Chemistry:Clonidine

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Clonidine, sold under the brand name Catapres and Kapvay, among others, is an α2-adrenergic receptor agonist, hypotensive and anxiolytic agent used to treat high blood pressure, attention deficit hyperactivity disorder, perioperative pain, drug withdrawal (e.g., alcohol, opioids, or nicotine), and menopausal flushing.[1][2][3] Clonidine is often prescribed off-label for tics. It is used orally (by mouth), by injection, or as a transdermal skin patch.[3] Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.[3] Xylazine is a structural analog of clonidine.[4]

Common side effects include dry mouth, dizziness, headaches, hypotension, and sleepiness.[3] Severe side effects may include hallucinations, heart arrhythmias, and confusion.[5] If rapidly stopped, withdrawal effects may occur, such as a dangerous rise in blood pressure.[3] Use during pregnancy or breastfeeding is not recommended.[5] Clonidine lowers blood pressure by stimulating α2-adrenergic receptors and imidazoline receptors in the brain, which results in relaxation of many arteries.[1][3]

Clonidine was patented in 1961 and came into medical use in 1966.[6][7][8] It is available as a generic medication.[3] In 2023, it was the 82nd most commonly prescribed medication in the United States, with more than 8 million prescriptions.[9][10]

Medical uses

Clonidine tablets and transdermal patch

Clonidine is used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD); drug withdrawal, including from (alcohol, opioids, and/or nicotine); menopausal flushing, diarrhea, and certain pain conditions.[11][12][13][3]

Hypertension

Hypertension is a chronic elevation of arterial blood pressure that increases the risk of cardiovascular disease and organ damage.[14] Many people with essential hypertension experience increased sympathetic nervous system activity, in addition to renin–angiotensin–aldosterone system activation.[14] Clonidine is a non-selective α2 adrenoreceptor and imidazoline receptor agonist that reduces sympathetic nervous system output from the brainstem, which lowers peripheral vascular resistance, heart rate and plasma renin activity, thereby reducing systolic and diastolic blood pressure as a consequence.[1]

Meta-analyses of randomized controlled trials in arterial hypertension have found that clonidine is an effective antihypertensive that leads to greater reductions in systolic and diastolic blood pressure than placebo.[15][16] A 2024 network meta-analysis of imidazoline receptor agonists (i.e., moxonidine and clonidine) reported that this drug class produced ambulatory blood pressure reductions that were close in magnitude to those of commonly used first-line antihypertensive drug classes, but with higher odds of adverse effects such as dry mouth and sedation, especially with clonidine.[16] Hypertension Canada’s 2020 clinical practice guideline on resistant hypertension similarly notes that clonidine significantly lowers blood pressure in clinical trials, though it is considered a second-line therapy due to its potential for side effects.[17] A 2025 review of randomized and observational studies on transdermal clonidine reported that once-weekly patch formulations achieve blood pressure reductions similar to beta blockers, calcium channel blockers and diuretics, while reducing the risk of withdrawal-related rebound hypertension compared with oral clonidine.[18]

Clonidine is not considered a first-line treatment for hypertension due to its propensity to cause sedation and xerostomia compared with other antihypertensive medications (e.g., angiotensin-converting enzyme inhibitors).[19] When used for blood pressure control, clonidine is typically reserved for hypertensive emergencies rather than routine management hypertension, but it is considered appropriate for treating resistant hypertension.[19]

