Clonidine and Guanfacine for ADHD, mast cell activation, sleep disorders, tics and some self-injurious behavior (SIB)

 

Both clonidine and guanfacine were raised recently to me, they have been covered in various earlier posts and in my book. Here is a round-up of the information.

These two drugs are α2A-adrenergic receptor agonists originally used to treat high blood pressure. Subsequently many additional uses of these drugs have been discovered.

I was asked about its use to treat mast cell activation syndrome (MCAS) and the mechanism by which it achieves this effect is interesting.

Calming mast cells – the ones that release histamine during an allergic reaction

Clonidine/guanfacine, as alpha-2 adrenergic agonists, inhibit mast cells primarily by interacting with the central and peripheral nervous systems, leading to a decrease in the release of inflammatory mediators. Its mechanism involves stimulating alpha-2 adrenergic receptors, which in turn suppresses the release of norepinephrine and other neurotransmitters.

In terms of mast cell stabilization, clonidine/guanfacine is thought to reduce intracellular calcium levels and inhibit the degranulation process that releases histamine and other pro-inflammatory substances. Lower intracellular calcium prevents the activation of key signaling pathways that normally trigger mast cell activation and degranulation.

This stabilizing effect helps prevent excessive allergic and inflammatory responses, making clonidine/guanfacine beneficial in conditions where such inhibition is useful.

Clonidine/guanfacine have some calcium channel-blocking properties, though they are not classified as a traditional calcium channel blocker. By indirectly lowering intracellular calcium levels, clonidine/guanfacine inhibit the signaling pathways that lead to mast cell degranulation and the release of inflammatory mediators. The end result is a reduction in cellular excitability and a dampening of the inflammatory response, including mast cell stabilization.

Clearly, you could just go directly to a calcium channel blocker like verapamil.

Clonidine/guanfacine and indeed verapamil are not seen as first line treatments for MCAS but may well be beneficial.

Conventional First-Line Treatments for MCAS

Antihistamines

H1 blockers (e.g., cetirizine, loratadine) to manage allergic-type symptoms like itching, hives, and flushing.

H2 blockers (e.g., famotidine, ranitidine) to control gastrointestinal symptoms and histamine release in the stomach.

Mast Cell Stabilizers

Cromolyn sodium is often considered one of the most effective mast cell stabilizers for MCAS, especially for gastrointestinal symptoms.

Ketotifen, another mast cell stabilizer with antihistamine properties, can also be helpful.

Rupatadine and azelastine are also potentially beneficial as mast cell stabilizers.

Leukotriene Inhibitors

Medications like montelukast can help manage symptoms related to leukotrienes, which are other mediators released by mast cells.

Aspirin

Aspirin can play a role in managing MCAS, particularly in controlling specific symptoms like flushing, hives, and inflammation. Its primary action in MCAS involves inhibiting prostaglandin D2 (PGD2), which is one of the inflammatory mediators released by mast cells and contributes to the vascular symptoms seen in MCAS.

Sleep disorders

Some people with autism do not sleep well.

Clonidine/guanfacine can help some individuals fall asleep faster and stay asleep longer by promoting relaxation and calming overactivity in the brain.

It is sometimes used in pediatric populations, such as children with autism or ADHD, to help with sleep initiation and minimize frequent nighttime awakenings.

Clonidine/guanfacine, being alpha-2 adrenergic agonists, lower the activity of the sympathetic nervous system (the fight-or-flight response).

Clonidine/guanfacine is typically prescribed at a low dose for sleep, as higher doses can lead to daytime drowsiness. Taking clonidine at night, about 30-60 minutes before bed, is common practice.

Guanfacine has a longer half-life than clonidine, which means it provides a more sustained effect throughout the night and may lead to fewer night-time awakenings. This can be particularly useful for individuals who need consistent support for sleep through the night.

Tics

Clonidine/guanfacine have long been used off-label to treat Tourette’s syndrome, which is a tic disorder.

Clonidine/guanfacine can help manage some stereotypical behaviors (repetitive, non-functional behaviors) in individuals with autism, when these behaviors are driven by hyperactivity, impulsivity, or anxiety.

