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Guanfacine for ADHD

Guanfacine for ADHD

Completely revised 09/2026

 

Guanfacine is approved in Germany as a sustained-release tablet (Intuniv) for the treatment of ADHD in children and adolescents aged 6 to 17 for whom stimulants are not an option, are not tolerated, or are not sufficiently effective. Guanfacine is not approved for use in adults in Germany. As a non-stimulant, it is not subject to narcotics laws.

The effectiveness of guanfacine in treating ADHD has been confirmed in several studies. For children and adolescents who do not respond optimally to stimulants, guanfacine is a viable alternative. There is also evidence of improvement with guanfacine in adults with ADHD who do not respond optimally to stimulants.

Its effectiveness is well documented by numerous studies, but it is weaker than that of stimulants and roughly as strong as that of atomoxetine. The full effect usually does not become apparent until after a few weeks. Guanfacine can also be given in combination with a stimulant. There is evidence that the combination of guanfacine and methylphenidate yields the best results. Improvements have also been observed in cases of comorbid oppositional behavior, while the results regarding tics are inconsistent. The evidence from studies in adults is mixed.

Guanfacine acts primarily in the prefrontal cortex, the region of the brain that controls attention, working memory, and impulse control. There, it mimics the effect of the neurotransmitter norepinephrine at specific receptors (alpha-2A adrenoceptors). As a result, guanfacine improves working memory and attention in people with reduced norepinephrine levels in the PFC. It also has positive effects on hyperactivity and impulsivity, as well as on comorbid disorders such as autism symptoms, oppositional defiant disorder, and emotional dysregulation. Guanfacine influences signal transmission in the frontal lobe by reducing norepinephrine release and enhancing catecholaminergic transmission.

It is important to consider adjusting the dosage of guanfacine in women and to take into account interactions with CYP3A4 inducers and inhibitors. The side effects of guanfacine are similar to those of other ADHD medications, but less severe than those of clonidine.

There are no signs of tolerance with long-term use of guanfacine.

Theoretical considerations suggest that guanfacine may be more effective for the predominantly inattentive subtype (ADHD-I) than for the predominantly hyperactive-impulsive subtype (ADHD-HI). A patient report describes positive effects of guanfacine on sleep, stress, and concentration. However, individual experiences with ADHD medications cannot be generalized. The use of guanfacine must always be discussed with a doctor.

The most common side effects are drowsiness and fatigue—especially during the first few weeks—as well as headaches and upper abdominal pain. Guanfacine lowers blood pressure and heart rate. Blood pressure and heart rate should therefore be monitored during the titration phase. Guanfacine must not be stopped abruptly; instead, it must be tapered off gradually, as otherwise blood pressure and heart rate may rise.

Guanfacine is taken once daily, with or without food, but not with a high-fat meal or grapefruit juice. The tablets must not be chewed, crushed, or split. Guanfacine is metabolized in the liver by the enzyme CYP3A4. Active ingredients that inhibit this enzyme (e.g., certain antibiotics and antifungal medications) or induce it (e.g., certain antiepileptic drugs and St. John’s wort) can significantly alter guanfacine levels. Such combinations should be avoided or carefully coordinated with a doctor.

1. Approval, Active Ingredient, Dosage

Implications for People with ADHD

Guanfacine (Intuniv) is approved in Germany for children and adolescents aged 6 to 17 when stimulants are not appropriate, are not tolerated, or are not sufficiently effective. It acts via alpha-2A adrenoceptors in the prefrontal cortex. The tablet is taken once daily, not with high-fat meals or grapefruit juice. It must not be chewed, crushed, or split.

(E 4): In Germany, sustained-release guanfacine was approved in 2015 and introduced in January 2016 for children and adolescents aged 6 to 17 for whom stimulants are not an option, are not tolerated, or have proven ineffective. (Review article, E 4)1(Fachinformation, E 4)2

Guanfacine extended-release has been approved in the U.S. since 2009 for children and adolescents aged 6 to 17 (Approval Letter, E 4)3 and, since 2011, also as an adjunct to long-acting stimulants. (Approval Letter, E 4)4
(E 4): There is no U.S. approval for adults. (Approval letter, E 4)3(Zulassungsschreiben, E 4)4 (Different and likely incorrect: kompendium-news, Heiser, Benkert 2016)

Guanfacine is a

  • Selective postsynaptic α-2A adrenoreceptor agonist in frontal pyramidal neurons. (Animal study, rats, N = 126, E 2b)5

    • Stimulation of postsynaptic α2A-adrenoceptors, which are located on the dendritic spines of prefrontal pyramidal cells alongside HCN channels: (animal study, monkeys and rats, E 2b)6
      • inhibited cAMP production in monkeys and rats,
      • closed HCN channels and
      • enhanced the networking activity of working memory.
    • Low-dose, topically applied guanfacine increased the delay-related firing rate of prefrontal neurons, while high-dose guanfacine suppressed it, possibly via presynaptic α2A-adrenoceptors. (Animal study, monkeys and rats, E 2b)6

  • Alpha-2-D-adrenoreceptor agonist (animal study, monkeys and rats, E 2b)6

    • The alpha-2-D adrenoceptor is a variant of the human α2A adrenoceptor found in rodents

  • Imidazoline receptor agonist (animal study, monkeys and rats, E 2b)6

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

  • TAAR1 agonist (in vitro on human TAAR1, EC50 = 20 nM). (In vitro and animal study, n = 6 DAT-KO rats, E 2b)7

  • In vitro (Xenopus oocytes, 86 µM), guanfacine inhibited ion currents from NaV1.7 channels (encoded by SCN9A) by 22% and from other NaV channel subtypes by 6% to 31%. The authors assumed a saturating concentration. The clinical relevance is unclear. (In vitro study and case series, E 2b)8

  • Guanfacine inhibits MATE1 in vitro. Clinical relevance cannot be ruled out. Plasma levels of MATE1 substrates taken concomitantly may increase. (Prescribing Information, E 4)2

    • MATE1 (Multidrug and Toxin Extrusion Transporter 1) is a transport protein that is primarily expressed in the kidney And the liver and excretes cationic drugs such as metformin into urine and bile. (Structural biology study, E 2b)9

      Inhibition of MATE1 may reduce the renal excretion of its substrates and cause interactions. (In vitro study, E 2b)10 Particularly relevant:

      • Metformin (diabetes medication)
      • Creatinine (a waste product produced by the muscles)
      • Platinum-based cancer 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 OCT2 (in vitro). At maximum portal vein concentrations, guanfacine may inhibit OCT1. This may increase the maximum levels of OCT1 substrates with a Tmax similar to that of metformin. (Prescribing Information, E 4)2

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. (Drug Evaluation, E 4)11
Alpha-2-adrenoceptors (also known as alpha-2-adrenoreceptors) are activated by the neurotransmitters 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 locus coeruleus itself) is associated with inhibition. (Narrative review, E 4)12
Agonists activate receptors; antagonists block them.
Alpha-2 agonists (guanfacine and clonidine) influence the balance between phasic and tonic activity of locus coeruleus neurons by stimulating postsynaptic α2A adrenoceptors (autoreceptors). (Narrative review, E 4)13
Guanfacine mimics the effects of norepinephrine at α2A-adrenoceptors. In rats, it acutely reduced norepinephrine release in the locus coeruleus, orbitofrontal cortex, and reticular thalamic nucleus. Animal study, rats, N = 126, E 2b)5

