the dopaminergic pathways). Clustering of proteins into distinct functional groups is shown by dashed lines.

The strongest evidence for the role of dopamine genes in neuropsychiatric disorders is not in schizophrenia or autism, but in ADHD. As you can see in the paper below, even there the association is weak.


Although twin studies demonstrate that ADHD is a highly heritable condition, molecular genetic studies suggest that the genetic architecture of ADHD is complex. The handful of genome-wide scans that have been conducted thus far show divergent findings and are, therefore, not conclusive. Similarly, many of the candidate genes reviewed here (i.e. DBH, MAOA, SLC6A2, TPH-2, SLC6A4, CHRNA4, GRIN2A) are theoretically compelling from a neurobiological systems perspective, but available data are sparse and inconsistent. However, candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. The literature published since recent meta-analyses is particularly supportive for a role of the genes coding for DRD4, DRD5, SLC6A3, SNAP-25, and HTR1B in the etiology of ADHD.

Yet, even these associations are small and consistent with the idea that the genetic vulnerability to ADHD is mediated by many genes of small effect.


In the ideal world you would take a sample of spinal fluid and measure 5-HIAA, to look for low brain serotonin and measure HVA for low brain dopamine.

For low serotonin you would give 5-HTP, with Dr Ramaekers suggesting 1mg/kg.

For low dopamine you would give levodopa or carbidopa.

In the real world even blood draws can be problematic so most people will never have their spinal fluid analyzed. Perhaps one day in the future this will be standard practice after an autism diagnosis, with numerous test being run at the same time and justifying this invasive procedure.   Many blood tests tell you little about brain disorders because the blood brain barrier means that the levels outside the brain will be completely different to those inside the brain. Measuring spinal fluid should be a good proxy for inside the brain.

The research suggests that 1mg/kg of 5-HT could have a long term beneficial effect, particularly if given from a very early age, in those with low serotonin in their brains, which is a large group of autism.

There are 5 types of dopamine receptors and in some genetic disorders the receptors’ response can be up/down regulated.  That would trigger a chain reaction with the non dopamine neurotransmitter receptors that are known to interact with that type of dopamine receptor.

There are associations between some autism genes and some dopamine genes, but it looks much more fruitful to target the autism genes themselves.

Avoid drug induced Parkinson’s Disease and other drug induced disorders, by very selective use of drugs.


  1. Is that 1mg/kg per day or 1mg/kg 3x a day (the standard 5-HTP schedule)? 1mg/kg for a 100 pound child is 45mg which is roughly the standard adult dose of 50mg (for 5-HTP).

    In my past experience, this didn't work well for reasons I don't really know for sure at this time. As per one of the other commenters suggestions, I have been trying a much lower dose of 5-HTP which is more like 4 mg once or twice a day and have not had any acute negative symptoms as before but nothing miraculous either. I have been also doing a 10x lower dose of agmatine sulfate as well along with the 5-HTP and any good it is doing is likely slow and steady and not something I would notice day to day. Nevertheless, due to the problems you mentioned above, I don't know if he has low levels of serotonin in the brain, though I do know he has risk factors for it due to serotonergic developmental complications linked with maternal obesity and the high serotonin and inflammatory markers associated with the condition in mouse models as well as correlated in human studies.

    But again the serotonin system in the brain is becoming more and more complicated every year as just last year some important research found that another important group of neurons in the brainstem called the medial raphe nuclei perform an opposite signaling effect as the dorsal raphe nuclei which are classically associated as being the primary origin of serotonin signaling for the rest of the brain. This still makes it an open question as to what type of serotonergic interventions do the best good, though I do think 5-HTP is the safest and I would avoid SSRI's which are much more unpredictable due to the nature of how they change information flow at the synapse and the still poor understanding of how serotonin actually works in the brain. In other words, an intervention like 5-HTP changes a variable with regards to the inputs into the serotonergic system while SSRI's modulate the function of the system itself. It is amazing how much more is known about how other neurotransmitters objectively function in the brain even though the amount of research dollars poured into serotonin studies are greater than that for any other neurotransmitter, but more research dollars does not always equate to better results. That being said, I think much more will be known about how serotonin actually works in the next 10 years than in the last 100 (just my opinion), so until then it is good to tread carefully here.