Attention deficit hyperactivity disorder

Clonidine is used as a non-stimulant pharmacological treatment for ADHD and is USFDA-approved in its extended-release formulation as both a monotherapy and an adjunctive therapy to psychostimulants.[note 1][21][22] Clinical guidelines and comparative-efficacy reviews regard psychostimulant medications (i.e., amphetamine and methylphenidate) as first-line pharmacotherapy for ADHD, while non-stimulant agents such as clonidine are recommended as second-line options because their effect sizes are smaller than those of psychostimulants.[23][24][25] Non-stimulant medications, including clonidine, are typically used in individuals who do not respond adequately to psychostimulants, cannot tolerate psychostimulant adverse effects, have contraindications such as tic disorders or a high risk of psychostimulant misuse, or who have a preference for a non-stimulant treatment.[23][21][25] α2 adrenoreceptor agonists (i.e., clonidine and guanfacine) are one class of non-stimulant medications that treat ADHD by stimulating receptors expressed in the prefrontal cortex, thereby enhancing cognitive control of behavior.[21][25] Clonidine acts non-selectively at α2A, α2B and α2C receptor subtypes across the central nervous system, whereas guanfacine is selective for α2A adrenoreceptors in the prefrontal cortex, a difference that is believed to be partially responsible for clonidine’s greater propensity for sedative and hypotensive side effects.[1][24][25]

Randomized controlled trials show that clonidine monotherapy reduces core ADHD symptoms, including inattention, hyperactivity, impulsivity and disruptive behavior, compared with placebo.[21][25][22] Medical reviews on the efficacy of non-stimulant medications for ADHD indicate that clonidine produces moderate effect sizes for core symptom reduction, which are smaller than the large effect sizes reported for psychostimulants.[24][25] In contrast to the rapid onset seen with psychostimulant medications, clinically significant symptom improvement may be delayed by a few weeks.[21][24] Reviews of alpha-2 agonists suggest that this drug class may be more effective for managing hyperactivity and impulsivity than for inattentive ADHD symptoms, and that long-term treatment efficacy has been documented more extensively for guanfacine than for clonidine.[24][25][26] Unlike psychostimulants, clonidine is regarded as having no abuse potential due in part to a lack of dopaminergic activity along the mesolimbic pathway.[27]

Clonidine is also used as an add-on to psychostimulant medications in individuals who have a partial response to psychostimulants, cannot tolerate higher psychostimulant doses, or experience notable early-morning or evening symptoms.[21][24][25] In a randomized controlled trial of ADHD children with an incomplete response to psychostimulants, the addition of clonidine extended-release produced greater reductions in ADHD symptom scores than continuing psychostimulant monotherapy.[21] α2 adrenoreceptor agonists may also improve symptoms in comorbidities of ADHD such as tic disorders, oppositional or aggressive behavior, and insomnia.[21][25][28]

Sleep disturbances are common in individuals with ADHD and may arise both from the disorder itself and as adverse effects of psychostimulant medications, which can cause delayed sleep onset and insomnia.[29] Whilst clonidine's sedative properties, particularly in its immediate-release formulation, can limit its acceptability as a monotherapy for core ADHD symptoms during the daytime, it has been used as a sleep aid in ADHD individuals who are also treated with psychostimulants and experience insomnia.[24][25][28] Evidence suggests that immediate-release clonidine taken at bedtime can reduce sleep-onset difficulties and night-time awakenings, but its treatment effects do not persist into the following day and it is therefore not generally effective for daytime ADHD symptoms when used in this manner.[21][25][28]

Perioperative medicine

Clonidine is sometimes used in perioperative medicine as an adjunctive therapy during the perioperative period, where it is administered alongside other analgesics to provide sedation and pain-control.[30][31] Whilst clonidine itself has limited clinical utility as a monotherapy for postoperative pain, its combination with opioid medications may allow adequate pain relief to be achieved at lower opioid doses, which may reduce the frequency and severity of opioid-related adverse effects.[31] Compared with other sedative and opioid medications used perioperatively, clonidine does not produce respiratory depression or anterograde amnesia.[31] Moreover, its hemodynamic-stabilising effects and ability to reduce postoperative shivering are considered particularly useful in patients at high risk of myocardial ischaemia.[31] Clonidine also has anxiolytic properties that may help reduce preoperative anxiety.[31] In perioperative settings, clonidine may be orally ingested during the preoperative stage or administered intravenously or intramuscularly immediately before, during or shortly after surgery.[30] Clonidine can also be administered via epidural or intrathecal catheters as an adjuvant to local anesthetics to enhance perioperative and postoperative neuraxial blockade.[32][30] Clonidine's analgesic effects are attributed in part to activation of α2 adrenoreceptors within the dorsal horn of the spinal cord, which inhibits the release of pronociceptive neurotransmitters from primary afferent terminals and hyperpolarizes nociceptive interneurons.[32][1][31]

