GuanfacineIR (as brand name Tenex) is FDA approved for the management of hypertension.[4][9]
GuanfacineXR (as brand name Intuniv) isindicated for the treatment of attention deficit hyperactivity disorder (ADHD), primarily for hyperactive symptoms. It is used both as monotherapy and as adjunctive therapy tostimulant medications.[3][18] In some cases, it can also help control theside effect profile of stimulant medications.[12] Unlike stimulant medications, guanfacine is regarded as having noabuse potential.[19] However, stimulant medications still remain the first-line treatment for ADHD, and guanfacine is typically only prescribed by itself in patients who cannot take stimulant medications (due to mental or physicalside effects).
For attention deficit hyperactivity disorder (ADHD), it is claimed that guanfacine helps individuals better control behavior, inhibit inappropriate distractions and impulses, and inhibit inappropriate aggressive impulses.[20]Systematic reviews andmeta-analyses have found guanfacine to be effective in the treatment of ADHD in both children and adults, with a moderateeffect size found in adults (Hedges' g = -0.66).[21][22][23] A systematic review and meta-analysis also found that guanfacine reducedoppositional behavior in children and adolescents with ADHD who also had or did not also haveoppositional defiant disorder, with a small-to-moderate effect size.[24] In any case, guanfacine and other α2-adrenergic receptor agonists are considered to be less effective than stimulants in the treatment of ADHD, at least when compared on rating scales developed to assess stimulant efficacy.[24][25][23]
Guanfacine is also used off-label to treat tic disorders, anxiety disorders such as generalized anxiety disorder, and PTSD.[26][17] Guanfacine and otherα2A-adrenergic receptor agonists haveanxiolytic-like action,[27] thereby reducing the emotional responses of theamygdala, and strengtheningprefrontal cortical regulation of emotion, action, and thought.[28] These actions arise from both inhibition ofstress-inducedcatecholamine release, and from prominent,post-synaptic actions in the prefrontal cortex.[28] Due to its prolongedelimination half-life, it also has been seen to improve sleep interrupted bynightmares in PTSD patients.[29] All of these actions likely contribute to the relief of thehyperarousal, re-experiencing ofmemory, andimpulsivity associated with PTSD.[30] Guanfacine appears to be especially helpful in treating children who have beentraumatized orabused.[28]
Other indications for guanfacine are drug (opioid, nicotine, cocaine) withdrawals, migraineprophylaxis, andFragile X Syndrome, among others.[19][31]
Guanfacine has been reported to cause high rates ofsomnolence in children with attention deficit hyperactivity disorder, for instance 73% with guanfacine versus 6% with placebo in one trial.[34][35]
Guanfacine may worsensleep in children with attention deficit hyperactivity disorder, including reducedtotal sleep time.[34][35]
Guanfacine availability is significantly affected by theCYP3A4 andCYP3A5enzymes. Medications thatinhibit orinduce those enzymes change the amount of guanfacine in circulation and thus its efficacy and rate of adverse effects. Because of its impact on theheart, it should be used with caution with othercardioactive drugs. A similar concern is appropriate when it is used withsedating medications.[33]
In ADHD, guanfacine is thought to work by strengthening the regulation of attention and behavior by theprefrontal cortex.[46][20] These enhancing effects on prefrontal cortical functions are believed to be due to drug stimulation of post-synaptic α2A-adrenoceptors ondendritic spines, and are not dependent on activation of pre-synaptic α2A-adrenoceptors.[20]Cyclic adenosine monophosphate (cAMP)-mediated opening ofHCN andKCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity andneuronal firing.[46][47] In monkeys, guanfacine improvesworking memory,attention regulation, andbehavioral inhibition, and these actions are independent of its sedative effects.[20] The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab atYale University.[46][20]