    With regards to dopamine, most studies and reviews I have read suggested an excess of dopamine in autism which is correlated with the severity of intellectual disability and aggression, perhaps due to low serotonin which can be due to a multitude of potential factors from gut bacteria as you mentioned above, to chronic inflammatory upregulation of IDO which promotes the kynurenine pathway at the expense of the serotonin pathway (that is my best hypothesis at this time). Simply supplementing more tryptophan (which generally raises serotonin levels in healthy people) won't solve the problem in this regard and could even exacerbate (this is the reasoning behind BCAA + NR + optional 5-HTP/Mucuna Pruriens (L-DOPA).

    I really wish there were better answers even though you would think these topics would be beaten to death over the last 30 years, but it seems like every time I learn something new about serotonin or dopamine, I come up with more questions than answers.

    1. I must apologize for that second to last paragraph as I apparently kind of went off course there and meant to clarify my opinion on dopamine and autism and instead rambled on some more about the tryptophan pathway because I was tired or distracted or whatever last night.

      The segway I was trying to initially discuss was that serotonin and dopamine synthesis compete for the same enzyme and that carbidopa works to inhibit this enzyme in the gut so it affects both 5-HTP usage and L-DOPA usage with the idea being that by preventing serotonin and dopamine synthesis in the gut and the periphery, more 5-HTP or L-DOPA makes it into the brain where it is synthesized into serotonin and dopamine.

      But really, if you can't get a prescription for 5-HTP or L-DOPA, your next best option (especially in the United States which has more liberal laws than Europe on so-called "supplements" is purified griffonia seed extract (5-HTP) or purified Mucuna Pruriens (L-DOPA) and start out at small amounts and work up from there. As an alternative to carbidopa (if it is unavailable), EGCG from Green Tea Extract has some affinity for blocking the AADC enzyme in the gut as well.

      I also have tried both interventions, but it was quite a while ago when I had a much less sophisticated understanding of how these neurotransmitters work and why any intervention may require trying both standard doses as well as very small doses as the efficacy in how these substances are processed orally can vary greatly.

  2. Tyler,while I wait for NR, I want to know between niacin flush and no flush and niacinamide, which one is more effective and in wich dose?. I know that niacinamide in high doses is bactericidal but is it safe?

    1. Never do large doses of niacinimide as it can be toxic. I would just do regular niacin, but not large amounts of it unless you are trying to test for some histamine intolerance.

      In the United States, niacin is by law required to be added to various flours in order to prevent pellagra which used to be a problem a long-time ago in the southern states as poorer people would have diets based largely on milled flour, and especially cornmeal which is low in tryptophan. What doctors found out was that you really didn't need a lot of niacin to prevent pellgra throughout the body so it is just added to flour now. In the case of this BCAA therapy, you will never have pellagra in the periphery, but hypothetically you could have very low B3 levels in the brain due to the tryptophan block by the BCAA's.

      I also supplemented vitamin B6 (in particular the form called P5P) as it is a required cofactor with quinolinic acid in producing NAD+. B6 depletion is hypothesized to be part of the problem in rising quinolinic acid levels in neurodegenerative diseases like Alzheimer's as well as in some studies on autism. Of course your concern is dopamine and things seem to be working well for you, so these recommendations are really just to be safe with long-term use.

    2. Ok Tyler, I will do regular niacin 250 mg and p5p low dose,things are much better,now he wants to become a youtuber and is working for that!, but some challenging episodes appear from time to time,some as dangerous as opening the door while the car is moving. He had never done it before. The link between autism and schizoprenia is undeniable,I hope the magic pill or treatment for the future,today,it is a shame that antipsycotics are so bad.