A 2017 systematic review and meta-analysis of 57 randomized controlled trials (RCTs) found that clonidine improved postoperative pain control.[30] In a subset of trials reporting detailed postoperative analgesia outcomes, clonidine delayed the time until patients required additional pain medication and reduced cumulative postoperative analgesic consumption over the first 24 hours by ~24%.[30] The same review reported that clonidine reduced the incidence of postoperative nausea and vomiting compared with placebo.[30] Meta-analyses of α2 adrenoreceptor agonists (i.e., clonidine and dexmedetomidine) likewise report small to moderate reductions in postoperative pain intensity and opioid consumption during the first postoperative day, consistent with an opioid-sparing effect, but are limited by substantial statistical heterogeneity.[33][34] In one meta-analysis of clonidine RCTs, overall adverse event rates did not differ significantly between clonidine and placebo.[30] However, that same paper noted that a large included trial reported a higher incidence of hypotension and non-fatal cardiac arrest with clonidine, and that the available data were insufficient to rule out uncommon but serious hemodynamic complications.[30]

Drug withdrawal

Clonidine may be used to ease drug withdrawal symptoms associated with abruptly stopping the long-term use of opioids, alcohol, benzodiazepines, and nicotine.[35] It can alleviate opioid withdrawal symptoms by reducing the sympathetic nervous system response such as tachycardia and hypertension, hyperhidrosis (excessive sweating), hot and cold flashes, and akathisia.[36] It may also be helpful in aiding smokers to quit.[37] The sedation effect can also be useful. Clonidine may also reduce severity of neonatal abstinence syndrome in infants born to mothers that are using certain drugs, particularly opioids.[38] In infants with neonatal withdrawal syndrome, clonidine may improve the neonatal intensive care unit Network Neurobehavioral Score.[39]

Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.[40]

Clonidine suppression test

The reduction in circulating norepinephrine by clonidine was used in the past as an investigatory test for phaeochromocytoma, which is a catecholamine-synthesizing tumor, usually found in the adrenal medulla.[41] In a clonidine suppression test, plasma catecholamine levels are measured before and 3 hours after a 0.3 mg oral test dose has been given to the patient. A positive test occurs if there is no decrease in plasma levels.[41]

Other uses

Clonidine also has several off-label uses, and has been prescribed to treat psychiatric disorders including stress, hyperarousal caused by post-traumatic stress disorder, borderline personality disorder, and other anxiety disorders.[42][43][44][45][46][47][48] It has also been studied as a way to calm acute manic episodes.[49] Clonidine can be used in restless legs syndrome.[50] It can also be used to treat facial flushing and redness associated with rosacea.[51] It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy.[52] Clonidine can also be used for migraine headaches and hot flashes associated with menopause.[53][54] Clonidine has also been used to treat refractory diarrhea associated with irritable bowel syndrome, fecal incontinence, diabetes, diarrhea associated with opioid withdrawal, intestinal failure, neuroendocrine tumors, and cholera.[55] Clonidine can be used in the treatment of Tourette syndrome (specifically for tics).[56] Clonidine has also had some success in clinical trials for helping to remove or ameliorate the symptoms of hallucinogen persisting perception disorder (HPPD).[57]

Adverse effects

The most common adverse side effects of clonidine are dry mouth and sedation.[58][59][28][31] Many side effects are dose-related and tend to diminish with tolerance that develops from continued use.[58][59] For the same reason that clonidine has efficacy for treating hypertension, hypotension and bradycardia are predictable dose-dependent effects.[31] However, with overdose in children, the degree of central nervous system depression does not clearly correlate with the ingested dose.[60]