Guanfacine is much more selective for α2A-adrenergic receptors thanclonidine, which binds to and activates not only the α2A-adrenergic receptor but alsoα2B- andα2C-adrenergic receptors and theimidazoline receptor.[20] It is weaker than clonidine in producinghypotension andsedation, has weakerpre-synaptic actions on the α2A-adrenergic receptor than clonidine (10-fold less effective in decreasinglocus coeruleus activity andnorepinephrinerelease), and may have greater efficacy in activating post-synaptic α2A-adrenergic receptors (as suggested by guanfacine being more potent than clonidine in enhancing prefrontal cortex-relatedworking memory in aged monkeys).[20]
Activation of the 5-HT2B receptor is a well-knownantitarget and is associated withcardiac valvulopathy.[40][41] However, not all 5-HT2B receptor agonists, for instanceropinirole, have this effect.[40][41] Guanfacine has not been associated with cardiac valvulopathy despite a long history of use, perhaps due to modestpotency as a 5-HT2B receptor agonist.[43][48][49][50] Inin vitro studies, guanfacine showed 100-fold loweraffinity for the 5-HT2B receptor than for the α2A-adrenergic receptor, 30-fold lower affinity for the 5-HT2B receptor thanserotonin, and 1,000-fold lower potency in activating the 5-HT2B receptor compared to serotonin.[48] It was concluded that at clinically relevant concentrations, guanfacine would not be expected to show significant binding to or activation of 5-HT2B receptors, and that it is unlikely that guanfacine is a cardiac valvulopathogen in humans.[48] In any case, different studies have reported different potencies of guanfacine as a 5-HT2B receptor agonist,[42][43][48][49] and as of 2018, no clinical data on the risk of cardiac valvulopathy with guanfacine were available.[51] As such, while the likelihood is thought to be low, guanfacine might still have a risk of cardiac valvulopathy.[48]
Guanfacine has been found to act as a full agonist of thetrace amine-associated receptor 1 (TAAR1) with anEC50Tooltip half-maximal effective concentration andEmaxTooltip maximal efficacy of 20nM and ≥85% respectively.[52][53]
In December 2024, theCommittee for Medicinal Products for Human Use of theEuropean Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Paxneury, intended for the treatment of attention deficit hyperactivity disorder in children.[6] The applicant for this medicinal product is Neuraxpharm Pharmaceuticals S.L.[6] Paxneury is a generic of Intuniv, which has been authorized in the EU since September 2015.[6] It is also a hybrid medicine of Intuniv.[6] It contains the same active substance as Intuniv, but is available at higher strengths.[6] Paxneury was authorized for medical use in the European Union in February 2025.[6][7]
Guanfacine has been studied as a treatment forpost-traumatic stress disorder (PTSD). Evidence of efficacy in adults is limited, but one study found positive results in children with comorbid ADHD.[68] It may be also useful in adult PTSD patients who do not respond toselective serotonin reuptake inhibitors (SSRIs).[69]
Guanfacine does not appear to be effective for improvingsleep in children with ADHD and behavioralinsomnia.[34] Instead, guanfacine worsened certain sleep parameters, for instancetotal sleep time, in one clinical trial.[34][35]
Guanfacine has been investigated for treatment ofwithdrawal foropioids,ethanol, andnicotine.[71] Guanfacine has been shown to help reduce stress-induced craving of nicotine in smokers trying to quit, which may involve strengthening of prefrontal cortex-mediated self-control.[72]
^"Intuniv EPAR".European Medicines Agency. 17 September 2015. Retrieved13 June 2024.
^abcdefgh"Paxneury EPAR".European Medicines Agency (EMA). 12 December 2024. Retrieved16 December 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ab"Paxneury PI".Union Register of medicinal products. 4 March 2025. Retrieved22 March 2025.
^Yu S, Shen S, Tao M (March 2023). "Guanfacine for the Treatment of Attention-Deficit Hyperactivity Disorder: An Updated Systematic Review and Meta-Analysis".J Child Adolesc Psychopharmacol.33 (2):40–50.doi:10.1089/cap.2022.0038.PMID36944092.S2CID257664282.