    3. Well congratulations on him doing much better. My son is much younger than yours (8) but I have gone through a few weird periods where some very dangerous behaviors occurred that were impossible to predict until they happen (which of course as a parent always keeps you on edge). They come and go, but my guess is they are dopamine related and similar to the hyperkinesia symptoms (tics, flailing of arms) except that instead of affecting motor function, they affect cognitive or emotional systems.

      The basal ganglia system (Peter covers it in detail a few blog posts back) was thought for a long time to be just a motor system for action selection whereas among a repetoire of many similar motor actions, one is selected for the appropriate context while all similar motor actions are inhibited so that you can have the kind of finely tuned motor control that allows human beings to do amazing things like handwriting and using chopsticks with our amazing opposable thumbs. Since we are not opossums (who also have opposable thumbs) we also have better developed cognitive control as well and like the action selection of motor programs, the basal ganglia also assists in selecting the appropriate cognitive programs for the given context as well as emotional programs for a given context. If you look at Huntington's syndrome which generally causes hyperkinetic symptoms and Parkinson's which generally causes hypokinetic symptoms (assuming no use of L-DOPA), the cognitive and emotional symptoms follow with that. In the case of those people with Parkinson's who swing their dopaminergic tone in the opposite direction with long-term L-DOPA treatment, one major side-effect is impulsiveness whereas without treatment you have depression and anhedonia which mirror the problems of hypokinetic behavior.

      So in your case, these spontaneous, unpredictable, and dangerous situations that make no sense to us at times can be viewed through the lens of the complex interplay of dopaminergic and gabaergic inhibitory neurons in the basal ganglia which generally (but not always) cause these kind of impulsive behaviors when the so-called indirect pathway is not doing its job (when it is working too hard you get hypokinesis).

      So for interventions in this area, again you will want to look at Parkinson's related drugs/treatments as they now have drugs to deal with side-effects of L-DOPA which is the mainline treatment as impulsive behaviors and hyperkinesis end up being the long-term problems of L-DOPA treatment.

      Nevertheless, a while ago I read about a suggested explanation for dyskinesias with Parkinsons disease and never bothered bookmarking the paper but I dug it up with a quick search:

      What they suggest here (or at least what it sounds like to me) is GABA receptor dysfunction or even desensitization from long-term use of L-DOPA. Now these neural circuits are very specific and very selective, but you might get lucky on minimizing these sorts of behaviors to build on your other recent gains with looking at GABAergic manipulations which Peter probably has several dozen blog posts on alone if you look back far enough. Bumetanide (if you are not already employing it) might be one idea and even though I have not intervened with low-dose clonazepam in my child yet, Peter highly recommends it as one of his best interventions. Also, I would avoid benzodiazepenes in prescription doses for the same reason as SSRI's as I feel neuromodulator interventions need to be understood and employed perfectly or else you are just playing with fire and you can really screw up your kid in the long run. Anything you do with GABA (if you are not already) should likely be very low-dose to start.

    4. Tyler,my son is taking sodium valproate sprinkle since he was 3.I think it activates Gaba receptors and inhibits dopamine. He takes 500 mgs a day. I don´t know if it is too much or if very low doses would work better.What do you think? When I had to decide and change it for bumetanide, I didn´t dare.Besides it was impossible for me to get bumetanide in a regular basis. Ashwagandha could help in addition to valproate?

    5. Well that is very interesting. Valproate is a strong drug and actually used to cause autism symptoms in one model of environmentally induced autism in mice (which is why it is strongly recommended women stop taking it during pregnancy now).

      I can only guess your doctor recommended valproate as an adjunct to risperidone therapy in dealing with the dyskinesia side effects just as is commonly done with Parkinson's treatment where L-DOPA will be given at first and then the dosage is increased as tolerance builds and then dyskinesias and impulsivity develop and then valproate is prescribed on top of L-DOPA to attenuate the disinhibited motor, cognitive, and emotional behaviors from long-term use of L-DOPA.

