Thursday 14 November 2013

Clonidine, ADHD and Autism

Clonidine has been used for more than half a century as an antihypertensive drug, to lower blood pressure.

It later found favour as a treatment for ADHD, drug withdrawal treatment, tobacco withdrawal treatment and a wide range of psychiatric disorders.  Off label usage of Clonidine includes autism.

Until recently it appeared to researchers to be a centrally acting α2 adrenergic agonist, but recent research indicates than instead it is a centrally as an imidazoline receptor agonist.  This would account for its actions other than lowering blood pressure. Maybe it is both.  The good thing is that it is centrally acting (i.e. acting on the brain and the CNS) and it does appear to work. 

Adrenergic Agonist
As a centrally-acting α-adrenergic receptor agonist, Clonidine has more affinity for α2 than α1. It selectively stimulates receptors in the brain that monitor catecholamine (epinephrine, norepinephrine and dopamine) levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that controls the production of catecholamines.  By fooling the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure.

Imidazoline Receptors
There are three classes of imidazoline receptors:
  • I1 receptor – mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure
  • I2 receptor – an allosteric binding site of monoamine oxidase and is involved in pain modulation and neuroprotection.
  • I3 receptor – regulates insulin secretion from pancreatic beta cells

L-Monoamine oxidases (MAO)
MAOs are enzymes that act as catalysts.  There are two types of MAO: MAO-A and MAO-B
MAO- A is an enzyme that degrades amine neurotransmitters such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT).

MAO-B is an enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters, including dopamine (DA).
The differences between the selectivity of the two enzymes are utilized clinically.  MAO- A inhibitors have been used in the treatment of depression, and MAO-B inhibitors are used in the treatment of Parkinson's disease

Selective MAO-B inhibitors preferentially inhibit MAO-B, which mostly metabolizes DA. If MAO-B is inhibited, then more DA is available for proper neuronal function, especially in Parkinson's Disease. 

Clinical significance
Because of the vital role that MAOs play in the inactivation of neurotransmitters, MAO dysfunction (too much or too little MAO activity) is thought to be responsible for a number of psychiatric and neurological disorders. For example, unusually high or low levels of MAOs in the body have been associated with schizophrenia, depression, attention deficit disorder, substance abuse, migraines, and irregular sexual maturation.
MAO inhibitors are one of the major classes of drug prescribed for the treatment of depression, although they are often last-line treatment due to risk of the drug's interaction with diet or other drugs. Excessive levels epinephrine, norepinephrine or dopamine may lead to a hypertensive crisis, and excessive levels of serotonin may lead to serotonin syndrome.
MAO-A inhibitors act as antidepressant and antianxiety agents, whereas MAO-B inhibitors are used to treat Alzheimer’s and Parkinson’s diseases.

Clonidine in ADHD
In the US, the FDA has licensed clonidine for use in children with ADHD.
Pediatric doses of clonidine are calculated based on the child's body weight. Clonidine dosage for ADHD in children is 5 micrograms per kilogram of body weight per day orally in four divided doses. Children who require a daily dosage of 0.2 mg usually can use the 0.3 mg trans-dermal patch. If ADHD is associated with sleep disturbances, low to moderate doses of clonidine can be taken at bedtime.

Clonidine in Autism
Not surprisingly, since clonidine is effective in ADHD, it also shows promise in autism. 

Other ADHD drugs, like Ritalin, have problematic side effects.  The US Center for Disease Control reported in 2012 that an estimated 6.4 million children ages 4 to 17 had been diagnosed with ADHD at some point, a 53 percent increase over the past decade. Approximately two-thirds of those currently diagnosed have been prescribed drugs such as Ritalin or Adderall. Those drugs can help patients with both mild and severe symptoms, but they can also cause addiction, anxiety and psychosis.  In the UK, it is suggested that about 3% of children may have ADHD.  Drug use is far lower than in the US, but 657,000 prescriptions were written by doctors for drugs like Ritalin in 2012.
There have been studies of clonidine in autism; here a fairly recent one:-
Perhaps even more interesting is a lively debate among parents who have tried it:-
It does seem to work, but nobody seems to be following it up.

Clonidine Stimulation Test
Regular readers will know my interest in TRH and GH.  At least there is no doubt about Clonidine’s effect on GH (growth hormone).  If you want to test pituitary function to see how well GH is being produced, the standard test is the:-
For those interested in GH, if you were to take Clonidine, smoke a cigarette and then have your GH measured, the Endocrinologist would have a surprise.

“These findings suggest that in man nicotinic cholinergic and adrenergic mechanisms might interact in the stimulation of GH secretion.”

Interestingly, one of the milder side effects of the ADHD drug Ritalin is growth retardation. According to Professor Tim Kendal, who created the national guidelines in the UK for treating ADHD: - “In children, without doubt, if you take Ritalin for a year, it's likely to reduce your growth by about three-quarters of an inch.

Clonidine looks like another old drug that has been stumbled upon by somebody doing some off label experimentation.  It does seem to have good results in ADHD and Autism.  The good thing is that it is FDA approved and is available in both oral and time release transdermal forms.
I do not think anybody really understands how it works in ADHD or other psychiatric disorders; undoubtedly, there is another, as yet unidentified, mode of action.
For those who want more info:- 

Note ulcerative colitis, ADD and even growth delay.