Clonidine/guanfacine helps manage tics by calming the nervous system, modulating norepinephrine release, reducing stress, and helping with impulse control.

This effect has been noted by our reader AW.

Self-injurious behavior (SIB)

Self-injurious behavior (SIB) is usually considered the worst feature of autism. It becomes a learned behavior which can be very hard to extinguish.

Clonidine/guanfacine is on the long list of sometimes effective therapies. Take a note of this!

 

Clonidine as a Treatment of Behavioural Disturbances in Autism Spectrum Disorder: A Systematic Literature Review

Clonidine has a limited evidence base for use in the management of behavioural problems in patients with ASD. Most evidence originates from case reports. Given the paucity of pharmacological options for addressing challenging behaviours in ASD patients, a clonidine trial may be an appropriate and cost-effective pharmaceutical option for this population.

Beneficial Effects of Clonidine on Severe Self-Injurious Behavior in a 9-Year-Old Girl with Pervasive Developmental Disorder

ADHD

ADHD is very commonly diagnosed these days.

The genes involved in ADHD, autism, bipolar and schizophrenia are overlapping, so it is not surprising that many people are now being diagnosed with both ADHD and autism.

What I find very odd is that people with ADHD line up for medical treatment, but most people with comorbid autism think there cannot be a medical treatment for their autism because it is just how their brain is “wired-up differently.” It is hard to reconcile these views - both conditions are clearly treatable.

Most ADHD treatments are stimulants. Medications like methylphenidate (Ritalin, Concerta) and amphetamine-based drugs (Adderall, Vyvanse) are typically considered first-line treatments for ADHD. They work by increasing levels of dopamine and norepinephrine in the brain, which help improve focus, attention, and impulse control in people with ADHD.

Not all individuals with ADHD can tolerate stimulants, and in some cases, they may experience unwanted side effects like anxiety, sleep disturbances, or increased irritability.

The most common non-stimulant options are Clonidine and Guanfacine. They does not directly increase dopamine or norepinephrine but instead reduces norepinephrine release, promoting a calming effect.

Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor (NRI), which increases norepinephrine in the brain by blocking its reuptake.

After years of off-label use in by 2010 both clonidine and guanfacine were FDA approved for use in ADHD.

 

Conclusion

As I mentioned to one reader, we should take note that both clonidine and guanfacine are approved for use in children (with ADHD) and so there is plenty of safety information and dosage guidance.

The effective dose for MCAS, sleep disorders, tics and SIB may well vary from person to person but the safe boundaries are well established from ADHD.

In general, guanfacine tends to be better tolerated than clonidine.

AW might note that guanfacine can cause sleep problems, including insomnia or vivid dreams.

Here is a useful list I found:

Common Side Effects:

Sedation/Drowsiness: Like clonidine, guanfacine can cause drowsiness, especially during the initial stages of treatment or when the dose is increased.

Fatigue: Many people report feeling fatigued or tired when starting guanfacine, which can affect daytime functioning.

Low Blood Pressure (Hypotension): Guanfacine also lowers blood pressure, potentially leading to dizziness or light-headedness, particularly when standing up quickly.

Dry Mouth: This is another common side effect, similar to clonidine, and may cause discomfort.

Headache: Some people experience headaches, especially when starting treatment.

Stomach Problems (e.g., abdominal pain, constipation): Gastrointestinal side effects can occur in some individuals, such as constipation or stomach discomfort.

Irritability and Mood Swings: In some cases, guanfacine may cause irritability or emotional instability.

Less Common but Serious Side Effects:

Bradycardia (slow heart rate): As with clonidine, guanfacine can cause a slow heart rate, which could be concerning for individuals with underlying heart issues.

Rebound Hypertension: Discontinuing guanfacine too abruptly can cause rebound hypertension (a sudden increase in blood pressure), so it should be tapered gradually under a healthcare provider’s guidance.

Sleep disturbances: In some cases, though less common than with clonidine, guanfacine can cause sleep problems, including insomnia or vivid dreams.

Taurine – a cheap Autism intervention worth a trial

 

I did recently write a post all about Taurine and the many effects it has on the body, some of which really should affect autism. 