Maximum plasma concentrations are reached after about 5 hours. The elimination half-life is about 18 hours, making it suitable for once-daily dosing. (Drug Evaluation, E 4)14Increased absorption of the active ingredient when taken with a high-fat meal (Cmax increased by approximately 75%, AUC increased by approximately 40%). Therefore, take with or without food, but not with high-fat meals. (Prescribing Information, E 4)2
Guanfacine is metabolized by CYP3A4 and should therefore not be taken with grapefruit juice. (Drug Evaluation, E 4)14 (E 4): Metabolized via CYP3A4 and CYP3A5, thus posing a potential for drug interactions with medications such as ketoconazole and rifampicin. (Drug Evaluation, E 4)14(Narrativer Review, E 4)15 Ketoconazole increased the Cmax and AUC of guanfacine by 2-fold and 3-fold, respectively, while rifampicin decreased them by 54% and 70%, respectively. (Prescribing Information, E 4)2 According to the prescribing information, guanfacine may increase plasma levels of concomitantly administered CYP3A4/5 substrates; however, it did not inhibit CYP3A4 or CYP3A5 in human liver microsomes. (Prescribing Information, E 4)2
The tablets must not be chewed, crushed, or split, as this accelerates the release of the active ingredient. (Prescribing Information, E 4)2

2. Efficacy, Use

Implications for People with ADHD

The efficacy of guanfacine in children and adolescents has been demonstrated in numerous controlled studies. In these studies, approximately 6 out of 10 patients responded to treatment, compared with about 3 to 4 out of 10 in the placebo group. Guanfacine can also be given in addition to a stimulant if the stimulant alone is not sufficient. Results in adults are inconsistent. In Germany, guanfacine is not approved for use in adults.

Guanfacine Extended-Release for Children and Adolescents with ADHD

The efficacy of extended-release guanfacine in children and adolescents with ADHD has been demonstrated by numerous RCTs. (E 1a): A meta-analysis (k = 12, n = 2,653) found that the response rate (CGI-I “very much” or “much better”) in 58.5% of patients on guanfacine compared with 29.4% on placebo for treatment durations of less than 10 weeks, and in 63.6% compared with 39.7% for longer treatment durations (overall RR 1.78). (Drug Evaluation, E 4)14(Metastudie, k = 12 RCT, N = 2.653, E 1a)16(Narrativer Review, E 4)17(Metastudie, k = 12 RCT, N = 2.653, E 1a)18
In children and adolescents who responded inadequately to a long-acting stimulant, the addition of extended-release guanfacine in a 9-week RCT (placebo-adjusted reduction in the ADHD-RS-IV score of 4.5 points with morning dosing and 5.3 points with evening dosing). (Narrative review, E 4)19 As of 2012, there was a lack of positive evidence of efficacy for guanfacine monotherapy in adolescents. (Review, k = 15, E 4)20 In Europe, guanfacine is approved for children and adolescents for whom stimulants are not an option, are not tolerated, or have proven ineffective. (Narrative review, E 4)15

An RCT involving adolescents aged 13 to 17 (n = 314) found that guanfacine monotherapy was superior to placebo (ADHD-RS-IV −24.55 vs. −18.53 points, effect size 0.52). 46.5% received an optimal dose that exceeded the maximum dose of 4 mg approved at the time. (RCT, N = 314, n = 157, E 1b, manufacturer-funded)21

According to clinicians, guanfacine was more effective than placebo in children and adolescents (SMD −0.67), but not according to parents (SMD −0.23, n.s.). Amphetamine medications were more effective than guanfacine. Discontinuations due to adverse effects were more common than with placebo (OR 2.64). No data on guanfacine were available for adults. (Network meta-analysis, k = 133 RCTs, N = 24,642, E 1a)22

Guanfacine resulted in a response more frequently than placebo (OR 3.29, 10 RCTs, n = 1,461), but less frequently than methylphenidate (OR 0.62). Loss of appetite occurred less frequently than with methylphenidate (OR 0.26). (Network meta-analysis, k = 190 RCTs, N = 26,114, E 1a)23

A response was observed in 59.0% of patients on guanfacine and 33.3% on placebo (OR 3.2). At least one adverse effect occurred in 82.4% versus 67.9% of patients, primarily somnolence (OR 4.9), sedation (OR 2.8), and fatigue (OR 2.2). (Meta-analysis, k = 7 RCTs, N = 1,752, n = 1,177, E 1a)24

Guanfacine extended-release reduced the ADHD-RS-IV score by 8.68 points after adjusting for placebo (lisdexamfetamine 14.98, methylphenidate extended-release 9.33, atomoxetine 6.88). Discontinuations due to adverse effects were more common than with placebo (RR 4.49). (Network meta-analysis, k = 36 RCTs, including 6 with guanfacine extended-release, evidence grade 1a, manufacturer-funded)25

In the U.S. clinical trials, guanfacine extended-release reduced the ADHD-RS-IV score by 16.18, 16.43, and 18.87 points, respectively, while placebo reduced it by 8.48 points (effect sizes 0.64, 0.66, and 0.86; weight-adjusted effect sizes 0.58 at 0.05 to 0.08 mg/kg, 1.19 at 0.09 to 0.12 mg/kg, and 1.34 at 0.13 to 0.17 mg/kg) (RCT, N = 345, n = 259, E 1b, manufacturer-funded)26, at 1 to 4 mg with effect sizes ranging from 0.43 to 0.62, and on a weight-adjusted basis from 0.41 (0.01 to 0.04 mg/kg) to 0.89 (0.13 to 0.16 mg/kg) (RCT, 9 weeks, N = 324, E 1b, manufacturer-funded)27. Morning and evening dosing had similar effects (ADHD-RS-IV −19.8 and −20.1, respectively; placebo −11.0; effect size 0.75 and 0.78, respectively). Somnolence occurred in 44.3% (placebo 12.5%); 7.2% discontinued due to side effects (placebo 0%). (RCT, N = 333, n = 221, E 1b, manufacturer-funded)28

Guanfacine extended-release was similarly effective in children and adolescents who had previously been treated with methylphenidate (placebo-adjusted ADHD-RS-IV −9.8, effect size 0.85) as in those who had not previously received stimulants (−7.6, effect size 0.65). Atomoxetine was effective only in stimulant-naive patients (effect size 0.43; 0.15 after methylphenidate, n.s.). The main reasons for discontinuing methylphenidate were lack of efficacy and side effects. (Post-hoc analysis of an RCT and an open-label study phase, n = 142 and n = 224 with prior methylphenidate treatment, E 2b, manufacturer-funded)29

When used as an adjunct to a stimulant, extended-release guanfacine improved ADHD symptoms, CGI-S, and CGI-I in patients with an inadequate response to stimulants, when taken in the morning and evening. (RCT, N = 461, 9 weeks, E 1b, manufacturer-funded)30

At an academic treatment center in the United States (retrospective chart review, n = 966 children aged 2 to 5 years with ADHD, conduct disorder (DBD), or autism spectrum disorder), alpha-agonists (such as guanfacine) were most commonly prescribed for 2- to 4-year-olds, while methylphenidate was most commonly prescribed for 5-year-olds. Children without autism spectrum disorder were prescribed stimulants more frequently than children with autism spectrum disorder (72.1% versus 37.0%). (Retrospective chart review, N = 966, E 3)31

Guanfacine Extended-Release in Adults with ADHD

According to the European prescribing information, safety and efficacy in adults have not been established; guanfacine should not be used in adults. (Prescribing Information, E 4)2 A British guideline advises against the use of guanfacine in adults without the advice of a specialized ADHD center (as of 2019).32

In adults with ADHD who did not respond optimally to stimulants, the addition of extended-release guanfacine did not improve symptoms any more than placebo in an RCT (n = 26). Both groups showed significant improvement. (RCT, N = 26, E 1b)33 A Canadian rapid review found only this one RCT on extended-release guanfacine in adults for the search period from 2013 to August 2018, in which extended-release guanfacine did not differ in efficacy from placebo. (Systematic Rapid Review, k = 1 RCT, N = 26, E 1b)34
This is not evidence against its effectiveness, but rather evidence that this question has not been researched. (ADxS assessment).

