Guanfacine for ADHD

Guanfacine has been approved in the USA since 2009, including for adult ADHD.
In Germany, guanfacine was approved in sustained release form in 2015 and came onto the market in 2016 with the indication for ADHD in children and adolescents.¹
Guafacine is a selective postsynaptic α-2A adrenoreceptor agonist in frontal pyramidal neurons.²
Guanfacine is also an imidazoline receptor agonist.
Guanfacine inhibited ionic currents elicited by NaV1.7 channels encoded by SCN9A and other NaV channel subtypes to varying degrees.³
It is not subject to the Narcotics Ordinance.

Former designation: BS 100-141 (in the 1970s)
Trade name: Intuniv

ADHD efficacy likely due to increased α-2A-adrenergic signaling, postsynaptically in the PFC.⁴

Alpha-2 adrenoreceptors (also: alpha-2 adrenoceptors) are activated by the neurotransmitters adrenaline and noradrenaline. They are therefore responsible for the effects mediated by adrenaline and noradrenaline. Activation of the alpha1-adrenoceptor is often associated with excitation, while activation of the alpha2-adrenoceptor (the predominant type in the LC itself) is associated with inhibition.⁵
Agonists strengthen the effect of the receptors, antagonists weaken it.
Alpha-2 agonists (guanfacine and clonidine) influence the balance between phasic and tonic activity of locus coeruleus neurons by acting on postsynaptic alpha2A autoreceptors.⁶

Guanfacine has a noradrenergic effect.

Maximum blood plasma values after 5 hours.
Elimination half-life 18 hours, therefore suitable for single daily intake.
Increased absorption of active ingredients when taken with a high-fat meal; should therefore be taken on an empty stomach
Guanfacine should not be taken with grapefruit juice.⁸
The tablets must not be chewed or crushed.
Metabolism also via CYP3A4 and CYP3A5, therefore potential for interactions with drugs such as ketoconazole and rifampicin.⁸
Inhibitor of CYP3A4 and CYP3A5.

• 1. Effectiveness, application
  • 1.1. Effect of guanfacine on symptoms
  • 1.2. Effect size of guanfacine
  • 1.3. Mechanisms of action of guanfacine
  • 1.4. Responding from Guanfacin
• 2. Side effects
• 3. Degradation of guanfacine
• 4. Interactions of guanfacine
  • 4.1. CYP3A4 inducer
    • 4.1.1. CYP3A4 inducer and guanfacine
  • 4.2. CYP3A4 inhibitors
    • 4.2.1. CYP3A4 inhibitors and guanfacine
  • 4.3. Other interactions of guanfacine
• 5. Long-term effect: No habituation effects of guanfacine
• 6. Theoretical considerations on guanfacine: only for ADHD-HI, not for ADHD-I / SCT?
• 7. Report of the person concerned

1. Effectiveness, application¶

Several studies have confirmed the effectiveness of guanfacine for ADHD.^89101112
Guanfacine is effective in children and adolescents who do not respond optimally to stimulants.¹³¹⁴ Guanfacine is also approved for this purpose in Europe.¹⁵
According to one study, an alpha agonist (such as guanfacine) was primarily used in an academic medical treatment center (probably in the US) for children with ADHD, conduct disorder (DBD), or autism spectrum disorder between the ages of 2 and 5. In children without autism spectrum disorder, stimulants were primarily used.¹⁶
There is no clear evidence of efficacy with regard to adult persons with ADHD who do not respond optimally to stimulants. One study found improvements with guanfacine and placebo compared to previous medication.¹⁷

1.1. Effect of guanfacine on symptoms¶

It is argued that guanfacine has a more selective effect on the PFC and the inattention and organization problems it harbors, while stimulants have a broader effect and, in addition to the PFC, also influence the striatum, which is primarily responsible for hyperactivity and impulsivity.¹⁸