  1. Peter, did you try Clonidine for your son? Any feedback from other parents? Readers?

    1. I did not try it, but it does help some people with ASD. If you can obtain it, a trial to see if it is effective in your specific case is the way to go.

  2. I have a 5 year old son with ASD. We give him Clonidine to help manage his hyperactivity and agitation. When I say manage, I am NOT talking about just making him quiet down so Mom and Dad can watch a movie. I am talking about stopping property destruction, SIB, and aggression towards his little brother. We use it as needed. Basically, it just makes him really sleepy, so it's not really a solution. Think of it like a sedative.

    Also, the patch form falls off way before it's time to apply another one. It's not really designed for active kids that get sweaty.

    I hope this helps.

  3. Clonidine is the only pharmaceutical that has been helpful for my son's hyperactivity and insomnia. We began using the regular form (pill) about 5 years ago to help him sleep. We had tried EVERYTHING to no avail. His doctor suggested we try Clonidine and we were amazed. We started wondering if a 1/2 a pill during the day would slow him down since he is ALWAYS on the move and extremely distracted. We didn't get the effect we were looking for. We then tried the long acting form and it has helped slow him down considerably. My son is 11 years old with Autism. No side effects that I have noticed. Unfortunately it doesn't help his anxiety (nothing does), but he seems to be more comfortable in his skin since he isn't in constant motion.

  4. I also wanted to add that we use the long acting form of Clonidine during the day and then the regular form at night for sleep. My son's doc said this is fine. He is on the lowest dose.

  5. Hi Peter! My 14- year-old son, diagnosed with Asperger's and Tourette's, is coming off Risperdal. I started giving him Clonidine which seems to calm him a bit but he tics all the time!! It's soo sad to see him suffer so much. He is a total wreck! I HAVE TWO QUESTIONS: 1) How much clonidine should i give him? He weighs 82 kg and his blood pressure is normal. 2) Can he take clonotril as well (to relax his muscles) or the combination with clonidine could be dangerous? Of course, in case you have any suggestions to make this ''transition'' a bit easier, please share with me! Coming off risperdal seems to be so difficult....

    1. You need to ask your doctor specific questions about drugs and their interactions.

      Most standard drugs used in autism seem to frequently make things worse. Clonotril (Clonazepam) at the usual dose is addictive.

      Clonidine's benefit seems to be a mild sedative effect and there are better ways to achieve that, like centrally active H1 antihistamines,

      Baclofen appears to be the drug that helps most people with Asperger's, without negative effects or addiction. It looks like 5mg two or three times a day is a good place to start. This dose does not seem to help people with more severe autism.

  6. Hi Peter, I give a try to clonidine for sleeping problem (difficult to fall in sleep) and did nothing after 3 weeks try at 0.5mg (my daughter is 7). Few days ago our doctor increased to 0.1 mg. At this dose she get very nervous, bite herself, very frustrate at bedtime even though it works this time for sleep (she fall in sleep in less then an hour). Could be that because of lowering too much the blood tension, or the tension in the brain? What are your thoughts about this reaction? Did has a link with a particularly sub-type of autism? Thank you for your generosity.

    1. Prada, clonidine seems to reduce anxiety in 85% of people but increase it in 15%. So increased anxiety is a known side effect.

      Your daughter's reaction probably does tell you something, but I am not sure how useful this will be regarding her autism.

      If you have a helpful doctor, you might ask about very low dose Mirtazapine. This is an old antidepressant derived from the original first generation antihistamines. It is used off-label in autism and also schizophrenia. It has several different effects. At 5mg, which is a 1/6 typical dose, it is very sedating, via H1 histamine receptors in the brain. A good night's sleep is almost guaranteed. This might help establish a new sleep pattern and then you could gradually reduce it to zero.

  7. Hi Peter
    I ask our doctor about Mirtazapine and she is not willing to try it. For constipation she give her oral lactulose. Constipation dose improve at high dose as her autistic symptoms. I really think that lactulose has positive effect on her autism. Do you think would be possible?
    We try again NAC without any effect (the third time). We tried also carnitine supplement without any effect. Two weeks ago we gave a try to levocarnitine (carnitor), this time with an effect. We saw after a few days positive effect on constipation even without lactulose, but after a week something strange happens. My daughter develop psychosis, she withdraws from the environment even gets aggressive and yield to herself calling her name repeatedly. Could have this state for hours. As a remedy we give her a product that contain (GABA 25mg, L-Theanine 25 mg and Glycine 12.5mg). With this product her aggression and psychosis were gone in less then ten minute. Since we stooped carnitor she went to her normal state. I thought that carnitine is also an antioxidant but in fact I read a study that say that carnitine can increase malondialdehyde that is a marker for oxidative stress. Do you think that my daughter reaction to carnitor can have an link with a predisposition for seizures? Thank you I have leaned a lot from your blog.

  8. Really interesting about the Clonidine. In my son's case, I believe he has too many catecholamines with nowhere to go, as supported by labs we've done. His MAO-A status is T, which means perhaps not enough degrading activity. Do you know of any substances that would increase MAO-A? I guess Clonidine is worth trying in his case. I'm a MAO-A TT myself and have Clonidine prescribed for the emotional dysregulation of ADHD. I haven't noticed any effects but perhaps have not been taking it long enough, or high enough dose.


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