Taurine for subgroups of Autism? Plus, vitamin B5 and L Carnitine for KAT6A syndrome?

 

Having read the literature, it looked to me that anyone over 50 years old is likely to benefit from a little extra Taurine, but it certainly was not clear whether it would make my 21 year old’s autism better or worse. I went ahead and ordered some to investigate.

In theory one of the many effects of Taurine is negative. Taurine does affect the KCC2 transporter that takes chloride out of neurons the “wrong” way. The other effects include on calcium homeostasis, which we know is disturbed in most autism.

 

N = 2 Trial

Subject #1 (Peter)

I took 2g a day for a month and noticed no effect at all, other than some mild GI irritation.

In adults the long-term effects are numerous and varied throughout the body. Even the cells that remodel your bones (osteoblasts and osteoclasts) have special taurine transporters, whose sole role is to let taurine inside – taurine makes the osteoblasts work harder, while encouraging osteoclasts to take a break. The net effect should be stronger bones.  As you get older your natural levels of taurine fall substantially. There are taurine-rich foods you can eat and if you engage in strenuous exercise your liver starts making more taurine.

 

Subject #2 (Monty)

There is a clear contradiction when it comes to Taurine and sleep. Many energy drinks contain Taurine to keep you alert, but in theory Taurine should be calming and many people take it add bedtime to improve sleep.

Monty, aged 21 with ASD, likes getting up early and going to bed early.

Adding 2g a day of Taurine at breakfast shifted his circadian rhythms, so that he now goes to bed at a time typical for a 21 year old, but still wants to get up at 7am. Monty even fell asleep on the sofa watching TV late one night, something big brother often does. Indeed, Monty received a nod of approval when big brother discovered him in the early hours. 

The most beneficial change has been on his spring and summertime aggression. This has been controlled for years using an L-type calcium channel blocker. This does not resolve the allergy at all, but it “switches off” the consequential anxiety/aggression. With the addition of allergy therapies and the immunomodulation of Pioglitazone (in peak allergy season) the problem behaviors are controlled.

It appears that Taurine has a similar anti-anxiety/aggression effect. Maybe its effect on calcium channels and broader calcium homeostasis is the reason why. Anyway, it works – simple, cheap, OTC and effective.  It has no effect on allergy, in case you are wondering.

  

Conclusion

Taurine can be bought as a bulk powder for very little money. It is not like those numerous expensive supplements that would cost you several hundred dollars/euros/pounds a year.

If you have your own “healthspan polytherapy”, to ward off high blood pressure, high cholesterol, type 2 diabetes, dementia, arthritis, osteoporosis etc, consider spending a few pennies more and add a scoop of taurine.

The people who write to me and tell me how Verapamil has transformed life at home, by banishing aggression and self-injurious behaviors, should seriously consider a trial of Taurine.

 

Melatonin for Kids with Autism, and indeed their Parents

I have long heard about kids with autism having sleeping problems; these range from difficulty falling asleep, waking frequently during the night and waking up very early in the morning.  The same problems apparently occur in ADHD.

I think some of the sleep related problems are behavioral in nature; some children with ASD live actually with less structure than typical kids.  Some kids with ASD do not get much physical exercise to tire them out by bed time.  

Having said all that, there does seem to be something else going on.

Long ago people found out that Melatonin, a hormone available cheaply without prescription in many countries, had a very positive effect on sleeping patterns.

What is also interesting, is the other properties of Melatonin and the other types of people who can benefit from it.  This does take us some way from our core theme of autism, towards treating cancer and other illnesses of older age.  I expect most my readers are parents of a child with ASD, well this time science has some news for you too.

What is Melatonin?

Melatonin is a hormone secreted by the Pineal Gland in the brain. It helps regulate other hormones and maintains the body's internal clock. The circadian rhythm is an internal 24-hour clock, that plays a critical role in when we fall asleep and when we wake up. When it is dark, your body produces more melatonin; when it is light, the production of melatonin drops. Being exposed to bright lights in the evening or too little light during the day can disrupt the body’s normal melatonin cycles.