In a recent RCT conducted in 2020 involving Japanese adults (n = 201, 10 weeks), extended-release guanfacine (4 to 6 mg/day) improved ADHD symptoms more than placebo (ADHD-RS-IV −11.55 vs. −7.27 points, Effect size 0.52). Discontinuations due to side effects were more common than with placebo (19.8% vs. 3.0%). (RCT, N = 201, n = 101, E 1b, manufacturer-funded)35

In adults, a meta-analysis of non-stimulants for guanfacine found an effect size of g = −0.66 (2 RCTs). (Meta-analysis, k = 18 RCTs, N = 4,308, E 1a)36 A component network meta-analysis found evidence of efficacy only for stimulants and atomoxetine. Guanfacine had lower acceptance (treatment discontinuations OR 3.70) and tolerability (discontinuations due to side effects OR 7.98) than placebo. (Component network meta-analysis, k = 113 RCTs, N = 14,887, E 1a)37 Another network meta-analysis found no significant difference in clinician-assessed response compared with placebo in adults in studies lasting 12 weeks or longer (2 RCTs with guanfacine). (Network meta-analysis, k = 81 RCTs, E 1a)38

Immediate-release guanfacine (mean dose 1.1 mg) and dexamfetamine reduced ADHD symptoms in adults more effectively than placebo. In the Stroop Color-Word Test, only guanfacine showed improvement. The most common side effect was fatigue. All but one participant reported increased motivation while taking dexamfetamine; none reported this while taking guanfacine. No participant withdrew from the study. (Double-blind crossover study, n = 17, E 1b)39

In a Japanese study of adults, the effect sizes were similar for ADHD-C (0.51) and ADHD-I (0.52), as well as for women (0.57) and men (0.50). Women (average body weight 58 kg; men, approximately 70 kg) experienced relevant side effects about three times as often (34.3% versus 10.6%), decreases in blood pressure (37.1% vs. 12.1%), and discontinuations due to side effects (34.3% vs. 12.1%). Among participants weighing less than 50 kg, side effects occurred in all participants during dose optimization (73.6% for those weighing 50 kg or more). (Post-hoc subgroup analysis of an RCT, N = 200, n = 100, Phase 2b, manufacturer-funded)40 A possible cause of the high incidence of side effects in patients with lower body weight could be the mandatory up-dosing to at least 4 mg/day.

2.1. Effect of Guanfacine on ADHD Symptoms

Implications for People with ADHD

Guanfacine reduces inattention, hyperactivity, and impulsivity in both the predominantly inattentive subtype and the combined subtype. Concomitant oppositional behavior and autism symptoms also improved in studies. The results regarding tics are inconsistent, and no effect on anxiety was found. An improvement in working memory has been demonstrated primarily in animal studies.

According to one hypothesis, guanfacine acts more selectively on the PFC and thus more specifically on attention and working memory deficits, whereas stimulants have a broader effect and, in addition to the PFC, also influence the striatum via D2 receptors, affecting alertness and motor impulsivity as well. (Theoretical review, E 4)41

  • Improved working memory (animal studies, including primates) (Drug Evaluation, E 4)11
  • (E 1b): Improved attention (Drug Evaluation, E 4)11(Gepoolte Post-hoc-Analyse von 2 RCT, N = 631, n = 490, E 1b)42
  • Guanfacine reduced the total ADHD-RS-IV score by 8.9, while atomoxetine reduced it by only 3.8. (Drug Evaluation, E 4)11
  • According to an expert opinion not supported by study evidence, rejection sensitivity and dysphoria are expected to improve with guanfacine or, if that is ineffective, with clonidine. (Expert opinion, E 4)43
  • (E 1b): Hyperactivity (including in the NF1 mouse model) (animal study, mice, E 2b)44(Narrativer Review, E 4)45(Gepoolte Post-hoc-Analyse von 2 RCT, N = 631, n = 490, E 1b)42
    • Guanfacine reduced hyperactivity in female DAT-KO rats (n = 6) (in vitro and animal study, n = 6 DAT-KO rats, E 2b)7
  • (E 1b): Impulsivity (animal study, mice, E 2b)44(Arzneimittelbewertung, E 4)11(Gepoolte Post-hoc-Analyse von 2 RCT, N = 631, n = 490, E 1b)42
  • (E 1a): Comorbid Disorders in Children and Adolescents with ADHD (Systematic Review, E 1a)46(Narrativer Review, E 4)47
    • Symptoms of autism
    • oppositional defiant behavior (narrative review, E 4)45
    • possible emotional and behavioral dysregulation resulting from traumatic stress experiences (narrative review, E 4)47
    • possibly tics
    • no effect on anxiety symptoms
    • The effect on depression is unclear
    • The side effects of guanfacine are similar in patients with comorbid conditions and in those with ADHD alone
  • Effective for ADHD-I and ADHD-C (pooled post hoc analysis of two RCTs, n = 631). For ADHD-I, the difference from placebo was significant starting in week 3; for ADHD-C, it was significant starting in week 1. No direct comparison of efficacy between the subtypes was conducted. (Pooled post-hoc analysis of 2 RCTs, N = 631, n = 490, E 1b)42
  • Guanfacine has long been used to treat high blood pressure. In ADHD, it is said to be particularly beneficial in the treatment of comorbid tic disorders. (Expert opinion, E 4)48
  • While stimulants primarily increase dopamine levels and secondarily increase norepinephrine levels, guanfacine, as an alpha-2 receptor agonist, improves signal transmission in the frontal lobe by making the signal clearer and more distinct. (Expert opinion, E 4)48

In an RCT involving children with ADHD (combined type) and tic disorder, immediate release guanfacine (n = 34, 8 weeks) by 31% (placebo 0%) and improved ADHD symptoms as assessed by teachers by 37% (placebo 8%). (RCT, N = 34, n = 17, E 1b)[NEU6] In a pilot RCT involving children and adolescents with chronic tic disorders (n = 34, 8 weeks), guanfacine extended-release did not reduce tic severity any more than placebo (19% responders versus 22%). (RCT, N = 34, n = 16, E 1b)49

In an open-label study without a control group involving children and adolescents with symptoms of traumatic stress (n = 17 evaluated, 68.4% of participants with PTSD), guanfacine extended-release improved flashbacks, avoidance, and hyperarousal, as well as ADHD symptoms. (Open-label study without a control group, n = 17, E 2b)50

Guanfacine extended-release reduced functional impairment as assessed by parental reports (WFIRS-P, effect size 0.448)—when taken in the morning or evening—in the areas of family, school, social functioning, and risk behavior, but not in daily living skills or self-image. (Secondary analysis of an RCT, N = 333, n = 221, E 1b, manufacturer-funded)51

