Clonidine for ADHD

Clonidine is an alpha-2 agonist.
The brand names for clonidine are:

• Catapresan (A, D, CH)
• Haemiton (Germany)
• Isoglaucon (A, D)
• Paracefan (Germany)
• Kapvay (U.S.; extended-release clonidine hydrochloride)
• Onyda XR (U.S.; extended-release clonidine hydrochloride)

Clonidine is available in both immediate release and sustained release forms.
Sustained-release clonidine is approved by the FDA for the treatment of ADHD in children 6 years of age and older.¹ To ensure full-day coverage, it must be taken twice daily.
Immediate-release clonidine is used off-label in people with ADHD who have difficulty swallowing tablets. Immediate-release clonidine must be taken 3 to 4 times a day.

Clonidine is a rather atypical medication for ADHD.

Effect sizes related to ADHD:

• 0.71 for children and adolescents², which seems too high to us and appears to be due to an insufficient number of studies included in the analysis³
• 0.03 (meta-analysis)⁴

Clonidine is frequently used to treat autism spectrum disorders and may be helpful in treating comorbid ASD and ADHD in young children.⁵
There are 12 evidence-based guidelines on the use of clonidine for:⁶

• High blood pressure: 1
• Substance abuse: 4
• Menopause: 4
• Restless legs: 2
• Tourette’s: 1
• ADHD: none
• Migraine prevention: none

1. Mechanisms of Action of Clonidine¶

Clonidine acts in the PFC⁷ as:

• σ-2A adrenoreceptor agonist⁸⁷
• σ-2B-adrenoreceptor agonist⁸⁷
• σ-2C adrenoreceptor agonist⁸⁷
• Imidazoline receptor agonist
• σ-1-adrenoceptor agonist administered too quickly or in too high a dose (by injection)⁹

Clonidine reduces the effect of epinephrine.

Alpha-2-adrenoceptors are activated endogenously by the neurotransmitters epinephrine and norepinephrine. They are therefore responsible for the effects mediated by epinephrine and norepinephrine.¹⁰
Alpha-2-A receptor agonists such as clonidine and guanfacine are thought to enhance phasic norepinephrine release in the locus coeruleus, which improves attention, working memory, and visuomotor-associated learning (in contrast to long-term, tonic norepinephrine release, which impairs performance).¹¹

Clonidine therefore has a noradrenergic effect.

As an alpha-2-adrenoceptor agonist, clonidine (like guanfacine) significantly reduces dopamine release in the nucleus accumbens in laboratory studies.¹²

Clonidine and guanfacine are said to be helpful in treating rejection sensitivity in ADHD.¹³

A 2019 study from India reports that clonidine was the most commonly used medication for ADHD there among a group of children aged 3 to 6 with ADHD:¹⁴

• Clonidine: 44.6%
• Risperidone: 28.7%
• Methylphenidate: 10.7%
• Atomoxetine: 10.7%

Clonidine was more effective than methylphenidate combined with haloperidol in children with ADHD and comorbid tic disorders.¹⁵

For children and adolescents, the optimal dosage is 0.9 mg per day.¹⁶

It may take several months for ADHD symptoms to respond to clonidine.¹⁷

2. Side Effects¶

Clonidine has more side effects than methylphenidate and atomoxetine.⁸

Side effects of clonidine are dose-dependent, particularly¹

• Sedation
  • may decrease after the dose is administered¹⁸
• Daytime sleepiness
  • may decrease after the dose is administered¹⁸
  • In a comparative study, 48% of those treated with clonidine reported fatigue, compared with 14% of those treated with methylphenidate and 6% of those receiving a placebo. ¹⁷
• Drop in blood pressure
  • especially in cases of kidney dysfunction
  • may decrease after dosing¹⁸
• Decrease in heart rate
  • especially in cases of kidney dysfunction
• Vascular damage and thrombosis, particularly in older adults with endothelial damage (damage to the inner layer of blood vessels)¹⁹
• REM sleep disturbance
  • Clonidine suppresses REM sleep in a dose-dependent manner:²⁰
    • Moderate to high doses (0.15–0.30 mg) significantly suppress REM sleep
      • In men with hypertension, clonidine 0.15 mg reduced²¹
        • the total REM sleep duration (95 vs. 54 minutes)
        • the percentage of REM sleep (23% vs. 14%)
      • REM suppression²²²³
        • begins about 2 hours after taking it
        • can last 9–10 hours
        • followed by a REM rebound 18–30 hours after administration
        • REM suppression can be used therapeutically to treat nightmares, particularly in cases of PTSD²⁴
          • In female patients with PTSD, clonidine 0.1 mg twice daily resulted in polysomnographically confirmed REM suppression and significantly reduced the frequency of nightmares
  • Very low doses (25 µg) can, paradoxically, increase REM sleep²⁰
    • This suggests that low doses act primarily presynaptically on alpha-2 receptors of locus coeruleus neurons, while higher doses mediate postsynaptic effects
  • Guanfacine did not interfere with REM sleep and also had fewer side effects than clonidine.²³

Both the initiation and discontinuation of treatment should be done slowly and gradually.¹ To prevent rebound hypertension, it is recommended that clonidine be tapered at a rate of 0.1 mg per day every 3 to 7 days until it is discontinued.¹⁸

The sedative effect can also be used to one’s advantage by administering higher doses before bedtime.¹