Guanfacine for ADHD

Guanfacine has been approved in the U.S. since 2009, where it is also approved for adult ADHD.
In Germany, guanfacine in a sustained release formulation was approved in 2015 and was launched in 2016 for the treatment of ADHD in children and adolescents.¹

Guanfacine is a

• a selective postsynaptic α-2A adrenoreceptor agonist in frontal pyramidal neurons.²

• Alpha-2-D-adrenoceptor agonist

• Imidazoline receptor agonist

  • Imidazoline receptors are involved in, among other things, blood pressure regulation and insulin secretion.

• TAAR1 agonist.³

  • TAAR1 is a trace amine receptor. More on the interaction between the dopamine system and the trace amine system in the article “ ” (Trace Amines) In the section “Neurotransmitters in ADHD” in the chapter “ ” (Neurological Aspects).

• Guanfacine inhibited ion currents generated to varying degrees by NaV1.7 channels encoded by SCN9A and other NaV channel subtypes.⁴

• Guanfacine inhibits MATE1 in vitro⁵

  • MATE1 (Multidrug and Toxin Extrusion Transporter 1) is an important transport protein found primarily in the kidney And the liver.⁶

    The main function of MATE1 is to transport certain medications, waste products, and toxins from the cells into the urine or bile so that they can be excreted. Inhibition of MATE1 causes a sharp increase in their levels in the blood, which can lead to side effects or toxicity.⁷ Of particular relevance:

    • Metformin (diabetes medication)
    • Creatinine (a waste product produced by the muscles)
    • Platinum-based anticancer drugs, such as oxaliplatin. Risk of kidney damage (nephrotoxicity).
    • Heart medications (e.g., dofetilide or procainamide), where taking too high a dose can be life-threatening.

• Substrate of OCT1 and OCT2⁵

Guanfacine is not subject to the Narcotics Control Act.

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

The efficacy of ADHD treatment is likely due to increased α-2A-adrenergic signaling, postsynaptically in the PFC.⁸
Alpha-2 adrenoceptors (also known as alpha-2 adrenoceptors) are activated by the neurotransmitters epinephrine and norepinephrine. They are therefore responsible for the effects mediated by epinephrine and norepinephrine. Activation of the alpha-1 adrenoceptor is often associated with excitation, while activation of the alpha-2 adrenoceptor (the predominant type in the LC itself) is associated with inhibition.⁹
Agonists enhance the effect of receptors, while 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.¹⁰
Guanfacine ultimately exerts a noradrenergic effect.

Maximum blood plasma levels are reached after 5 hours. The elimination half-life is 18 hours, making it suitable for once-daily dosing.
Absorption of the active ingredient is increased when taken with a high-fat meal; therefore, it should be taken on an empty stomach
Guanfacine is metabolized by CYP3A4 and should therefore not be taken with grapefruit juice.¹¹ Metabolized via CYP3A4 as well as CYP3A5, hence the potential for interactions with medications such as ketoconazole and rifampin.¹¹ Guanfacine is also an inhibitor of CYP3A4 and CYP3A5.
The tablets must not be chewed or crushed.

1. Efficacy, Use¶

Numerous studies have confirmed the effectiveness of guanfacine in treating ADHD.^1112131415
Guanfacine is effective for children and adolescents who do not respond optimally to stimulants.¹⁶¹⁷ Guanfacine is also approved for this use in Europe.¹⁸
According to a study, an alpha-agonist (such as guanfacine) was primarily used at an academic medical treatment center (presumably in the U.S.) for children between the ages of 2 and 5 with ADHD, conduct disorder (CD), or autism spectrum disorder. For children without autism spectrum disorder, stimulants were primarily used.¹⁹
With regard to adults with ADHD who do not respond optimally to stimulants, there is no clear evidence of efficacy. One study found improvements with guanfacine and with a placebo compared to previous medication.²⁰

1.1. Effect of Guanfacine on Symptoms¶

It is argued that guanfacine acts more selectively on the prefrontal cortex (PFC) and the inattention and organizational problems associated with it, whereas stimulants have a broader effect and influence not only the PFC but also the striatum, which is primarily responsible for hyperactivity and impulsivity.²¹