Guanfacine extended-release (1 to 3 mg) did not slow reaction time or increase daytime sleepiness (ADHD-RS-IV, placebo-adjusted −6.3). (RCT, non-inferiority trial, N = 182, n = 121, E 1b, manufacturer-funded)52 A single dose of guanfacine extended-release worsened reaction time variability compared with placebo (Cohen’s d = 1.3), while lisdexamfetamine improved it. (Randomized, double-blind crossover study, n = 22, E 1b)53

Immediate release guanfacine (1 to 3 mg) improved working memory less than the combination with dexmethylphenidate. There were no differences in other cognitive domains. (RCT, N = 182, E 1b)54 In the same study, guanfacine impaired accuracy on a spatial working memory task, dexmethylphenidate left it unchanged, and the combination improved it. (RCT, n = 172, E 1b)55 When added to stimulants, extended-release guanfacine improved executive functions as assessed by parental ratings (BRIEF-P). (Double-blind crossover study, N = 50, E 1b, manufacturer-funded)56

In children with ADHD and oppositional symptoms, extended-release guanfacine reduced oppositional symptoms (effect size 0.59) and ADHD symptoms (effect size 0.92). Sedation, somnolence, or hypersomnia occurred in 62.5% of participants and usually subsided before the end of the study. (RCT, N = 217, n = 138, E 1b, manufacturer-funded)57 When used as an adjunct to stimulants, extended-release guanfacine reduced oppositional symptoms by 2.4 (in the morning) and 2.2 points (in the evening). (Secondary analysis of an RCT, E 1b, manufacturer-funded)58 In cases of comorbid disorder with oppositional defiant behavior, the effect sizes ranged from 0.688 to 0.962; without this comorbidity, they ranged from 0.598 to 0.842. (Pooled post hoc analysis of 4 RCTs, N = 1,084, E 1b, manufacturer-funded)59

In children with autism spectrum disorder and hyperactivity, extended-release guanfacine reduced hyperactivity (ABC) by 43.6%, while placebo reduced it by 13.2% (effect size 1.67). 50% responded to treatment (placebo 9.4%). (RCT, N = 62, n = 30, E 1b)60 Oppositional behavior decreased by 44% (placebo 12%); anxiety and sleep patterns remained unchanged. (Secondary analysis of the same RCT, N = 62, n = 30, E 1b)61

2.2. Effect size of Guanfacine

Implications for People with ADHD

Guanfacine is less potent than stimulants and about as potent as atomoxetine. It is therefore generally considered a second-line medication. In one study, the combination with a stimulant was more effective than either drug alone.

  • In the European registration trial, the effect size for sustained-release guanfacine was 0.76. According to this source, the effect size for sustained-release stimulants is approximately 0.5 higher. (Review article, E 4)1 In placebo-controlled registration trials, the effect size for monotherapy ranged from 0.43 to 0.86, which is lower than that of stimulants and similar to that of atomoxetine (0.59 to 0.67). (Narrative review, E 4)15 According to a review, extended-release guanfacine is effective, but to a lesser extent than stimulants. (Narrative review, E 4)62
  • In the European registration study (children and adolescents aged 6 to 17 years), guanfacine extended-release reduced the ADHD-RS-IV total score by 8.9 points after adjustment for placebo (effect size 0.76), and the reference arm, atomoxetine, by 3.8 points (effect size 0.32). (E 1b, manufacturer-funded): The study was not designed to compare the two active ingredients. (RCT, N = 338, E 1b, manufacturer-funded)63 (Regulatory assessment report, E 4)64
  • Reduction in the total ADHD-RS-IV score (placebo-adjusted) by 8.9 with guanfacine and by 3.8 with atomoxetine. (E 4): The study was not designed to directly compare the two active ingredients. (Drug Evaluation, E 4)11(Narrativer Review, E 4)15- A combination therapy of dexmethylphenidate and guanfacine achieves a higher response rate than guanfacine or methylphenidate alone. In an 8-week RCT involving children aged 7 to 14 years (n = 207 treated), 69% of those on guanfacine (1 to 3 mg/day), 81% of those on extended-release dexmethylphenidate (5 to 20 mg/day), and 91% of those on the combination responded (CGI-I “much better” or “somewhat better”). When the ADHD-RS-IV was also taken into account, the response rates were 63% (guanfacine), 62% (dexmethylphenidate), and 75% (combination). (RCT, N = 207, E 1b)65 More on this at Combination Therapy for ADHD.- The effect size of extended-release guanfacine is smaller than that of stimulants, which is why it is generally considered a second-line medication. The evidence of efficacy is more robust in children than in adolescents. (Narrative review, E 4)47
  • The efficacy of guanfacine increased in children and adolescents up to 4 mg/day (SMD −0.66), with no evidence of additional benefit from higher doses (wide uncertainty intervals). The risk of discontinuation due to adverse effects rose to 9.8% at doses up to 4 mg/day. (Dose-effect network meta-analysis, k = 113 RCTs, N = 25,154, E 1a)66
  • The effect was not primarily due to sedation. Even participants without sedative side effects showed significant improvement after adjusting for placebo. Sedative side effects peaked during the first week at the target dose and then decreased. (Pooled post-hoc analysis of 4 RCTs, E 1b, manufacturer-funded)67

2.3. Mechanisms of Action of Guanfacine

Implications for People with ADHD

Guanfacine is thought to act via alpha-2A adrenoceptors in the prefrontal cortex. When treatment begins, it reduces the release of norepinephrine. Animal studies suggest that this effect is reversed after about 2 weeks due to receptor adaptation. The details are derived primarily from animal studies.

  • The alpha-2-adrenoceptor agonist clonidine significantly reduced potassium-induced dopamine release in slices of the nucleus accumbens of rats. Guanfacine was not studied. (Animal study, rats, E 2b)68
  • Effects of the EEG
    • Guanfacine and atomoxetine did not increase the power of the alpha band in the EEG in rats, whereas methylphenidate and amphetamine-based medications did. (Animal study, rats, n = 5 per group, E 2b)69
    • Immediate release guanfacine reduced global alpha power in the resting EEG, which was associated with slower and more variable reaction times. Dexmethylphenidate and the combination increased centroparietal beta power. (RCT, n = 179, E 1b)70
  • Guanfacine appears to have multiple mechanisms of action (rats, N = 126, acute local and subchronic systemic administration of 0.12 mg/kg/day for 7 days): - reduced direct noradrenergic transmission between the locus coeruleus and the orbitofrontal cortex (OFC) at rest (animal study, rats, N = 126, E 2b)5
    • reduced norepinephrine release in the locus coeruleus, orbitofrontal cortex, and reticular thalamic nucleus (animal study, rats, N = 126, E 2b)5
    • enhanced direct catecholaminergic transmission from the locus coeruleus to the orbitofrontal cortex (OFC) (animal study, rats, N = 126, E 2b)5
    • enhanced catecholamine release by inhibiting GABA in the intermediate pathway from the locus coeruleus through the reticular and mediodorsal thalamic nuclei to the orbitofrontal cortex (OFC) (animal study, rats, N = 126, E 2b)5
    • reduced GABA release in the mediodorsal thalamic nucleus (animal study, rats, N = 126, E 2b)5
    • Increased AMPA-induced release of L-glutamate, norepinephrine, and dopamine in the orbitofrontal cortex (OFC) following subchronic administration (animal study, rats, N = 126, E 2b)5
    • Administration of guanfacine directly into the OFC did not alter catecholamine release in the OFC (animal study, rats, N = 126, E 2b)5
    • Clinical improvement with guanfacine was associated, as measured by fMRI during a go/no-go task, with reduced activation in the right middle cingulate cortex/supplementary motor area and in the left posterior cingulate cortex. (Randomized, placebo-controlled pilot study, N = 25, n = 12, mean dose 2.8 mg/day, E 1b, manufacturer-funded)71
  • Acute local administration into the locus coeruleus at a therapeutically relevant concentration resulted in the following in rats (animal study, rats, N = 48, E 2b)72
    • reduced norepinephrine release in the OFC, VTA, and reticular nucleus (of the thalamus)
    • unchanged dopamine release in the OFC
  • Chronic systemic administration (0.12 mg/kg/day for 14 days) resulted in the following in rats (animal study, rats, N = 48, E 2b)72
    • 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). (Textbook, E 4)73