      Unless your child has epilepsy I would not feel comfortable using this drug as long term use of strong GABAergics leads to mental retardation and Parkinsonian symptoms and valproate itself is highly controversial even though it is one of the oldest and most popular drugs worldwide.

      Overall, Valproate is a very strong drug in my opinion (dosage of course is a big parameter here) and does a lot of different things and even though it is such an old drug, the reviews I have read still can't conclusively point to any clear mechanism of action other than indirect observations of increased GABA synthesis in the brain. It is also thought to work at a very low level on sodium channels and is a potent HDAC inhibitor on top of that which can be good or bad depending on the circumstances (very bad if you are pregnant). Drug companies are always working on better anti-epileptic drugs all the time, but once someone has epilepsy the long-term choices are grim (best to do whatever you can to prevent seizures in the first place). So does your child have seizures already and what was the reasoning the doctor gave you for prescribing valproate in the first place? If your child does not have seizures, your child should probably not be using valproate at all, though I don't really know enough about it as far as what happens if you end treatment with it. One study I read suggested the cognitive declines of long-term valproate usage are reversible, but if you feel you need to use it, you should probably slowly taper down the dose as low as you can until you start getting the negative behavior symptoms it is supposed to treat (unless it is for seizure activity that has already transpired, in which case your options are limited).

      Also I must also say that in many studies on autism now it seems clear the GABAergic system is compromised, but what is not clear is whether simply increasing the levels of GABA in the brain or else increasing GABA's potency with benzo's will improve things long-term.

      I mean, in theory you can reduce aggressive or problematic behaviors in a person by giving them big doses of horse tranquilizers short of the amount that would kill them, but does that really count as a successful treatment? I suppose it is better than what they used to do in the good old days with the frontal lobotomy as was done to the sister of one of our past President's named Rosemary Kennedy (a very sad story that will make your blood boil if you have a child with special needs).

      I guess you are caught between a rock and a hard place here, but unless your kid has ictal activity already, you might want to ask yourself what is the valproate really for here and maybe slowly lowering the dose would be something to try in light of other recent improvements you have had lately.

    6. Speaking from personal experience. My son was taking Depakote sprinkles and some horrible things happened. I wish I would have never used it. His blood chemistry changed, he developed cognitive delay, zombie like behavior. Supplements were prescribed to help but he could not stomache them and I did not want to continue that kind of existence with him. There really should be an epigenetic study on Valproate in relation to Autism to determine how it changes the brain.

    7. Tyler,technically speaking, some headlines about his last brain mapping awake, last year:¨ mild asimmetry of the values of interhemispheric in the fronto temporal, middle temporal and frontal levels.Intermediate electronegativity values, which I don´t know what means exactly.No ictal activity is written, which means seizures, and he hasn´t them but preadolescence is a risky period that we face. I will lower valproate, this was something that the neurologist had in mind, to take it out definitely, but he never concreted. So,he knew exactly what he was doing,and the threats, what you said in your 2nd paragraph was exactly what he did. I will lower valproate but stil hadn´t found a well substitute. Bacilor was something good and could be working at gaba subunits,said Peter, but he hadn´t been taking it latley. Now he is having sleeping problems, he wakes up in the middle of the night and doesn´t go back to sleep. The lack of triptophan could be the cause? I give him melatonin 3 mg and triptopan 25 mg. I will have to increase 5htp again up to 50 mg and give half dose at bedtime.

    8. Another option you could try and it may or may not help would be L-Aspartate. Now, just about nobody would recommend this but me as this intervention was pretty much 100% based on my research stemming from a series of research papers from a professor in Turkey literally over 3 decades ago. What he hypothesized was that L-Aspartate oral administration helped attenuate opioid withdrawal symptoms in animals as well as heroin addicts based upon a mechanism that was never clearly explained from my understanding which could partially be because our understanding of opioids is much better than it was 30 years ago. Nevertheless, this is an intervention I employed with great acute results.

