On 2016 Dec 22, Peter Good commented:

New insights into studying fever’s dramatic benefit were recently published online at Clinical Nutrition ESPEN: "Simplifying study of fever’s dramatic relief of autistic behavior". Instead of studying only how fever helps, it recommends studying how autistic behavior returns soon after fever. All the complex mechanisms that generated fever have abated or reversed; simpler cooling mechanisms prevail. How many plausible explanations can there be?

It also recommends studying improvements appearing hours before fever’s onset, and improvements persisting days after fever subsides – when stress and heat of brain imaging will be minimal. A scan as autistic behavior returns will be more stressful – but most revealing. Studying fever’s benefit in phases also invites triangulation of decisive factors in relief and recurrence. The full-text PDF can be downloaded at <www.autismstudies.net>

On 2015 Oct 07, Peter Good commented:

Report of a ‘single case clinical trial’ of citrulline for ASD. Glutamine is immediate precursor of citrulline, a (usually) nonprotein amino acid like taurine. Citrulline is immediate precursor of arginine, a protein amino acid most critical as substrate for nitric oxide, primary vasodilator in the brain and body.

After learning that most ingested arginine is taken up by the liver, whereas citrulline bypasses the liver and forms arginine in the kidneys, increasing systemic arginine [Romero MJ, 2006] I replaced 2g/day of arginine I’d been taking for a year with 2–4g/day of citrulline in two doses – before breakfast (fasted state) and several hours after breakfast or lunch (between meals). After five months of 2–4g/day of citrulline (plus 2–4g of taurine), I’ve concluded:

Considerable evidence argues the brain hemispheres of autistic children are chronically isolated and atypically asymmetric in anatomy, function, neurochemistry, and blood flow. Low brain blood flow in hyperexcitable children is especially anomalous – suggesting failure of neurovascular coupling from lack of nitric oxide, the primary vasodilator, or its substrate arginine. Is too much arginine taken up by the liver to detoxify ammonia? One test is oral citrulline, which bypasses the liver and forms arginine in the kidneys, increasing systemic arginine. Replacing 2g/day of oral arginine with 2–4g/day oral citrulline (+ 2–4g taurine) evoked spontaneous speech, calmed anxiety, and enhanced focus and planning – left hemisphere attributes. Evidence that glutathione sustains release of nitric oxide prompted addition of undenatured whey protein for glutathione precursors. Evidence that glutathione also matures myelin argues glutathione depletion is a key mechanism in autism – keeping myelin immature, brain hemispheres isolated, and brain blood flow low. Is autism reversible?

Was my trial of citrulline too subjective? My best evidence is spontaneous speech. I rarely notice right away I’m reading or thinking aloud; in other words, I hear myself speaking, I didn’t intend to. Who is speaking?

My citrulline trial was recently mentioned at Cortical Chauvinism http://corticalchauvinism.com/2015/10/04/peter-good-a-single-case-clinical-trial-with-citrulline/ with a link to a more comprehensive explanation of citrulline’s potential as a remedy for autistic disorders (and the need for glutathione) Chronic neurochemical asymmetry and dysconnection in autism. Implications of a personal trial of citrulline + taurine at: http://www.autismstudies.net

Peter Good Autism Studies La Pine, OR autismstudies1@gmail.com

On 2015 Jun 21, Peter Good commented:

At the 7th International Meeting for Autism Research (IMFAR) pediatric neurologist Andrew Zimmerman and colleagues presented parents’ reports of dramatic improvements of their child’s autistic behavior during fever [1]. These reports were spontaneous responses to their study published the previous year (2007) confirming fever’s benefit in 30 children with autism spectrum disorders (ASD) [Curran LK, 2007]. A few parents reported improvements in a sauna, steam room, or hot tub/bath – rare events. A single sentence on their IMFAR poster lay dormant: “Improvements were reported both during and prior to the onset of fever.” The first formal report of improvements of autistic behavior before fever – a critical clue to the phenomenon.

Zimmerman summarized parents’ anecdotal reports of improvements before fever [3]: “My impression has been that those children who improve before the appearance of fever are those who also have the most striking improvements overall during fever (and are more likely to have enduring effects after fever subsides), possibly 10% of those who have the ‘fever effect’. The ‘fever effect’ may be more common than we realize because there are different gradations of the responses. Also, the improvements in social relatedness and language may then be obscured by sickness behavior during the illness and are subject to a ‘threshold effect’ (i.e. caregiver recognition).” Zimmerman suggested a low grade fever might explain early benefits. “It is usually a period of hours [up to 6–8] when benefits are seen before fever is recognized. . . . Unfortunately we do not have clinical data to support these observations.”