• Improved working memory⁴
• Attention improved⁴¹⁹
• Reduction of the ADHD-RS-IV total score by 8.9 with guanfacine, atomoxetine only by 3.8.²⁰
• Rejection sensitivity and/or dysphoria in ADHD: Guanfacine or, if this is not effective, clonidine, are said to be helpful.²¹
• Hyperactivity²²²³¹⁹
• Impulsiveness²²⁴¹⁹
• Comorbid disorders in children and adolescents with ADHD²⁴²⁵
  • Autism symptoms
  • Oppositional defiant behavior²³
  • Emotional and behavioral dysregulation due to traumatic stress experiences.²⁵
  • Possibly for tics
  • No effect on anxiety symptoms
  • Effects on depression are open
  • The side effects of guanfacine are similar in comorbid conditions and in pure ADHD
• Effect comparable in ADHD-I and ADHD-C.¹⁹
• Guanfacine has long been used as a treatment for high blood pressure. In ADHD, it has particular benefits in the treatment of comorbid tic disorders.²⁶
• While stimulants primarily increase the dopamine effect level and secondarily the noradrenaline level, guanfacine, as an alpha2 receptor agonist, improves signal transmission in the frontal lobe by making the signal clearer and more distinct.²⁶

1.2. Effect size of guanfacine¶

• The mean Effect size of guanfacine is said to be 0.76. Stimulants, on the other hand, are between 0.9 and 1.1 (in responders).¹ Other studies come to comparable results.²⁷
• Reduction of the ADHD-RS-IV total score by 8.9 with guanfacine, atomoxetine only by 3.8²⁰
• A combination medication of methylphenidate and guanfacine achieves a higher response rate than guanfacine or methylphenidate alone. In one study, guanfacine alone was found to be inferior to methylphenidate alone (81% of people with ADHD had a symptom reduction of at least 50%) in 68% of those affected. However, a combination medication of MPH and guanfacine was the most successful (91% of people with ADHD showed a symptom reduction of at least 50%).²⁸
• The effect on ADHD symptoms is slightly worse than that of stimulants if the latter respond well. The effect is better in children than in adolescents.²⁵

1.3. Mechanisms of action of guanfacine¶

• As an alpha-2-adrenoceptor agonist, guanfacine (like clonidine) significantly reduces the release of dopamine in the nucleus accumbens in the laboratory.²⁹
• Methylphenidate and amphetamine drugs increase the power of alpha (in rats), while atomoxetine and guanfacine do not.³⁰
• Guanfacine appears to have several modes of action:
  • Reduces direct noradrenergic transmission between locus coeruleus and orbitofrontal cortex (OFC) at rest²
  • Reduces the release of noradrenaline in the locus coeruleus, orbitofrontal cortex and reticular nucleus of the thalamus²
  • Improves direct catecholaminergic transmission from the locus coeruleus to the orbitofrontal cortex (OFC)²
  • Improved catecholamine release by inhibiting GABA in the intermediate pathway locus coeruleus - reticular nucleus of the thalamus - mediodorsal nucleus of the thalamus - orbitofrontal cortex (OFC)²
  • Reduced GABA release in the mediodorsal thalamic nucleus²
  • Increased AMPA-induced release of L-glutamate, noradrenaline and dopamine in the orbitofrontal cortex (OFC) through subchronic administration²
  • Guanfacine administration directly into the OFC did not alter the release of catecholamines in the OFC²
• Acute local administration in locus coeruleus in therapeutic dosage causes³¹
  • Reduced noradrenaline release in OFC, VTA and nucleus reticularis (of the thalamus)
  • Unchanged dopamine release in the OFC
• Chronic administration (14 days) in therapeutic dosage causes³¹
  • Downregulation of the α2A adrenoceptor in locus coeruleus, OFC and VTA, thereby
    • Increased basal noradrenaline release in OFC, VTA, nucleus reticularis (of the thalamus)
    • Increased dopamine release in the OFC
  • Unaltered GABAergic transmission within the thalamus
  • Phasewise increased glutamatergic transmission between thalamus and cortex.
• Alpha-2A receptor agonists such as guanfacine and clonidine are thought to improve phasic noradrenaline release in the nucleus coeruleus, which improves attention as well as working memory and visuomotor-associated learning (as opposed to long-term tonic NE release, which impairs performance).³²

1.4. Responding from Guanfacin¶

One study looked at characteristics that predicted good responding to guanfacine or MPH monotherapy and MPH/guanfacine combination medication:

• Higher hyperactivity-impulsivity and oppositional symptoms before treatment³³
  • Predictor for good results with MPH monotherapy, guanfacine monotherapy and MPH/guanfacine combination medication
• Less anxiety before the treatment³³
  • Predictor for good results with MPH monotherapy, guanfacine monotherapy and MPH/guanfacine combination medication
• High event-related mid-frontal beta power before treatment³³
  • EEG activity from cortical sources localized in the regions of the middle frontal bone and middle occipital bone
  • Stronger modulations during encoding and retrieval predictor for good results with MPH monotherapy and guanfacine monotherapy
• Weak event-related mid-frontal beta power before treatment³³
  • EEG activity from cortical sources localized in the regions of the middle frontal bone and middle occipital bone
  • Predictor for good results with MPH/guanfacine combination medication