• Improved working memory⁸
• Improved attention⁸²²
• Guanfacine reduced the total ADHD-RS-IV score by 8.9, while atomoxetine reduced it by only 3.8.⁸
• Rejection sensitivity and/or dysphoria in ADHD: Guanfacine—or, if that is not effective, clonidine—is said to be helpful.²³
• Hyperactivity²⁴²⁵²²
  • Guanfacine reduced hyperactivity in DAT-KO rats³
• Impulsivity²⁴⁸²²
• comorbid disorders in children and adolescents with ADHD²⁶²⁷
  • Symptoms of autism
  • oppositional defiant behavior²⁵
  • emotional and behavioral dysregulation resulting from traumatic stress experiences.²⁷
  • possibly due to tics
  • no effect on anxiety symptoms
  • The impact on depression is unclear
  • The side effects of guanfacine are similar in patients with comorbid conditions and in those with ADHD alone
• Equally effective for ADHD-I and ADHD-C.²²
• Guanfacine has long been used to treat high blood pressure. In cases of ADHD, it is particularly beneficial in treating comorbid tic disorders.²⁸
• While stimulants primarily increase dopamine levels and, to a lesser extent, norepinephrine levels, guanfacine—as an alpha-2 receptor agonist—improves signal transmission in the frontal lobe by making the signal clearer and more distinct.²⁸

Guanfacine was also effective in treating PTSD symptoms.²⁹

1.2. Effect size of Guanfacine¶

• The mean effect size for guanfacine is reported to be 0.76. In contrast, stimulants range from 0.9 to 1.1 (among responders).¹ Other studies have reached similar conclusions.³⁰
• Reduction in the total ADHD-RS-IV score by 8.9 with guanfacine, and by only 3.8 with atomoxetine⁸
• A combination therapy 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, with a symptom reduction of at least 50% in 68% of people with ADHD (compared to 81% of people with ADHD who experienced a symptom reduction of at least 50% with methylphenidate alone). However, the most successful treatment was a combination of MPH and guanfacine (91% of people with ADHD showed a reduction in symptoms of at least 50%).³¹
• Its effect on ADHD symptoms is somewhat less effective than that of stimulants, provided the child responds well to stimulants. It is more effective in children than in adolescents.²⁷

1.3. Mechanisms of Action of Guanfacine¶

• As an alpha-2-adrenoceptor agonist, guanfacine (like clonidine) significantly reduces dopamine release in the nucleus accumbens in laboratory studies.³²
• Methylphenidate and amphetamine-based medications increase alpha activity (in rats), while atomoxetine and guanfacine do not.³³
• Guanfacine appears to have several mechanisms of action:
  • reduces direct noradrenergic transmission between the locus coeruleus and the orbitofrontal cortex (OFC) at rest²
  • reduces the release of norepinephrine in the locus coeruleus, the orbitofrontal cortex, and the reticular thalamic nucleus²
  • enhances direct catecholaminergic transmission from the locus coeruleus to the orbitofrontal cortex (OFC)²
  • enhanced catecholamine release by inhibiting GABA in the intermediate pathway: locus coeruleus – reticular thalamic nucleus – mediodorsal thalamic nucleus – orbitofrontal cortex (OFC)²
  • reduced GABA release in the mediodorsal thalamic nucleus²
  • Increased AMPA-induced release of L-glutamate, norepinephrine, and dopamine in the orbitofrontal cortex (OFC) following subchronic administration²
  • Direct administration of guanfacine into the OFC did not alter catecholamine release in the OFC²
• Acute local administration into the locus coeruleus at a therapeutic dose results in³⁴
  • reduced norepinephrine release in the OFC, VTA, and reticular nucleus (of the thalamus)
  • unchanged dopamine release in the OFC
• Chronic administration (14 days) at a therapeutic dose results in³⁴
  • Downregulation of the α2A adrenoceptor in the locus coeruleus, OFC, and VTA, thereby
    • increased basal norepinephrine release in the OFC, VTA, and reticular nucleus (of the thalamus)
    • increased dopamine release in the OFC
  • Unaltered GABAergic transmission within the thalamus
  • intermittent increases in glutamatergic transmission between the thalamus and the cortex.
• Alpha-2A receptor agonists such as guanfacine and clonidine 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).³⁵

1.4. Reactions to Guanfacine¶

A study examined factors that predicted a good response to guanfacine or MPH monotherapy and to a combination of MPH and guanfacine:

• Higher levels of hyperactivity, impulsivity, and oppositional symptoms prior to treatment³⁶
  • Predictor of good outcomes with MPH monotherapy, guanfacine monotherapy, and MPH/guanfacine combination therapy
• reduced anxiety before treatment³⁶
  • Predictor of good outcomes with MPH monotherapy, guanfacine monotherapy, and MPH/guanfacine combination therapy
• high event-related beta power in the middle frontal cortex prior to treatment³⁶
  • EEG activity from cortical sources localized in the middle frontal and middle occipital regions
  • Greater fluctuations during encoding and retrieval: a predictor of good outcomes with MPH monotherapy and guanfacine monotherapy
• low event-related beta power in the middle frontal cortex prior to treatment³⁶
  • EEG activity from cortical sources localized in the middle frontal and middle occipital regions
  • Predictor of good outcomes with MPH/guanfacine combination therapy