      Now why would messing with the body's opioid receptors possibly help out your son? Well, for one endorphins (endogenous morphine) which are thought to be highly dysregulated in autism based upon multiple different hypotheses I have read, bind to the mu-opioid receptors with the greatest affinity and among the many things mu-opioid receptors do in the brain is disinhibit GABAergic neurons that are responsible for dampening down the release of dopamine in various parts of the brain (i.e. when the mu-opioid receptors are activated, inhibitory cells that inhibit dopamine release are inhibited). In effect, this leads to a rise in dopamine and if there is enough of it at once (such as with heroin injections, fentanyl, or oxycodone), enough dopamine floods the pleasure centers of the brain that you get high.

      So in your case even though L-Aspartate is classically thought of as an excitatory neurotransmitter, its effect on my son was quite the opposite, perhaps because of this very old research or else because of some other reason.

      Here is a link to what I use:

      Also, I have used aspartate myself (for testing purposes) for multiple months and it does have a strong anhedonia effect which can be both good and bad from one's perspective. The opioid system in the brain is most concerned with hedonic drive (pursuit of pleasure), and the anhedonia like effect is evidence to me that it is having an effect on the opioid system or at least on dampening down dopamine, though I have had no motor problems like you might have from a severe lack of dopamine in the brain like you have in Parkinson's disease, so it seems to be more a dopamine modulator than a direct antagonist which is more evidence for its action on the opioid system in the brain.

      There are also other products with aspartate in them such as ZMA, but you want 4-8 grams additional asparate a day.

      I probably have a dozen or so comment postings about this therapy on this blog as well if you want to read them all (if you have not seen me post about them already).

      Oh and one more thing about melatonin. Melatonin should not be used like a "sleeping pill", because that is not what it does. In fact, hyperactivity can be the result of the use of high doses of melatonin if you can outlast any sedating effects. Melatonin should be used to help deal with sleep quality and waking up in the middle of the night. And yes, the lack of tryptophan could easily be causing these sleeping problems if it is not dopamine excitability (could be both). I would not give 5-HTP right before bedtime though. If you give 5-HTP for sleep you want to give it in the late afternoon at the latest because serotonin levels are supposed to recede as evening approaches while melatonin levels are supposed to increase. Just give him melatonin and go up to 10mg if necessary.

    9. Tyler, your posts on aspartate are so interesting, may I suggest a guest blog on it! (unless already done and I missed it?). Very glad to hear it worked so well for your child!

      Just to add something to the subject of opioid systems in autism, something I posted about a while ago on ‘autistic' mice who lacked mu opioid receptors.

      What is striking is is that these mice had lowered activity of quite a few genes implicated in autism. Although the genes themselves were intact, something linked to the lack of mu receptor activity made all these genes go quiet.

      "Inactivation of the mu opioid receptor gene, therefore, alters expression of several candidate genes for ASD … We detected changes in the expression of genes coding for the adhesion and scaffold proteins ------ neuroligins (Nlgn1 and Nlgn2) and SHANK3 (Shank3).

      Transcriptional levels were also modified for the genes coding transporters of:

      ------ norepinephrine (NE, Slc6a2)
      ------ dopamine (DA, slc6a3)
      ------ serotonin (5HT, slc6a4),
      ------ as well as several receptors, including beta3 subunit of GABAA receptors (Gababrb3)
      ------ and 5HT2a serotonin
      ------ and D2 dopamine receptors.

      The most dramatic changes in expression were observed for the genes coding the neuropeptides CRH and OXYTOCIN.