^Padilha SC, Virtuoso S, Tonin FS, Borba HH, Pontarolo R (October 2018). "Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis".Eur Child Adolesc Psychiatry.27 (10):1335–1345.doi:10.1007/s00787-018-1125-0.PMID29460165.S2CID3402756.
^abRoth BL, Driscol J (12 January 2011)."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived fromthe original on 8 November 2013. Retrieved15 November 2013.
^abcJasper JR, Lesnick JD, Chang LK, Yamanishi SS, Chang TK, Hsu SA, et al. (April 1998). "Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding".Biochemical Pharmacology.55 (7):1035–1043.doi:10.1016/s0006-2952(97)00631-x.PMID9605427.
^abcUhlén S, Porter AC, Neubig RR (December 1994). "The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors".The Journal of Pharmacology and Experimental Therapeutics.271 (3):1558–1565.doi:10.1016/S0022-3565(25)24043-5.PMID7996470.
^abcBender AM, Parr LC, Livingston WB, Lindsley CW, Merryman WD (August 2023)."2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery".J Med Chem.66 (16):11027–11039.doi:10.1021/acs.jmedchem.3c01178.PMC11073569.PMID37584406.S2CID260924858.These results strongly indicate substantial risks for treatments involving 5-HT2B agonists, and it has been recommended that all serotonergic drugs be screened for this functional profile.43,59 [...] Additionally, there are cases of marketed drugs that were only later determined to have 5-HT2B activity. Of particular note is guanfacine, an FDA-approved medication for the treatment of attention deficit hyperactivity disorder (ADHD) that possesses potent 5-HT2B agonist activity in functional readouts to a similar degree as known valvulopathogens.66
^abRoihuvuo, E. (2022). Classical psychedelics and NBOMes as serotonin 2B receptor agonists: Valvulopathogenic signaling pathways and cardiac safety concerns (Master's thesis, Itä-Suomen yliopisto).http://urn.fi/urn:nbn:fi:uef-20220118
^"Recommendation for complete response action for SPD503 (guanfacine) extended release tablets for the treatment of attention deficit hyperactivity disorder (ADHD)"(PDF).fda.gov. 27 July 2009. Archived fromthe original(PDF) on 10 March 2025.Guanfacine IR has been marketed since 1986 for the treatment of hypertension, and in more recent years has also been used off-label for the treatment of ADHD. We have conducted an AERS search and have not found a single report of valvulopathy for this drug. We have also conducted a literature search and have found no reports of valvulopathy for this drug. This is somewhat reassuring, since reports emerged fairly quickly for the drugs believed to be valvulopathogens.
^US3632645A, Bream, John Bernard & Picard, Claude W., "Substituted phenylacetyl derivatives of guanidine o-alkylisoureas s-alkylisothioureas and p-nitrobenzylisothiourea", issued 4 January 1972
^Scholtysik G (1974). "Proceedings: Inhibition of effects of accelerator nerve stimulation in cats and rabbits by BS 100-141 and guanabenz".Naunyn-Schmiedeberg's Arch Pharmacol.282 (Suppl): suppl 282:R86.PMID4276642.
^Bream JB, Lauener H, Picard CW, Scholtysik G, White TG (October 1975). "Substituted phenylacetylguanidines: a new class of antihypertensive agents".Arzneimittelforschung.25 (10):1477–82.PMID1243024.
^Saameli K, Scholtysik G, Waite R (1975). "Pharmacology of BS 100-141, a centrally acting antihypertensive drug".Clinical and Experimental Pharmacology & Physiology.1975 (Suppl 2):207–212.PMID241524.
^Dubach UC, Huwyler R, Radielovic P, Singeisen M (1977). "A new centrally action antihypertensive agent guanfacine (BS 100-141)".Arzneimittelforschung.27 (3):674–6.PMID326262.
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages. See also:Receptor/signaling modulators
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