In preschool-aged children with ADHD, low levels of externalizing or internalizing symptoms correlated with a high probability of responding to stimulants. When externalizing or internalizing symptom severity was high, the response rate to stimulants approached that of alpha-2 agonists:³⁷

Responder	Symptom severity:	mild	moderate	severe
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¶

• More side effects than methylphenidate and atomoxetine⁸
• The side effects of guanfacine are similar in patients with comorbid conditions and in those with ADHD alone²⁶
• Fewer side effects than clonidine (less blood pressure-lowering and less sedating)³⁸
• Because of its blood pressure-lowering effect, guanfacine should
  • be closely monitored during dosing (for bradycardia and hypotension)³⁹
  • should not be stopped abruptly.¹¹
• A study found that when guanfacine was administered as a single 1-mg dose and the dose was increased in 1-mg increments, the optimal dose was:⁴⁰
  • Heart rate decreased by 12.3 bpm
  • P-wave axis reduced by 12.3 degrees
  • QT interval prolonged by 16.8 ms
  • Blood pressure unchanged
  • QTc duration unchanged
  • Other ECG parameters remain unchanged
  • 2 out of 37 patients withdrew from the study due to bradycardia or hypotension

A case study of a 6-year-old boy reports the following symptoms of overdose after taking 2 mg of immediate-release guanfacine instead of 2 mg of sustained-release guanfacine:⁴¹

• Lethargy
• Bradycardia
• Hypotension

There are no known cases of liver damage or elevated enzyme levels in blood serum caused by guanfacine.⁴²

Guanfacine had no effect on ocular structures such as the retina, choroid, optic nerve, refraction, or corneal thickness, but it did increase corneal aberrations.⁴³

Guanfacine is worth considering, especially in cases where stimulants cause a significant increase in blood pressure.

3. Metabolism of Guanfacine¶

Guanfacine is metabolized by cytochrome P450 3A4, or CYP3A4 for short.

This cytochrome is more active in women than in men,⁴⁴ so women may need a higher dose than men.
In addition, there are drug interactions that either increase (inducers) or decrease (inhibitors) the enzymatic 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.⁴⁵

4. Drug Interactions with Guanfacine¶

4.1. CYP3A4 inducers¶

• Phenobarbital (strong)⁴⁶⁴⁷
• Rifampin / Rifampicin (strong)⁴⁶⁴⁷
• Quinolones⁴⁶
• Anticonvulsants
  • Phenytoin (strong)⁴⁶⁴⁷
  • Carbamazepine (strong)⁴⁶⁴⁷
  • Oxcarbazepine (mild)⁴⁶⁴⁷
• Modafinil (mild)⁴⁶⁴⁷
• Armodafinil (mild)⁴⁷
• Topiramate (mild)⁴⁷
• Dexamethasone⁴⁶
  • not: prednisone⁴⁶
• St. John’s wort (mild)⁴⁶⁴⁷
• Ginger⁴⁶
• Garlic⁴⁶
• Licorice⁴⁶

4.1.1. CYP3A4 Inducers and Guanfacine¶

Strong CYP3A4 inducers reduce blood levels of guanfacine within 2 to 3 weeks after starting treatment; weak and moderate CYP3A4 inducers may also cause this effect.⁴⁷ Conversely, guanfacine levels rise again 2 to 3 weeks after discontinuing CYP3A4 inducers.

While the package insert recommends doubling the guanfacine dose when taken concomitantly with CYP3A4 inducers, in one individual case, the addition of phenobarbital required a 5-fold increase in the dose.⁴⁷ It appears advisable to avoid strong CYP3A4 inducers when taking guanfacine concomitantly.

4.2. CYP3A4 inhibitors¶

• Antibiotics.
  • Macrolides
    • Erythromycin (strong)⁴⁷⁴⁶
    • Clarithromycin (strong)⁴⁷⁴⁶
    • Telithromycin⁴⁶
  • Chloramphenicol⁴⁶
• Antifungal medications:
  • Fluconazole⁴⁶
  • Ketoconazole (strong)⁴⁷⁴⁶
  • Itraconazole⁴⁶
• Diltiazem (strong)⁴⁷
• Grapefruit juice (strong)⁴⁷⁴⁶
• Fluoxetine (mild to moderate)⁴⁷
• Fluvoxamine (mild to moderate)⁴⁷
• Protease inhibitors:
  • Ritonavir⁴⁶
  • Indinavir⁴⁶
  • Nelfinavir⁴⁶
• Verapamil⁴⁶
• Aprepitant⁴⁶
• Nefazodone⁴⁶
• Amiodarone⁴⁶
• Cimetidine⁴⁶
• Valerian⁴⁶
• Goldenseal⁴⁶
• Ginseng⁴⁶