      "... expression of Homer3, coding a key molecular interactor of mGluR5 receptors, was significantly downregulated…"

      They conclude that "Stereotyped and perseverative behaviors detected in Oprm1−/− mice further complete autistic-like core symptoms in these animals. In addition, mutant mice show multiple comorbid symptoms of ASD, including aggressiveness, exacerbated anxiety, motor clumsiness, and increased susceptibility to seizures. …”

      The paper was published in Nature

  3. A very important paper on schizophrenia just came out which suggests a possible in-utero therapy for the disease based upon addressing one particular gene that regulates many other genes (a regulatory gene):

    Press Release:


    Of course this is schizophrenia, but considering the similarities between it and autism, this does give some hope (to me at least) that a master regulatory pathway might exist in autism. Of course, none of us parents have time machines but the trillion dollar question of "what causes autism" or at least a large subset of "autisms" might in theory exist and even though any in-utero therapies would be impossible, it might give a roadmap for treating the most dysregulated genes that pop up as a result of a hypothetical singular master regulatory gene (as is suggested in this paper for schizophrenia).

  4. Hi Peter et al, In light of this article and basal ganglia dysfunction how does inositol factor into these findings? or NAC? It all gets too confusing for me. Thanks, MH

    1. MH, it is confusing for everyone. I assume your interest is related to OCD, Tourette’s, tics, stereotypy etc.

      NAC seems to be effective in treating repetitive stereotypy caused by oxidative stress. This may or may not have anything to do with the basal ganglia, I do not see how anyone can tell.

      There are many types of OCD, there are repetitive behaviors and compulsive behaviors, all slightly different. Compulsive hair pulling (Trichotillomania) often responds to NAC, when might expect it to be a classic case of OCD and not responsive to NAC.

      Some OCD responds to inositol. You just have to try these things.

      If you have a case of involuntary physical movements (tics), I doubt NAC will help. When combined with autism, I would label that as Tourette’s type autism.

      If you have a case of compulsive picking of wild flowers while walking down the street, buy some NAC.

      Having low brain serotonin may very well underlie some people’s anxiety and may respond well to 5-HTP.

      Having low brain dopamine and autism appears to be much more rare, but should respond to levodopa/carbidopa.

  5. Sorry to keep spamming your blog Peter, but I thought you would be very interested in this new research on epilepsy which suggests perhaps half of all epilepsies could be the result not of excitotoxicity from hyperactivity, but rather from a simple lack of oxygen to the cells via capillary dysfunction:

    Press Release:


    You covered CocoaVia and similar interventions before about 6 months ago I believe (I still use CocoaVia for my son thanks to your suggestions), but considering how autism is so comorbid with epilepsy, vasodilation interventions might be worth taking the time in giving them a second look. As I mentioned before, agmatine sulfate has had paradoxical effects on behavior and cognition in my son and even though the primary idea I had for its use was related to its mild NMDA antagonism and A2A adrenoreceptor agonism properties, its primary use commercially is for bodybuilders and athletes to get extra blood flow (i.e. the pump) to their muscles due to is not terribly well understood effect on nitric oxide where you first get an acute vasoconstrictive effect and then a longer term vasodilative effect.

    Another thing to consider for children with large heads (such as my son) is that blood pressure in the body and brain is largely dependent on certain assumptions about the relative size of the rest of the body and brain. This is one reason why having a bigger heart does not mean having a better heart and can lead to death if it enlarges. Perhaps there are blood pressure abnormalities in the brain of those with enlarged heads, leading to the oxygenation problems suggested in this study that eventually leads to epilepsy.

  6. Oh and this will be my last post, but some extremely important research on seizures and Bumetanide (in adults) just came out today:

    Press Release:


    What is new here is that it was found that seizures themselves drive a change in GABA's function in the brain from being inhibitory to being excitatory (which of course drives more seizures) and that this process was diminished greatly by long-term use of bumetanide in that it "is the first time that bumetanide has been found to have a long-term effect on the neural network structure of the brain".

    Of course posting this is bit of confirmation bias on my part, but it does feel good to know we are probably making the right decisions (or at least trying to) while many of the doctors and other so-called "professionals" that are supposed to be actually trying to help us are just twiddling their thumbs with no sense of urgency for a population of people who need help right now.