Parents and practitioners have known for decades that fever often relieves a child’s autistic behavior dramatically, and rarely aggravates. It’s also known that improvements in some children persist days after fever breaks, although improvements in most children subside when fever does. Is there a temperature-independent mechanism and a temperature-dependent one? The temperature-dependent mechanism may simply be fever increasing brain metabolism and blood flow – consistently low in these children. The temperature-independent mechanism may be release of free glutamine from skeletal muscles for anabolic responses to infection.

Why would glutamine relieve autistic behavior? Glutamine is precursor (via citrulline) of arginine – required to detoxify ammonia to urea in the liver, synthesize the ATP-transporter creatine, and only substrate for the vasodilator nitric oxide. Ammonia is often high in these children from intestinal bacteria and yeast, yet plasma glutamine is consistently low and brain glutamine often low. Arginine required to detoxify ammonia may deplete arginine as substrate for brain nitric oxide and creatine. Most dietary arginine is taken up by the liver. Because citrulline bypasses the liver and becomes arginine in the kidneys, oral citrulline may be a better source of arginine for brain nitric oxide and creatine than arginine itself.

For further evidence and citations, see A critical clue to fever’s dramatic relief of autistic behavior at www.autismstudies.net.

1. Zimmerman AW, Connors SW, Curran LK. Fever in autism spectrum disorders (ASDs): spontaneous reports. Poster presented at the 7th International Meeting for Autism Research (IMFAR) London 2008 https://imfar.confex.com/imfar/2008/webprogram/Paper2529.html

2. Curran LK, Newschaffer CJ, Lee LC, Crawford SO, Johnston MV, Zimmerman AW. Behaviors associated with fever in children with autism spectrum disorders. Pediatrics 2007;120:e1386–e1392.

3. Zimmerman A (MD). Personal communication 2014.

On 2015 Jun 21, Peter Good commented:

At the 7th International Meeting for Autism Research (IMFAR) pediatric neurologist Andrew Zimmerman and colleagues presented parents’ reports of dramatic improvements of their child’s autistic behavior during fever [1]. These reports were spontaneous responses to their study published the previous year (2007) confirming fever’s benefit in 30 children with autism spectrum disorders (ASD) [Curran LK, 2007]. A few parents reported improvements in a sauna, steam room, or hot tub/bath – rare events. A single sentence on their IMFAR poster lay dormant: “Improvements were reported both during and prior to the onset of fever.” The first formal report of improvements of autistic behavior before fever – a critical clue to the phenomenon.

Zimmerman summarized parents’ anecdotal reports of improvements before fever [3]: “My impression has been that those children who improve before the appearance of fever are those who also have the most striking improvements overall during fever (and are more likely to have enduring effects after fever subsides), possibly 10% of those who have the ‘fever effect’. The ‘fever effect’ may be more common than we realize because there are different gradations of the responses. Also, the improvements in social relatedness and language may then be obscured by sickness behavior during the illness and are subject to a ‘threshold effect’ (i.e. caregiver recognition).” Zimmerman suggested a low grade fever might explain early benefits. “It is usually a period of hours [up to 6–8] when benefits are seen before fever is recognized. . . . Unfortunately we do not have clinical data to support these observations.”

Parents and practitioners have known for decades that fever often relieves a child’s autistic behavior dramatically, and rarely aggravates. It’s also known that improvements in some children persist days after fever breaks, although improvements in most children subside when fever does. Is there a temperature-independent mechanism and a temperature-dependent one? The temperature-dependent mechanism may simply be fever increasing brain metabolism and blood flow – consistently low in these children. The temperature-independent mechanism may be release of free glutamine from skeletal muscles for anabolic responses to infection.