4.2.1. CYP3A4 inhibitors and guanfacine¶

Strong CYP3A4 inhibitors increase blood levels of guanfacine after treatment initiation; weak and moderate CYP3A4 inhibitors may also cause this effect.⁴⁷

While the package insert recommends halving the guanfacine dose when taken concomitantly with CYP3A4 inhibitors, halving the dose does not appear to be sufficient when taken in combination with antipsychotics.⁴⁷ It appears advisable to avoid CYP3A4 inhibitors when taking guanfacine concomitantly.

Grapefruit juice should always be avoided when taking psychiatric medications.⁴⁷

4.3. Other Drug Interactions with Guanfacine¶

Valproate is reported to result in elevated plasma levels when taken concurrently with guanfacine.⁴⁸

Guanfacine and clonidine are believed to be antagonized by tricyclic antidepressants and phenothiazines.⁴⁹

Concomitant use of beta-blockers or sudden discontinuation of guanfacine may lead to a hypertensive reaction.⁴⁹

5. Long-term effects: No tolerance to guanfacine¶

A meta-analysis of 87 RCTs found no evidence of a decline in the efficacy of methylphenidate, amphetamine-based medications, atomoxetine, or α2-antagonists with long-term use.⁵⁰

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

A sharp increase in norepinephrine and dopamine shuts down the PFC. This deactivation of the PFC occurs via alpha-1 adrenoceptors, which have a lower affinity for norepinephrine and cortisol than alpha-2 adrenoceptors and are therefore activated only at very high levels of norepinephrine and cortisol. ^5152535455

A particularly sharp increase in DA and NE during periods of severe stress could therefore lead to (frequent) underactivation of the PFC, as is typical in ADHD-I.
Against this backdrop, Raynaud’s phenomenon and high blood pressure issues in some people with ADHD-I—which are also mediated by alpha-1 adrenoceptors—could be explained.

The question is whether alpha-1-adrenoceptor antagonists—which are successfully used to treat Raynaud’s phenomenon and high blood pressure—might also be helpful in treating PFC blockages associated with ADHD-I.

The activation of the more specific alpha-2 receptors has an effect opposite to that of the antagonism of the alpha-1 receptors. As with cortisol receptors, the less-affine receptor (there: glucocorticoid receptor; here: alpha-1 adrenoceptor) is responsible for shutting down the system and is activated only when messenger substance levels are very high. If the higher-affinity receptors (there: mineralocorticoid receptor; here: alpha-2 receptor) are too strongly expressed, the lower-affinity shutdown receptors are not activated. Alpha-2 agonists occupy the unbound sites of the more affinity-rich receptors, leaving more neurotransmitter available to act on the alpha-1 adrenoceptors. In ADHD-I, guanfacine and yohimbine should therefore enhance PFC inhibition.

Guanfacine is a highly selective alpha-2-A-adrenoceptor agonist; yohimbine is an alpha-2-B-adrenoceptor agonist.

In our view, this connection raises the question of whether—at least in theory—guanfacine and yohimbine should be avoided in ADHD-I and might be particularly useful in ADHD-HI to help calm an overloaded prefrontal cortex

7. Personal Account¶

A person with ADHD shares her experience with guanfacine:

“I take 1 mg of guanfacine about 5 to 6 hours before bedtime.
When I take it in the morning, I get a little sleepy and don’t feel like it helps that much. When I time it so that the theoretical peak occurs at bedtime, I sleep much better.
My sleep is somehow deeper and more restful, and my brain feels kind of… more alive? Better supplied with blood? The first time I took it, after 5–6 hours I felt a strange tingling in the back of my neck and under my ears, then a sort of wet-feeling pressure wave went through my head, which made me feel briefly dizzy but went away immediately when I moved my head. Since then, I’ve been more aware of 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 cope with an extremely intense stress response that sometimes shuts down my brain.
When I first started college, I kept having blackouts during exams. It feels like a kind of “stress squeeze” in my stomach that gets squeezed out, causing a “wave of stress” in my abdomen, which then creeps upward and tries to tense up my chest, and it feels like it “shuts down” the brain above my eyes and “on top” of my head. I can’t think clearly anymore. This has been greatly reduced with guanfacine.”

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

Caution: Individual reports on the effects of medications should not be generalized.
Always consult your doctor about medication!