Guanfacine is a selective α2A-adrenoceptor agonist. The high affinity of α2A-adrenoceptors for norepinephrine (NE) explains why even low doses of guanfacine act on this receptor. (Narrative review, E 4)74 LC neurons inhibit one another via noradrenergic collaterals. Stimulation of α2 autoreceptors on LC neurons preferentially reduces their tonic baseline activity, while glutamatergic phasic responses are preserved (secondary citation from Aston-Jones & Cohen 2005, Original: Aston-Jones et al. 1991). It is assumed that the memory-enhancing doses of guanfacine and clonidine used in elderly monkeys preferentially activate postsynaptic α2-adrenoceptors on the target neurons of the LC, thereby potentiating the effect of norepinephrine. (Narrative review, E 4)12 Guanfacine thus has two opposing mechanisms of action. Presynaptically and somatodendritically in the locus coeruleus (LC), it reduces NE release. Postsynaptically in the prefrontal cortex (PFC), it mimics the effect of NE at α2A-adrenoceptors without increasing the NE concentration. In monkeys and rats, stimulation of postsynaptic α2A-adrenoceptors on the dendritic spines of prefrontal pyramidal cells inhibited cAMP formation and closed HCN channels. This enhanced the network activity of working memory. In contrast, high-dose, locally applied guanfacine suppressed the firing rate, possibly via presynaptic α2A-adrenoceptors. (Animal study, monkeys and rats, E 2b)75

Acute administration: NE release decreases

In rats, guanfacine administered via microdialysis reduced extracellular NE release in the LC, the orbitofrontal cortex (OFC), and the reticular thalamic nucleus (RTN). This was true for both acute local administration into the LC and subchronic systemic administration (0.12 mg/kg/day for 7 days). Guanfacine administered locally into the OFC did not alter NE release. At the same time, subchronic administration enhanced AMPA-induced release of glutamate, NE, and dopamine (DA) in the OFC. (Animal study, rats, N = 126, E 2b)5 Acute perfusion of guanfacine (200 nM) into the LC reduced extracellular NE in the OFC, the ventral tegmental area (VTA), and the RTN. DA release in the OFC remained unchanged. (Animal study, rats, N = 48, E 2b)72 In rats, intravenous guanfacine completely suppressed the firing rate of noradrenergic LC neurons. It was ten times less potent than clonidine. Guanfacine (1 and 10 mg/kg), by inhibiting catecholamine synthesis, slowed the breakdown of NE in the whole brain and thereby reduced NE turnover. The α2-receptor blocker EEDQ attenuated this effect. A low dose of EEDQ reversed the effect of clonidine on NE turnover without altering the inhibition of LC firing rate. The authors concluded that α2 agonists reduce NE turnover primarily via presynaptic α2 receptors in the terminal regions and to a lesser extent via inhibition of the LC firing rate. Regional measurements were not performed. (Animal study, rats, E 2b)76 In mice with vitamin B6 deficiency, basal extracellular NA in the PFC and striatum was unchanged, but potassium-induced NA release was increased. NA turnover (MHPG/NA) in the tissue was increased in the PFC, nucleus accumbens, and hippocampus. Guanfacine (1.0 mg/kg/day s.c. for 7 days) normalized NA turnover and the social and cognitive deficits. Inhibition of NA release by guanfacine was not measured directly but was inferred from the normalized turnover. (Animal study, mice, E 2b)77

Chronic administration: basal NE increases

After 14 days of systemic administration, basal extracellular NE levels increased in the OFC, VTA, and RTN in rats, as did basal DA levels in the OFC. The authors attributed this to downregulation of α2A-adrenoceptors in the LC, OFC, and VTA. (Animal study, rats, N = 48, E 2b)72 The direction of the effect thus depends on the duration of treatment. NE release decreases acutely and subchronically. After two weeks, basal NE in the cortex rises again above the baseline value. (ADxS assessment)

The Periphery in Humans

In 30 patients with essential hypertension, long-term treatment with guanfacine reduced plasma levels of NE, epinephrine, and DA. Urinary excretion of NE, epinephrine, and the NE metabolite MHPG also decreased. (Open-label study without a control group, n = 30, E 2b)78 The measured values reflect peripheral sympathetic tone and do not allow conclusions to be drawn about central NE concentrations in individual brain regions. (ADxS assessment)

Extracellular or synaptic?

All of the brain findings listed above are derived from microdialysis or turnover measurements. Microdialysis measures the extracellular concentration—that is, NE—that has diffused out of the synaptic cleft (volume transmission). The concentration in the synaptic cleft itself was not directly measured in any of the studies found. Conclusions regarding synaptic NE under guanfacine are therefore based on extracellular values and receptor localization. (ADxS assessment) Since the cognitive effect is mediated via postsynaptic α2A-adrenoceptors in the PFC, an increase in synaptic NE is not necessary for the effect. (ADxS assessment)

2.4. Reactions to Guanfacine

Implications for People with ADHD

In one study, higher levels of hyperactivity, impulsivity, and oppositional symptoms, as well as lower levels of anxiety prior to the start of treatment, predicted a good response to guanfacine, methylphenidate, and a combination of the two. In preschool-aged children with mild symptoms, stimulants were significantly more effective than alpha-2 agonists, while in those with severe symptoms, the two were similarly effective.

A study (n = 181 children aged 7 to 14) examined the characteristics that predicted a good response to monotherapy with guanfacine or d-methylphenidate and to combination therapy with both:

  • Higher levels of hyperactivity-impulsivity and oppositional symptoms prior to treatment (secondary analysis of an RCT, N = 181, E 1b)79
    • Predictor of good outcomes with d-MPH monotherapy, guanfacine monotherapy, and d-MPH/guanfacine combination therapy
  • reduced anxiety prior to treatment (secondary analysis of an RCT, N = 181, E 1b)79
    • Predictor of good outcomes with d-MPH monotherapy, guanfacine monotherapy, and d-MPH/guanfacine combination therapy
  • Strong event-related beta modulation in the middle frontal cortex prior to treatment (secondary analysis of an RCT, N = 181, E 1b)79
    • EEG activity from cortical sources in the midfrontal and midoccipital regions of the brain—stronger modulation during encoding predicted good outcomes with d-MPH monotherapy, while stronger modulation during retrieval predicted good outcomes with guanfacine monotherapy
  • Weak event-related beta modulation in the middle frontal cortex prior to treatment (secondary analysis of an RCT, N = 181, E 1b)79
    • EEG activity from cortical sources in the midfrontal and midoccipital regions of the brain - A predictor of good outcomes with d-MPH/guanfacine combination therapy

EEG characteristics and clinical characteristics together explained approximately twice as much variance in treatment success with guanfacine monotherapy and combination therapy (R² = 0.34 to 0.41) than clinical characteristics alone (R² = 0.14 to 0.21). (Secondary analysis of an RCT, N = 181, E 1b)79