    1. Diamox is also a good addition. Here is a good paper:

      This excerpt from a book on acetazolamide:

  7. Tyler,
    I once met a mother who told me her experience.Her son had learning disability and till he was 10 years old he had no speech and didn't learn to read and write. Along with other therapies (especially Glenn Doman method of teaching)she tied his legs and hung him upside down for fifteen minutes daily. She said that this helped him a
    lot and he learnt to speak, read and write. So more blood and oxygen to the brain certainly helps.

    1. Sounds like a very bizarre therapy for a child at least even though many people use inversion therapy to help deal with back and posture problems. Nevertheless, I can see the logic in it even though I don't really have the answer off the top of my head if such a therapy actually helps improve blood flow to the brain (it might increase pressure though).

      I used to do handstand pushups on an exercise apparatus before my wife and kids pretty much crowded out every square centimeter of the house for my stuff so that I now have less space and privacy to myself than a prisoner in solitary confinement, but that is besides the point. Anyways, that definitely increases the blood pressure to the head, but I am not so sure it really increases circulation as a few times I would feel a little lightheaded after doing a dozen or so of the exercises. One thing I know that will increase circulation to the brain is activating the mammalian dive reflex which in essence means submerging the entire facial area with cold water for a period of time. This will cause the carotid arteries to expand in an effort to pump more blood to the brain so that you don't pass out from the pressure of diving under water. Of course how you get your child to safely submerge their face in cold water and not end up getting a visit from child protective services is a more complicated matter.

    2. It does sound bizarre, rather like a woolly hat for people with mitochondrial disease to raise their reduced brain temperature.

      Some suggest that inversion therapies will cause capilliaries to exapand (under the increased blood pressure)and so perhaps when you return to the right way up some people's weak cerebral blood flow has increased. This might be complete nonsense and if you have normal blood flow you would gain nothing.

      This would not be good idea in older people because you might trigger a stroke.

      I think it is as likely to help as hyperbaric oxygen therapy, but very much cheaper!

    3. In yoga, Sirsasana, the headstand, is supposed to improve circulation, mental focus etc.

    4. RG since you mention yoga - maybe pranayama breathing techniques in place of headstand. Like buteyko/re-breathing treatments to increase carbon dioxide and improve blood flow? I was always so paranoid to try headstand in yoga because of stroke in my family history. I once took my son to a practitioner who used "neurological reorganization" techniques and inversion therapy was one of the things he used. The kids love it apparently. Looks like acrobatics. I thought my son wpuld love it bc he is a thrill seeker and a little monkey - he immediately wanted out. I think Peter's point about stroke triggering is valid maybe not just for older people. A doctor read my son's first brain MRI as noting not enough "room" around his right cerebellar tonsil. hmmm maybe that inversion created a kink? Interesting all the things you will try when mainstream cannot or does not help or your kid is extremely sensitive.

    5. Yes Tanya, I have also stayed away from the headstand for my daughter. Pranayama and shavasana with focus on breathing and expanding the diaphragm have had enormous ROI for us. It has taught her to relax herself, to wind down when she is getting worked up. Example, if she is working herself up into a state, I can ask her to close her eyes, close her lips and relax herself, and she can pretty quickly get into that wherever she is, and then I tell her to relax her fingers, relax her hands, breathe deeply, basically guide her into it, counting very slowly up to 20. This pretty much gets her out of the emotional spiral. When she is tired, she is now able to stretch out, cover herself with a blanket and close her eyes and lips, breathe deeply and lie still. Helps her fall asleep or just relax and be calm.

    6. Tanya, I also think something like Diamox is a much more reliable way to increase oxygenation and blood flow.

  8. Insulin levels affect the brain's dopamine systems

    Insulin, long known as an important regulator of blood glucose levels, now has a newly appreciated role in the brain.
    Here is a paper saying that improper control of insulin levels in the brain may influence the effectiveness of current ADHD medication.