Melatonin helps control the timing and release of female reproductive hormones. Some researchers also believe that melatonin levels may be related to aging.

Young children have the highest levels of night time melatonin. Researchers believe these levels drop as we age. Some people think lower levels of melatonin may explain why some older adults have sleep problems.

Melatonin has powerful antioxidant effects. Research suggests that it may help strengthen the immune system.

Melatonin is derived from serotonin. Serotonin levels in autism are often high in the blood, but can be low in the brain.  Serotonin cannot cross the blood brain barrier.  The Pineal Gland is inside the brain, but outside the blood brain barrier.

 

Dose Response

One clever study tried to establish the dose at which Melatonin had an effect on sleep.  It is interesting that they found the dosage was not correlated to weight.  The vast majority of drugs are dosed on how big you are, and often trials assume this to be the case.

Melatonin for Sleep in Childrenwith Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

Dose-response

All 24 children who completed study procedures obtained a satisfactory response (as defined above) to melatonin at doses between 1 mg and 6 mg. Seven children obtained a satisfactory response at 1 mg, 14 at 3 mg, and only 3 required 6 mg. The child’s age or weight was not associated with melatonin dose response. The mean age/weight (standard deviation) of children responding to 1 mg was 5.9 (1.9) years/26.4 (11.1) kg; and to 3 or 6 mg was 5.9 (2.3) years/25.4 (11.2) kg.

In effect you are treating a hormone deficiency, like any other.  Just as a small person may need more thyroid hormone than a very big person; the same appears to be true with Melatonin.

Much of the “specialist advice” from "doctors" on the web looks incorrect on this subject:-

Melatonin. This naturally occurring peptide released by the brain in response to the setting of the sun has some function in setting the circadian clock. It is available without prescription at most pharmacies and health food stores. Typically the dosage sizes sold are too large. Almost all of the published research on Melatonin is on doses of 1 mg or less, but the doses available on the shelves are either 3 or 6 mg. Nothing is gained by using doses greater than one milligram. Melatonin may not be effective the first night, so several nights' use may be necessary for effectiveness.

(this was advice for people with ADHD, which I regard as part of ASD)

 

Abnormal Melatonin Synthesis in ASD and in Parents

A surprising amount of work has been done looking at abnormalities in melatonin synthesis in both kids with ASD and their parents.  Hence the title of this post.

The low level of melatonin synthesis is acquired from one or more parent, who will probably also have a sleep disorder.  Not only that, but low melatonin is also linked to increased risk to some serious health conditions, more on that later. 

Abnormal Melatonin Synthesis in ASD

"In autism spectrum disorders (ASD), low melatonin levels have been reported by three independent groups,^13–15 but the underlying cause of this deficit and its relationship to susceptibility to ASD was unknown

the serotonin level was significantly higher in individuals with ASD (P=2×10⁻¹¹) and their parents (P=10⁻⁸) than in controls

 Our results confirm that low plasma melatonin concentration (half the mean of the control values) is a frequent trait in ASD patients, as observed in 65% of the patients tested, a proportion very similar (63%) to that previously reported by Tordjman et al.¹⁵ We show for the first time that abnormal melatonin levels are also present in the unaffected parents of ASD patients, suggesting a genetic origin. Indeed, the melatonin deficit observed in the patients was associated with low ASMT activity, suggesting that variations in the ASMT gene could be the cause of this deficit."

Effect of Hormone Supplementation on the Pineal Gland

If you start interfering with human hormones, you need to be aware of the possible consequences.  For example, a relatively common autism therapy in the US is to give thyroid hormones T4 and T3 to children who are not clinically hypothyroid.  Some parents report great improvements, but some comment that over time they have to increase the dosage.  This is because the feedback loops that control the thyroid gland are telling it to gradually shut down.  Over time, such a child might become entirely dependent on the T4/T3 tablets.

So, if you have a pineal gland that does not produce enough melatonin, what happens to it when you take supplements?  I do not think anyone can tell you with certainty.

There have been long term trials over a few years in sleep disorders.  When supplementation stops the sleep disorder returns.  Nothing bad was reported.