Among children with profound developmental disorders and hyperactivity, carriers of a C allele of the MDR1-C3435T polymorphism (ABCB1, P-glycoprotein) showed approximately three times greater improvement (−50.7%) on guanfacine than T/T carriers (−15.6%). (Open-label study, n = 22 genotyped, E 2b)80

In preschool-aged children with ADHD (a retrospective chart review at 7 centers, n = 195 with data on symptom severity), low levels of externalizing or internalizing symptoms correlated with a high probability of response to stimulants. For high levels of externalizing or internalizing symptoms, the response rate to stimulants approached that of alpha-2 agonists. For alpha-2 agonists, response rates did not differ significantly across symptom severity levels. The response rates were calculated from the reported non-response rates (symptom severity based on T-score: mild < 60, moderate 60 to < 70, severe ≥ 70). (Retrospective chart review, N = 309, n = 195, E 3)81

Responder Symptom severity: mild moderate severe
Stimulants Externalizing 96.4% 74.3% 66.7%
Alpha-2 agonists Externalizing 40% 50% 66.7%
Stimulants Internalizing 80.6% 77.5% 50%
Alpha-2 agonists Internalizing 57.7% 70% 57.7%

 

Among preschool-aged children with ADHD, 66% showed improvement after starting treatment with an alpha-2 agonist (guanfacine or clonidine), and 78% showed improvement after starting treatment with a stimulant. Daytime sleepiness was more common with alpha-2 agonists (38% vs. 3%), while irritability (29% vs. 50%) and decreased appetite (7% vs. 38%) were less common. (Retrospective chart review, N = 497, n = 175, E 3)82

3. Side Effects

Implications for People with ADHD

The most common side effects are drowsiness, headaches, fatigue, and upper abdominal pain. Drowsiness occurs mainly during the first few weeks and usually subsides. Guanfacine lowers blood pressure and heart rate; fainting spells are rare. Blood pressure and heart rate should be monitored during dose titration. When discontinuing the medication, the dose should be reduced gradually (by no more than 1 mg every 3 to 7 days). There are no known cases of liver damage. An accidental overdose can cause severe fatigue, a slow pulse, and low blood pressure and requires medical treatment.

  • The most common side effects in children and adolescents were drowsiness (40.6%), headache (27.4%), fatigue (18.1%), upper abdominal pain (12.0%), and sedation (10.2%). More serious common side effects included hypotension (3.2%), weight gain (2.9%), bradycardia (1.5%), and syncope (0.7%). (Prescribing Information, E 4)2
  • In a meta-analysis, approximately 80% of patients taking guanfacine experienced at least one adverse effect (placebo: 66.5%); the most common were somnolence (38.6%), headache (20.5%), and fatigue (15.2%). No serious side effects occurred. (Meta-analysis, k = 12 RCTs, N = 2,653, E 1a)18
  • A higher rate of side effects than atomoxetine in the only direct comparative study conducted to date. The AkdÄ noted a high potential for side effects. (Drug Evaluation, E 4)11
  • The side effects of guanfacine are similar in patients with comorbid conditions and in those with ADHD alone (Systematic Review, E 1a)46
  • Dry mouth, sedation, and orthostatic hypotension occurred less frequently with immediate release guanfacine for the treatment of hypertension than with other centrally acting antihypertensive agents. Withdrawal symptoms were less common than after abrupt discontinuation of clonidine. (Narrative review, E 4)83
  • Because of its blood pressure-lowering effect, guanfacine should
    • should be closely monitored during dose titration (for bradycardia and hypotension) (Expert Presentation, E 4)84
    • Should not be discontinued abruptly, but rather tapered off by no more than 1 mg every 3 to 7 days. Abrupt discontinuation may cause an increase in blood pressure and heart rate. (E 4): Hypertensive encephalopathy has been reported very rarely. (Drug Evaluation, E 4)14(Fachinformation, E 4)2

A retrospective study (n = 37, ages 6 to 16) found that, with weekly up-dosing starting at 1 mg, two weeks after reaching the optimal dose: (Retrospective study, N = 37, E 3)85

  • Heart rate decreased by 12.3 beats per minute
  • P-wave axis reduced by 12.3 degrees
  • QT interval prolonged by 16.8 ms
  • Blood pressure unchanged
  • QTc duration and PR interval unchanged
  • Other ECG parameters remain unchanged

Two out of 37 patients discontinued treatment (one due to a 40-ms prolongation of the QTc interval and a 25-beats-per-minute decrease in heart rate, and one due to dizziness, visual disturbances, and hypotension)

 

Headaches occurred more frequently with guanfacine than with placebo (OR 1.43). (Meta-analysis, k = 58 RCTs, E 1a)86

Compared with placebo, guanfacine reduced systolic blood pressure by 2.83 mmHg, diastolic blood pressure by 2.08 mmHg, and heart rate by 4.06 beats/min in children and adolescents; in adults, it reduced systolic blood pressure by 10.1 mmHg, 7.73 mmHg, and the pulse by 6.83 beats/min (certainty of evidence: low to very low). Long-term data were lacking. (Network meta-analysis, k = 102 RCTs, N = 22,702, E 1a)87 Immediate release guanfacine reduced heart rate and blood pressure during up-dosing. During a one-year maintenance phase, the heart rate returned to baseline. There were no discontinuations due to cardiovascular side effects. (RCT with open-label extension, N = 207, E 1b)88

In healthy adults, the upper confidence limit of the QTcF change exceeded the 10-ms threshold (10.34 ms) only after administration of a supratherapeutic dose of immediate release guanfacine (8 mg). (Double-blind crossover study, n = 83, Phase 1b, manufacturer-funded)89 In a 21-year-old woman with ADHD taking 3 mg of extended-release guanfacine and sertraline, presyncope, bradycardia, hypotension, and a QTcF prolongation to 648 ms, which correlated with the serum level. (Case report, E 4)90

In healthy young adults, abrupt discontinuation of 4 mg of extended-release guanfacine did not result in a clinically significant increase in blood pressure. A few participants experienced systolic increases of more than 10 mmHg following abrupt discontinuation, but these did not exceed baseline levels. Adverse events, particularly headaches, were more common after abrupt discontinuation (93.3%) than after gradual tapering (53.3%). (RCT, Phase I, N = 45, n = 15 per group, E 1b, manufacturer-funded)91

In a polysomnography study, guanfacine extended-release reduced total sleep time (−57 minutes; placebo +31 minutes), primarily due to longer periods of wakefulness after falling asleep. Sedation occurred in 73% of participants (placebo 6%). The study was terminated early following an interim analysis due to the reduced sleep duration. The study included children with ADHD and sleep problems. (RCT, N = 29, n = 11 evaluated, E 1b, manufacturer-funded)92 Discontinuations due to somnolence occurred predominantly during the first 70 days of treatment (44.0% versus 8.3% thereafter). (Retrospective study, N = 96, E 3)93

A 6-year-old boy who had been mistakenly prescribed 2 mg of immediate release guanfacine instead of the usual 2 mg of sustained release guanfacine experienced the following: (Case Report, E 4)94

  • Lethargy
  • Bradycardia
  • Hypotension
  • Treatment with vasopressors was required in the pediatric intensive care unit; the patient’s condition improved within 34 hours

Among 10,927 cases of guanfacine exposure in children and adolescents reported to U.S. poison control centers from 2000 to 2016, the most common symptoms—usually appearing within 8 to 24 hours—were: (Registry study, N = 10,927, E 3)95