In preschool-aged ADHD, low externalizing or internalizing symptom severities correlated with a high likelihood of responding to stimulants. At high externalizing or internalizing symptom levels, the response rate of stimulants approached that of alpha-2 agonists:³⁴

Responder	Symptom severity:	weak	medium	strong
Stimulants	Externalizing	96.4 %	74.3 %	66.6 %
Alpha-2 agonists	Externalizing	40 %	50 %	67 %
Stimulants	Internalizing	80.6 %	77.5 %	50 %
Alpha-2 agonists	Internalizing	57.7 %	70 %	57.7 %

2. Side effects¶

• Higher side effects than methylphenidate and atomoxetine⁴
• The side effects of guanfacine are similar in comorbid conditions and in pure ADHD²⁴
• Fewer side effects than clonidine (less antihypertensive and less sedative)³⁵
• Guanfacine should not be discontinued abruptly due to its antihypertensive effect.⁸

No liver damage or increased enzyme levels in the blood serum due to guanfacine are known.³⁶

Guanfacine is particularly worth considering in cases where stimulants have a strong blood pressure-increasing effect.

3. Degradation of guanfacine¶

Guanfacine is broken down via cytochrome P450 3A4, CYP3A4 for short.

This cytochrome is more active in women than in men,³⁷ so women may need a higher dose than men.
There are also interactions that increase (inducers) or inhibit (inhibitors) the enzyme activity of CYP3A4.

In vitro, the 3-OH guanfacine signaling pathway accounted for at least 2.6% of guanfacine metabolism in cryopreserved, plated human hepatocytes and 71% in pooled human liver microsomes.³⁸

4. Interactions of guanfacine¶

4.1. CYP3A4 inducer¶

• Phenobarbital (strong)³⁹⁴⁰
• Rifampin / Rifampicin (strong)³⁹⁴⁰
• Quinolones³⁹
• Anticonvulsants
  • Phenytoin (strong)³⁹⁴⁰
  • Carbamazepine (strong)³⁹⁴⁰
  • Oxcarbazepine (weak)³⁹⁴⁰
• Modafinil (weak)³⁹⁴⁰
• Armodafnil (weak)⁴⁰
• Topiramate (weak)⁴⁰
• Dexamethasone³⁹
  • Not: Prednisone³⁹
• St. John’s wort (weak)³⁹⁴⁰
• Ginger³⁹
• Garlic³⁹
• Licorice³⁹

4.1.1. CYP3A4 inducer and guanfacine¶

Strong CYP3A4 inducers reduce the blood level of guanfacine within 2 to 3 weeks after the start of administration, while weak and moderate CYP3A4 inducers can cause this.⁴⁰ Conversely, the guanfacine level rises again 2 to 3 weeks after discontinuation of CYP3A4 inducers.

While the package leaflet recommends doubling the dose of guanfacine with concomitant administration of CYP3A4 inducers, augmenting ingestion of phenobarbital required a 5-fold dose in one individual case.⁴⁰ Avoiding strong CYP3A4 inducers appears to be advisable when taking guanfacine at the same time.

4.2. CYP3A4 inhibitors¶

• Antibiotics.
  • Macrolides
    • Erythromycin (strong)⁴⁰³⁹
    • Clarithromycin (strong)⁴⁰³⁹
    • Telithromycin³⁹
  • Chloramphenicol³⁹
• Antifungals:
  • Fluconazole³⁹
  • Ketoconazole (strong)⁴⁰³⁹
  • Itraconazole³⁹
• Diltiazem (strong)⁴⁰
• Grapefruit juice (strong)⁴⁰³⁹
• Fluoxetine (weak to moderate)⁴⁰
• Fluvoxamine (weak to moderate)⁴⁰
• Protease inhibitors:
  • Ritonavir³⁹
  • Indinavir³⁹
  • Nelfinavir³⁹
• Verapamil³⁹
• Aprepitant³⁹
• Nefazodon³⁹
• Amiodarone³⁹
• Cimetidine³⁹
• Valerian³⁹
• Turmeric³⁹
• Ginseng³⁹

4.2.1. CYP3A4 inhibitors and guanfacine¶

Strong CYP3A4 inhibitors increase the blood level of guanfacine after the start of administration, weak and moderate CYP3A4 inhibitors may do so.⁴⁰

While the package leaflet recommends halving the dose of guanfacine with concomitant administration of CYP3A4 inhibitors, halving the dose does not appear to be sufficient when taking augmenting antipsychotics.⁴⁰ Avoiding CYP3A4 inhibitors appears to be advisable when taking guanfacine at the same time.