Natural release of melatonin is controlled by exposure to light and dark.  To what extent does this change when supplements are added?

To what extent to supplements interfere with other less well understood melatonin mechanisms?  

On balance, common sense would tell you to leave a fully functioning pineal gland well alone; but if you have an autistic child with a challenging sleep disorder, this would be suggest that the pineal gland needs some external help.  In an ideal world, your doctor would test the pineal gland function and check Melatonin levels were age appropriate.

Melatonin and Behaviours

Research in ADHD suggests that while Melatonin improves sleep disorders it does not improve behaviour.

Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. 

Abstract

OBJECTIVE:

To investigate the effect of melatonin treatment on sleep, behavior, cognition, and quality of life in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia.

METHOD:

A total of 105 medication-free children, ages 6 to 12 years, with rigorously diagnosed ADHD and chronic sleep onset insomnia participated in a randomized, double-blind, placebo-controlled trial using 3 or 6 mg melatonin (depending on body weight), or placebo for 4 weeks. Primary outcome parameters were actigraphy-derived sleep onset, total time asleep, and salivary dim light melatonin onset.

RESULTS:

Sleep onset advanced by 26.9 +/- 47.8 minutes with melatonin and delayed by 10.5 +/- 37.4 minutes with placebo (p < .0001). There was an advance in dim light melatonin onset of 44.4 +/- 67.9 minutes in melatonin and a delay of 12.8 +/- 60.0 minutes in placebo (p < .0001). Total time asleep increased with melatonin (19.8 +/- 61.9 minutes) as compared to placebo (-13.6 +/- 50.6 minutes; p = .01). There was no significant effect on behavior, cognition, and quality of life, and significant adverse events did not occur.

CONCLUSION:

Melatonin advanced circadian rhythms of sleep-wake and endogenous melatonin and enhanced total time asleep in children with ADHD and chronic sleep onset insomnia; however, no effect was found on problem behavior, cognitive performance, or quality of life.

 

The studies in autism indicate a different story; behaviours do improve.  After a good night’s sleep, most people’s behaviour improves; it would be odd if it did not.

I think this is another case of ADHD disorders being of a different magnitude to disorders further along the autistic spectrum.  

For the impact in autism, it best to read the studies; here is an excerpt from Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes:-

“The behavioral outcome measures that showed change with melatonin (e.g., attention-deficit hyperactivity, withdrawn, affective problems, stereotyped behaviors, compulsive behaviors) resemble that of prior work. The literature emphasizes that the behavioral construct of hyperactivity is affected by sleep disturbance—this had been documented in ASD populations (Goldman et al 2009; Mayes and Calhoun 2009) as well as typically developing children treated for obstructive sleep apnea (Chervin et al 2006). Other behavioral parameters which have been associated with poor sleep in children with ASD include repetitive behavior, including compulsive behavior, and oppositional and aggressive behavior, anxiety, depression, and mood variability (Malow et al 2006; Goldman et al, 2009; Mayes and Calhoun 2009). In an intervention study of parent education, hyperactivity and restricted behaviors showed improvements with treatment (Reed 2009).”

Strangely, when it came to parental stress, they found less impact:-

“Parenting stress, as measured by the Difficult Child Subscale, improved with treatment. We did not find improvement in the PSI parent-related domains (Parental Distress or Parent-Child Dysfunctional Interaction) suggesting that parental stress in autism is multifactorial and may not be addressed with a single intervention.”

 

Why is Melatonin so good for the CNS (Central Nervous System)?

It appears that Melatonin does some very useful things

·        It is an antioxidant/free radical scavenger

·        It stimulates the production of the body’s other key antioxidants

·        It inhibits the production of pro-oxidative enzymes

·        Protects nuclear and mitochondrial DNA

Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.