  • Dizziness (39%)
  • Bradycardia (15.5%)
  • Hypotension (10.3%)

In an earlier analysis (1993 to 1999), 62.8% remained symptom-free, while 0.9% experienced severe disease progression. (Registry study, N = 870, E 3)96 In Victoria (Australia), 63% of exposures were due to dosing errors, mostly accidental double doses. Orthostatic hypotension persisted for 24 to 42 hours in 3 of 32 isolated exposures. Intubation or circulatory support was not required. (Retrospective multicenter study, N = 275, E 3)97

To date, guanfacine has not been associated with elevated liver enzyme levels or clinically evident liver damage. (Database entry, E 4)98

In a prospective study (n = 32; examinations conducted before and 6 months after the start of treatment), guanfacine had no effect on ocular structures such as the retina, choroid, optic nerve, refraction, or corneal thickness; however, it increased corneal aberrations. (Prospective study without a control group, N = 32, E 2b)99

In our view, guanfacine is worth considering, particularly in cases of high blood pressure or a significant rise in blood pressure caused by stimulants. (ADxS assessment)

4. Metabolism of Guanfacine

Implications for People with ADHD

Guanfacine is metabolized in the liver primarily by the enzyme CYP3A4. It has not been studied whether women, in whom this enzyme is more active, require a higher dose. The dose is based on body weight.

Guanfacine is metabolized by cytochrome P450 3A4 (CYP3A4 for short) and by CYP3A5. (Prescribing Information, E 4)2
This cytochrome is more active in women than in men. (Scientific article, E 4)100 To the best of our knowledge, no studies have been conducted to determine whether women therefore require a higher dose of guanfacine. (ADxS assessment) Dosage is based on body weight anyway (target range 0.05 to 0.12 mg/kg/day). (Prescribing Information, E 4)2Furthermore, interactions occur with active ingredients that increase (inducers) or inhibit (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. (In vitro study, E 2b)101

5. Drug Interactions with Guanfacine

Implications for People with ADHD

Active ingredients and foods that induce the CYP3A4 enzyme (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) can significantly lower guanfacine levels. Those that inhibit CYP3A4 (e.g., ketoconazole, clarithromycin, grapefruit juice) can significantly increase guanfacine levels. Such combinations should be avoided or taken only after a doctor has adjusted the dose. Guanfacine may also increase valproate levels.

5.1. CYP3A4 inducers

Implications for People with ADHD

These active ingredients can lower guanfacine levels and thus reduce its effectiveness.

  • (E 2b): Phenobarbital
    • (Reference work, E 4)102(Systematischer Review, E 2b)103
    • (low) (Government overview, E 4) 104
  • (E 2b): Rifampin / Rifampicin (strong) (Reference work, E 4)102(Systematischer Review, E 2b)103
  • Anticonvulsants
    • (E 2b): Phenytoin (strong) (Reference work, E 4)102(Systematischer Review, E 2b)103
    • (E 2b): Carbamazepine (strong) (Reference work, E 4)102(Systematischer Review, E 2b)103
    • (E 2b): Oxcarbazepine (mild) (reference work, E 4)102(Systematischer Review, E 2b)103
  • (E 2b): Modafinil (mild) (reference work, E 4)102(Systematischer Review, E 2b)103
  • Armodafinil (weak) (Systematic Review, E 2b)103
  • Topiramate (weak) (Systematic Review, E 2b)103
  • Dexamethasone (Reference Work, E 4)102
    • Not: Prednisone (Reference Work, E 4)102
  • (E 2b): St. John’s wort
    • (Reference Work, E 4)102(Systematischer Review, E 2b)103
    • (severe) (Official Overview, E 4) 104
  • Garlic (Reference Work, E 4)102
  • Licorice (Reference Work, E 4)102

5.1.1. 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. (Systematic review, E 2b)103 Conversely, guanfacine levels rise again 2 to 3 weeks after discontinuation of CYP3A4 inducers. (Systematic review, E 2b)103 Rifampicin reduced the Cmax and AUC of guanfacine by 54% and 70%, respectively. (Prescribing information, E 4)2
The European prescribing information recommends, when used in combination with strong enzyme inducers, up-dosing as necessary up to a maximum of 7 mg daily. (Prescribing Information, E 4)2 The U.S. prescribing information recommends doubling the guanfacine dose. (Systematic Review, E 2b)103 Based on a case report involving phenobarbital (requiring a 5-fold increase in dose) and experience with antipsychotics metabolized via CYP3A4, this adjustment factor may be too low. (Systematic review, E 2b)103 Avoiding strong CYP3A4 inducers appears advisable when taking guanfacine concomitantly. (Systematic review, E 2b)103

5.2. CYP3A4 inhibitors

Implications for People with ADHD

These active ingredients can increase guanfacine levels and thereby intensify side effects such as fatigue, low blood pressure, and a slow heart rate. According to the prescribing information, the guanfacine dose should be halved when taken concurrently with strong or moderately strong inhibitors.

  • Antibiotics.
    • Macrolides
      • (E 2b): Erythromycin (Reference Work, E 4)102
        • (strong) (Systematic review, E 2b)103
        • (moderate) (Government overview, E 4)104
      • (E 2b): Clarithromycin (strong) (Systematic review, E 2b)103(Nachschlagewerk, E 4)102
      • Telithromycin (Reference Work, E 4)102
    • Chloramphenicol (Reference Work, E 4)102
    • (E 4): Quinolones (ciprofloxacin, moderate) (Reference work, E 4)102(Fachinformation, E 4)2- Antifungals:
    • Fluconazole (Reference Work, E 4)102
      • (moderate) (Government overview, E 4)104
    • (E 2b): Ketoconazole (strong) (Systematic review, E 2b)103(Nachschlagewerk, E 4)102
    • Itraconazole (Reference Work, E 4)102
  • Diltiazem
    • (strong) (Systematic review, E 2b)103
    • (moderate) (Government overview, E 4)104
  • (E 2b): Grapefruit juice
    • (strong) (Systematic review, E 2b)103(Nachschlagewerk, E 4)102
    • (moderate; may be high depending on preparation) (Official Overview, E 4)104
  • Fluoxetine (weak to moderate) (Systematic review, E 2b)103
  • Fluvoxamine
    • (low to moderate) (Systematic review, E 2b)103
    • (weak) (Government Overview, E 4)
  • Protease inhibitors:
    • Ritonavir (Reference Work, E 4)102
    • Indinavir (Reference Work, E 4)102
    • Nelfinavir (Reference Work, E 4)102
  • Verapamil (Reference Work, E 4)102
    • (moderate) (Official overview, E 4)104
  • Aprepitant (Reference Work, E 4)102
  • Nefazodone (Reference Work, E 4)102
  • Amiodarone (Reference Work, E 4)102
  • Cimetidine (Reference Work, E 4)102
    • (weak) (Government Overview, E 4)104
  • Valerian (Reference Work, E 4)102
  • Goldenseal (Reference Work, E 4)102
  • Ginseng (Reference Work, E 4)102
  • Ginger (Reference Work, E 4)102

 

5.2.1. CYP3A4 Inhibitors and Guanfacine

Strong CYP3A4 inhibitors increase blood levels of guanfacine after initiation of treatment; weak and moderate CYP3A4 inhibitors may also cause this effect. (Systematic review, E 2b)103 Ketoconazole increased the Cmax and AUC of guanfacine by 2- and 3-fold, respectively. (Prescribing information, E 4)2

The prescribing information recommends halving the guanfacine dose when strong and moderate CYP3A inhibitors are administered concomitantly. (Prescribing Information, E 4)2 Based on experience with antipsychotics metabolized via CYP3A4, halving the dose may not be sufficient. (Systematic review, E 2b)103 Avoiding CYP3A4 inhibitors appears advisable when taking guanfacine concomitantly. (Systematic review, E 2b)103

Grapefruit juice should always be avoided when taking psychiatric medications. (Systematic review, E 2b)103

5.3. Other Drug Interactions with Guanfacine

Implications for People with ADHD

Guanfacine can increase valproate levels. Tricyclic antidepressants and phenothiazines may reduce the effectiveness of guanfacine. When taken with beta-blockers, sudden discontinuation of guanfacine can cause a sharp rise in blood pressure.