Why would glutamine relieve autistic behavior? Glutamine is precursor (via citrulline) of arginine – required to detoxify ammonia to urea in the liver, synthesize the ATP-transporter creatine, and only substrate for the vasodilator nitric oxide. Ammonia is often high in these children from intestinal bacteria and yeast, yet plasma glutamine is consistently low and brain glutamine often low. Arginine required to detoxify ammonia may deplete arginine as substrate for brain nitric oxide and creatine. Most dietary arginine is taken up by the liver. Because citrulline bypasses the liver and becomes arginine in the kidneys, oral citrulline may be a better source of arginine for brain nitric oxide and creatine than arginine itself.

For further evidence and citations, see A critical clue to fever’s dramatic relief of autistic behavior at www.autismstudies.net.

1. Zimmerman AW, Connors SW, Curran LK. Fever in autism spectrum disorders (ASDs): spontaneous reports. Poster presented at the 7th International Meeting for Autism Research (IMFAR) London 2008 https://imfar.confex.com/imfar/2008/webprogram/Paper2529.html

2. Curran LK, Newschaffer CJ, Lee LC, Crawford SO, Johnston MV, Zimmerman AW. Behaviors associated with fever in children with autism spectrum disorders. Pediatrics 2007;120:e1386–e1392.

3. Zimmerman A (MD). Personal communication 2014.

On 2015 Oct 07, Peter Good commented:

Report of a ‘single case clinical trial’ of citrulline for ASD. Glutamine is immediate precursor of citrulline, a (usually) nonprotein amino acid like taurine. Citrulline is immediate precursor of arginine, a protein amino acid most critical as substrate for nitric oxide, primary vasodilator in the brain and body.

After learning that most ingested arginine is taken up by the liver, whereas citrulline bypasses the liver and forms arginine in the kidneys, increasing systemic arginine [Romero MJ, 2006] I replaced 2g/day of arginine I’d been taking for a year with 2–4g/day of citrulline in two doses – before breakfast (fasted state) and several hours after breakfast or lunch (between meals). After five months of 2–4g/day of citrulline (plus 2–4g of taurine), I’ve concluded:

Considerable evidence argues the brain hemispheres of autistic children are chronically isolated and atypically asymmetric in anatomy, function, neurochemistry, and blood flow. Low brain blood flow in hyperexcitable children is especially anomalous – suggesting failure of neurovascular coupling from lack of nitric oxide, the primary vasodilator, or its substrate arginine. Is too much arginine taken up by the liver to detoxify ammonia? One test is oral citrulline, which bypasses the liver and forms arginine in the kidneys, increasing systemic arginine. Replacing 2g/day of oral arginine with 2–4g/day oral citrulline (+ 2–4g taurine) evoked spontaneous speech, calmed anxiety, and enhanced focus and planning – left hemisphere attributes. Evidence that glutathione sustains release of nitric oxide prompted addition of undenatured whey protein for glutathione precursors. Evidence that glutathione also matures myelin argues glutathione depletion is a key mechanism in autism – keeping myelin immature, brain hemispheres isolated, and brain blood flow low. Is autism reversible?

Was my trial of citrulline too subjective? My best evidence is spontaneous speech. I rarely notice right away I’m reading or thinking aloud; in other words, I hear myself speaking, I didn’t intend to. Who is speaking?

My citrulline trial was recently mentioned at Cortical Chauvinism http://corticalchauvinism.com/2015/10/04/peter-good-a-single-case-clinical-trial-with-citrulline/ with a link to a more comprehensive explanation of citrulline’s potential as a remedy for autistic disorders (and the need for glutathione) Chronic neurochemical asymmetry and dysconnection in autism. Implications of a personal trial of citrulline + taurine at: http://www.autismstudies.net

Peter Good Autism Studies La Pine, OR autismstudies1@gmail.com

On 2016 Dec 22, Peter Good commented:

New insights into studying fever’s dramatic benefit were recently published online at Clinical Nutrition ESPEN: "Simplifying study of fever’s dramatic relief of autistic behavior". Instead of studying only how fever helps, it recommends studying how autistic behavior returns soon after fever. All the complex mechanisms that generated fever have abated or reversed; simpler cooling mechanisms prevail. How many plausible explanations can there be?

It also recommends studying improvements appearing hours before fever’s onset, and improvements persisting days after fever subsides – when stress and heat of brain imaging will be minimal. A scan as autistic behavior returns will be more stressful – but most revealing. Studying fever’s benefit in phases also invites triangulation of decisive factors in relief and recurrence. The full-text PDF can be downloaded at <www.autismstudies.net>