Grapefruit juice should always be avoided when taking psychiatric medication.⁴⁰

4.3. Other interactions of guanfacine¶

Valproate is said to show increased plasma levels when taken in parallel with guanfacine.⁴¹

Guanfacine and clonidine should be antagonized by tricyclic antidepressants and phenothiazines.⁴²

Simultaneous use of beta-blockers or sudden discontinuation of guanfacine can lead to a hypertensive reaction.⁴²

5. Long-term effect: No habituation effects of guanfacine¶

A meta-analysis of 87 randomized placebo-controlled double-blind studies found no evidence of a decrease in the effect of methylphenidate, amphetamine drugs, atomoxetine or α2 antagonists with prolonged use.⁴³

6. Theoretical considerations on guanfacine: only for ADHD-HI, not for ADHD-I / SCT?¶

A strong increase in noradrenaline / dopamine shuts down the PFC. This deactivation of the PFC occurs via alpha-1 adrenoceptors, which have a lower noradrenaline and cortisol affinity than alpha-2 adrenoceptors and are therefore only addressed at very high noradrenaline and cortisol levels. ^4445464748

A particularly strong increase in DA and NE during severe stress could therefore lead to a (frequent) underactivation of the PFC, as is typical in ADHD-I.
This could explain Raynaud’s and high blood pressure problems in some people with ADHD-I, which are also mediated by alpha-1 adrenoceptors.

The question is whether alpha-1-adrenoceptor antagonists, which are successfully used against Raynaud’s and high blood pressure, might not also be helpful against PFC blockades in ADHD-I.

The agonization of the more affine alpha-2 receptors has the opposite effect to the antagonization of the alpha-1 receptors. As with the cortisol receptors, the less affine receptor (there: glucocorticoid receptor, here: alpha-1 adrenoceptor) is responsible for switching off the system and is only addressed at very high levels of messenger substances. If the more affine receptors (there: mineralocorticoid receptor, here: alpha-2 receptor) are too pronounced, the less affine switch-off receptors are not reached. Alpha-2 agonists occupy the free capacities of the more affine receptors, leaving more messenger substance free, which can now address the alpha-1 adrenoceptors. In ADHD-I, guanfacine and yohimbine should therefore enhance PFC deactivation.

Guanfacine is an alpha-2-A and alpha-2-D adrenoceptor agonist, yohimbine is an alpha-2-B adrenoceptor agonist.

This connection opens up the question of whether - at least theoretically - guanfacine and yohimbine should be avoided in ADHD-I and could have a particularly useful purpose in ADHD-HI to shut down an overloaded PFC

7. Report of the person concerned¶

A person with ADHD reports on Guanfacine:

“I take 1 mg of guanfacine about 5 to 6 hours before going to bed.
If I take it in the morning, I get a bit tired and don’t feel like it helps that much. If I take it so that the theoretical peak is at bedtime, I sleep much better.
My sleep is somehow deeper and more restful and my brain feels somehow… more alive? better supplied with blood? The first time I took it, after 5-6 hours I felt a funny crackling sensation in my neck/under my ears, then a kind of wet-feeling pressure wave came through my head, which made me dizzy for a short time, but went away immediately when I moved my head. Since then I can feel more clearly when my neck is tense. Relaxation exercises now also reduce the pressure at the top, front and sides of my head, not just in my neck.

It also helps me against an extremely strong stress response that sometimes paralyzes my brain.
When I started university, I kept having blackouts during exams. It feels like a kind of “stress squeeze” in my stomach, which is squeezed out and causes a “stress wave” in my abdomen, which then crawls up and tries to tense my chest, causing my brain to “switch off” above my eyes and “on top”. I can then no longer think clearly. This is extremely attenuated with guanfacine.“

This is the most vivid description of the deactivation of the PFC by alpha-1 adrenoceptors that we have found so far.

Caution: individual reports of drug effects must not be generalized!
Medication must always be discussed with the doctor!