Abstract

This review briefly summarizes the multiple actions by which melatonin reduces the damaging effects of free radicals and reactive oxygen and nitrogen species. It is well documented that melatonin protects macromolecules from oxidative damage in all subcellular compartments. This is consistent with the protection by melatonin of lipids and proteins, as well as both nuclear and mitochondrial DNA. Melatonin achieves this widespread protection by means of its ubiquitous actions as a direct free radical scavenger and an indirect antioxidant. Thus, melatonin directly scavenges a variety of free radicals and reactive species including the hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, peroxynitrite anion, and peroxynitrous acid. Furthermore, melatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Additionally, melatonin experimentally enhances intracellular glutathione (another important antioxidant) levels by stimulating the rate-limiting enzyme in its synthesis, gamma-glutamylcysteine synthase. Melatonin also inhibits the proxidative enzymes nitric oxide synthase and lipoxygenase. Finally, there is evidence that melatonin stabilizes cellular membranes, thereby probably helping them resist oxidative damage. Most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce election leakage and the generation of free radicals. These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis.

 

Why is Melatonin good for the Immune System?

It is known that Melatonin interacts with the immune system, but the mechanism is not fully understood yet.  As you see below, Melatonin is not just produced in the Brain, it is also sythesized by the immune system. 

A review of the multiple actions of melatonin on the immune system

Abstract

This review summarizes the numerous observations published in recent years which have shown that one of the most significant of melatonin's pleiotropic effects is the regulation of the immune system. The overview summarizes the immune effects of pinealectomy and the association between rhythmic melatonin production and adjustments in the immune system as markers of melatonin's immunomodulatory actions. The effects of both in vivo and in vitromelatonin administration on non-specific, humoral, and cellular immune responses as well as on cellular proliferation and immune mediator production are presented. One of the main features that distinguishes melatonin from the classical hormones is its synthesis by a number of non-endocrine extrapineal organs, including the immune system. Herein, we summarize the presence of immune system-synthesized melatonin, its direct immunomodulatory effects on cytokine production, and its masking effects on exogenous melatonin action. The mechanisms of action of melatonin in the immune system are also discussed, focusing attention on the presence of membrane and nuclear receptors and the characterization of several physiological roles mediated by some receptor analogs in immune cells. The review focuses on melatonin's actions in several immune pathologies including infection, inflammation, and autoimmunity together with the relation between melatonin, immunity, and cancer.

 

Anti-aging Treatment

There are all sorts of products and therapies put forward to an eager public to combat the aging process; melatonin is one of these products.   I think, in this case, they may very well have got is right.  Yet again, a drug for older people seems to be effective for kids with ASD. 

In anti-aging, one well known practitioner, Dr Pierpaoli, recommends:-

30-39 years of age             1.5mg at bedtime

40-49 years of age             1.5mg to 3mg at bedtime

50-74 years of age             3mg at bedtime

Above 75 years                   3mg to 6mg at bedtime

 

Other use of Melatonin, related to subjects covered in this blog

Melatonin appears to help in Alzheimer’s by interfering with Amyloid beta, which was covered in an earlier post.

Amyloids, APP, ADAM17 and Autism

Melatonin appears to reduce symptoms in irritable bowel symptom.

Melatonin has been used to treat cluster headaches.

Information for Parents

We have seen earlier in this post that parents of a child with ASD also tend to have a low level of Melatonin.  If you read the layperson’s guide from the University of Maryland, you will see that a low Melatonin level in women is linked to increased risk of breast cancer and in men an increased risk of prostate cancer. 

“Studies show that men with prostate cancer have lower melatonin levels than men without the disease. In test tube studies, melatonin blocks the growth of prostate cancer cells.”

“Laboratory experiments have found that low levels of melatonin stimulate the growth of certain types of breast cancer cells, while adding melatonin to these cells slows their growth”

Since Melatonin is a powerful antioxidant, this may just mean that breast cancer and prostate cancer are linked to oxidative stress and so Melatonin is being used up; but it might also mean that Melatonin is somehow protective.

I read a long time ago that NAC improves outcomes in breast cancer and I expect it does on other types of cancer.

I already take NAC daily, I should probably take some Melatonin as well.  And you?

Conclusion

Melatonin would seem a good candidate for a drug that can make small positive improvements in autism.  Based on an earlier post, it is under consideration for the yellow side of the Polypill.

 

Note that Melatonin has to be given just before bed time.

Note that Melatonin interacts with some drugs used in autism and ADHD.