In two case reports (children aged 8 and 9 years), valproate showed elevated plasma levels when taken concomitantly with guanfacine. After tapering off guanfacine, the valproate level decreased by 41% in one child. (Case reports, n = 2, Section 4)105 The prescribing information cites competitive inhibition of glucuronidation as a possible mechanism. (Prescribing information, Section 4)2
Guanfacine and clonidine are believed to be antagonized by tricyclic antidepressants and phenothiazines. (Narrative review, E 4)106

Concomitant use of beta-blockers or sudden discontinuation of guanfacine may lead to a hypertensive reaction. (Narrative review, E 4)106

6. Long-term effects: No tolerance to guanfacine

Implications for People with ADHD

To date, no decrease in efficacy has been observed with long-term use. In long-term studies lasting up to 2 years, the efficacy was maintained; however, many participants discontinued treatment prematurely.

A meta-analysis of 87 RCTs (treatment duration: 3 to 28 weeks) found no evidence of a decline in the efficacy of methylphenidate, amphetamine-based medications, atomoxetine, or α2-agonists with long-term use. (METASTUDY, k = 87 RCTs, E 1a)107 For more on this, see Medications: Development of Tolerance.

Among children and adolescents who had responded to 13 weeks of open-label treatment, treatment failure occurred less frequently over 26 weeks with continued guanfacine extended-release than after switching to placebo (49.3% versus 64.9%, effect size 0.51). After switching to placebo, blood pressure and heart rate usually rose slightly and temporarily above baseline levels. Somnolence occurred in 48.5% of patients during the open-label phase. (Randomized discontinuation study, N = 528, n = 316 randomized, E 1b, manufacturer-funded)108

In a 2-year open-label study, the ADHD-RS-IV score improved by 19.8 points. 82.7% experienced side effects, most commonly somnolence (36.0%), headache (28.5%), and fatigue (20.1%). Sedative side effects peaked in week 3 and then subsided. 3.3% discontinued treatment due to side effects, and 62.1% completed the study. The BMI-z score remained stable, the pulse rate decreased by 5.5 beats/min, blood pressure remained unchanged, and the QTcF did not change significantly (+0.7 ms). (Open-label long-term study, n = 214, Phase 2b, manufacturer-funded)109 Additional open-label long-term studies lasting up to 24 months found sustained symptom improvements, mostly transient drowsiness, sedation, and fatigue, as well as slight decreases in blood pressure and heart rate. 198 of 240 participants discontinued the study early; 52 did so due to side effects. Two cases of syncope and one case of orthostatic hypotension were considered possibly drug-related. (Open-label extension study, n = 240, E 2b, manufacturer-funded)110 22.9% completed a 2-year study; 87.3% experienced side effects, 6.2% had serious side effects, and 5 participants experienced syncope. (Open-label long-term study, n = 262, Phase 2b, manufacturer-funded)111

In adults, 94.2% experienced side effects in a 50-week extension study; 19.9% discontinued treatment as a result, most commonly due to drowsiness, decreased blood pressure, malaise, and bradycardia. ADHD symptoms improved. (Open-label extension study, n = 191, Phase 2b, author(s) employed by the manufacturer)112 In a Japanese post-marketing surveillance study of adults, 45.2% were still taking extended-release guanfacine after 12 months. The most common reason for discontinuation was side effects (36.0%). Somnolence occurred in 15.0%, and hypotension or bradycardia in 4.5%. No increases in blood pressure were reported after discontinuation. (Prospective post-marketing surveillance study, n = 912, Phase 2b, author(s) employed by the manufacturer)113 According to Canadian insurance data, 66.4% of children and adolescents had discontinued, added, or switched from guanfacine extended-release within one year, with discontinuation being the most common outcome (55.5%). (Retrospective cohort study, n = 229, E 3, author(s) employed by the manufacturer)114

7. Theoretical Considerations Regarding Guanfacine in ADHD-I / SCT

Implications for People with ADHD

Severe stress can temporarily shut down the prefrontal cortex due to very high levels of norepinephrine. Pharmacologically, guanfacine is not expected to enhance this effect. In studies, guanfacine was also effective in patients with the predominantly inattentive subtype.

A sharp increase in norepinephrine and dopamine shuts down the PFC. This deactivation of the PFC occurs via alpha-1 adrenoceptors (and possibly beta-1 adrenoceptors), which have a lower affinity for norepinephrine than postsynaptic alpha-2A adrenoceptors and are therefore only activated at high levels of norepinephrine, such as those seen during stress. (E 2b): Moderate levels of norepinephrine enhance the PFC via alpha-2A adrenoceptors. (Narrative review, E 4)74(Tierstudie, Ratten, E 2b)115(Tierstudie, Ratten und Affen, E 2b)116(Narrativer Review, E 4)117(Tierstudie, Ratten, E 2b)118

According to our hypothesis, a particularly sharp increase in dopamine and norepinephrine during periods of severe stress could lead to (frequent) underactivation of the PFC, as is suspected in ADHD-I. (ADxS assessment)
Guanfacine is a highly selective alpha-2A-adrenoceptor agonist. It directly stimulates postsynaptic α2A-adrenoceptors and does not release norepinephrine. (E 2b): In rats, it acutely reduced norepinephrine release in the locus coeruleus, orbitofrontal cortex, and reticular thalamic nucleus. (Animal study, rats, N = 126, E 2b)5(Tierstudie, Ratten, N = 48, E 2b)72 Since alpha-1 adrenoreceptors are only activated upon high levels of norepinephrine release (Narrative Review, E 4)74, this pharmacologically suggests an attenuation rather than an enhancement of stress-induced PFC shutdowns (ADxS assessment).

In a pooled analysis of two RCTs, guanfacine extended-release was empirically more effective than placebo in treating ADHD-I. (Pooled post-hoc analysis of 2 RCTs, N = 631, n = 490, E 1b)42 There is therefore no evidence that the effect is limited to ADHD-HI. (ADxS assessment)

Yohimbine is an alpha-2-adrenoceptor antagonist (narrative review, E 4)119120 and, by acting on this receptor, has the opposite effect of guanfacine.

8. A Personal Account

Implications for People with ADHD

People with ADHD reported better sleep and a significantly reduced stress response when taking the medication in the evening. Individual reports cannot be generalized.

(ADxS experience): 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 somehow… 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 kind 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 that 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.”

In our view, this is the most vivid description of a stress-induced shutdown of the PFC that we have found so far. The fact that guanfacine attenuated this effect is consistent with the reduced norepinephrine release observed with guanfacine (ADxS assessment).
Please note: Individual reports on the effects of medications should not be generalized.
Always consult your doctor about medication!

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