  9. I am curious about finding more research on Bacopa monniera and I don't know how to go about getting the research articles. Every year picking out something different to grow. I stumble across Bacopa monniera and realize that it could have some neuroprotective properties for epilepsies in relation to cholinergic pathway and GABA receptor site stimulation....Wonder if this could help someone and possibly my family. Could you help Peter?

    1. Just use google. Here are some I found.

      Neuropharmacological Review of the Nootropic Herb Bacopa monnieri

      An acute, double-blind, placebo-controlled cross-over study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood.

      Meta-analysis of randomized controlled trials on cognitive effects of Bacopa monnieri extract.

    2. I thank you kindly for this and wanted to pass on the following.
      Protective potential of Bacopa monniera (Brahmi) extract on aluminum induced cerebellar toxicity and associated neuromuscular status in aged rats.

      When I need to get his immune system a boost Nigella Sativa and it seems to help. I would like to learn more about its half life and the dosing for epilepsy. He seems to tolerate it ok. The problem I run into with plants is that they are a multipurpose sort of treatment. Finding what should and should not be mixed is the problem when you are looking at long-term treatment strategies. One compound might in the plant might not bode well with another from another plant or even supplements you take. Nigella Sativa is widely studied for its treatment in a variety of conditions. There is still a lot to be understood with this plant medicine. You run into the same things with pharmaceuticals. Some plants have neuroprotective properties that are amazing.

    3. I trialed it in the hopes of improving serotonergic signalling due to some small studies that suggested increased axonal sprouting of serotonin expressing neurons (in autism these fiber tracts from the brain stem seem to be diminished). I eventually dropped it because my son won't do pills and even diluting it in a strong chocolate drink won't deal with its bitter aftertaste. It is one of those supplements that some people claim as a nooptropic even though there is little objective evidence that describes how it actually works. It is pretty cheap so as long as you make sure you don't get a source high in metals, then it is probably good to try yourself.

  10. Hi, i dont know other ways to contact you but here. I am wondering if theres any way i could subscribe to your posts so that I'd get alerts through my email every time it's posted.

    1. Hi, I have just activated that feature. It is in the top right of the screen. You enter your email address and Feedburner/Google should send you an email every time there is a new post. Hopefully it works.

  11. Does anyone here have a good recommendation of 5htp brand? I'm reading quality makes a difference.

    1. The brand I got was LiftMode in powder form. It comes with a scooper for 50mg doses so I just scoop using a 4mg scooper I got from something else.

  12. I wanted to mention here that a friend of mine has a teenage son with autism who has been suffering from terrible anxiety and extremely aggressive behaviors. She tried a product called Obsess-Care and it seems to have almost completely eliminated the extreme aggression and anxiety. It has been quite miraculous for them. It seems to be mainly a rather large dose of 5htp, and magnesium, along with some GABA and NAC. It seems to me that the inactive ingredients are the actual active ones.

    1. One of the homeopathic ingredients included is barium carbonate, which is used to make rat poison.

      Better suggest she just tries 25mg HTP without the other ingredients. She will save a lot of money. NAC is added to many drugs to make them work better.

    2. I have suggested that, to quite a few people, and their response usually is that they have tried it alone in the past and it wasn't useful. When I tell them to try NAC, they don't want to. They would rather buy a formula. If you hobble together some version of a pill, you would be a rich man.


    1. Not all people with autism have a shortage of 5-HTP, if you have too much 5-HTP there will be negative effects. It sounds like your son does not need this supplement.

    2. Peter our child 7 years uses antihistamine which are of benefit to her but at the same time give her a ridiculous appetite all her thoughts are on food,which can lead to stomach issues and aggression.Do you think that trialling 5-HTP could balance this out if so what dosage would you suggest.

    3. You might want to try a different antihistamine, they are all slightly different.

      It is worth trying 5-HTP, but not specifically to affect appetite. Many people find 0.5mg/kg twice a day is helpful, in which case they likely have a low natural level of 5-HTP. It is a cheap supplement. If it does nothing, or makes things worse then you stop.


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