Physical

Cardiovascular side effects can include hypotension (including orthostatic hypotension) and bradycardia; atrioventricular block and other bradyarrhythmias have also been reported.[31] Raynaud's phenomenon and syncope may also occur.[28][31] Because clonidine can cause bradycardia and hypotension, precautions are advised in people with sinoatrial node dysfunction (e.g., sick sinus syndrome) or atrioventricular block, and in those with severe coronary artery disease, cerebrovascular disease, or chronic kidney failure.[61]

Gastrointestinal side effects can include xerostomia, constipation, nausea, and vomiting.[28][31] Colonic pseudo-obstruction has been described as a rare side effect.[59]

Other reported physical side effects include headache, fatigue or weakness and, less commonly, urinary retention and transient edema.[28][31] In addition to dry mouth, clonidine has been reported to reduce tear production (i.e., dry eyes), a rare side effect that may be more noticeable in people who wear contact lenses.[31]

Skin reactions appear to occur uniquely with transdermal formulations of clonidine;[58] contact dermatitis at the transdermal patch application site has been reported in about 15% to 20% of users.[58]

Psychological

Common psychological side effects from clonidine include sedation, drowsiness, and dizziness.[59][28][31] The sedative effect of intravenous clonidine is dose-dependent and attributed in part to α2B adrenoceptor activation in the thalamus.[1] Sleep disturbance and depressed mood have been reported, and the Australian Medicines Handbook advises caution in people with a history of depression.[28][61][31] Less common neuropsychiatric reactions reported with clonidine (i.e., <1%) include disturbed mental state, nightmares, confusion, hallucinations, and delusions.[59][28][31]

Dependence and withdrawal

Physical dependence can develop with long-term clonidine use, and abrupt discontinuation can cause a withdrawal syndrome marked by a pronounced rebound increase in blood pressure.[61][31] Symptoms of clonidine withdrawal include a marked rise in blood pressure with symptoms such as headache, sweating, insomnia, agitation, tremor, palpitations, nervousness], and nausea.[61][31] Among dependent individuals, the severity of drug withdrawal appears to be significantly more pronounced in people with pre-existing hypertension and after prolonged treatment at higher doses (i.e., >900 mcg/day), and severe cases (hypertensive encephalopathy, stroke, and death) have been reported albeit rarely.[61][31] The severity of withdrawal symptoms is attenuated by tapering the dose.[61][31]

Pregnancy and breastfeeding

Clonidine is classified by the Australian Therapeutic Goods Administration as pregnancy category B3, which means that it has shown some detrimental effects on fetal development in animal studies, although the relevance of this to human beings is unknown.[62] Clonidine appears in high concentration in breast milk; a nursing infant's serum clonidine concentration is approximately 2/3 of the mother's.[63] Caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.[64]

Pharmacology

Site Ki (nM) Species Ref
NET >1,000 Human [65]
5-HT1B >10,000 Rat [66]
5-HT2A >10,000 Human [67]
α1A 316.23 Human [65]
α1B 316.23 Human [65]
α1D 125.89 Human [65]
α2A 35.48 – 61.65 Human [65][68]
α2B 69.18 – 309.0 Human [68][65]
α2C 134.89 – 501.2 Human [68][65]
D1 > 10,000 Rat [69]
I1 31.62 Bovine [65]
I2 (cortex) >1,000 Rat [65]
MAO-A >1,000 Rat [65]
MAO-B >1,000 Rat [65]
σ >10,000 Guinea Pig [70]
The Ki refers to a drug's affinity for a receptor. The smaller the Ki, the higher the affinity for that receptor.[71] Reported imidazoline-2 binding is measured in the cortex — I2 receptor bindings measured in stomach membranes are much lower.[72]

Pharmacodynamics

Clonidine produces most of its pharmacodynamic effects by acting as a non-selective partial agonist at α2 adrenoceptors (α2A, α2B, and α2C), where it can mimic the actions of endogenous norepinephrine at these receptors in the central nervous system and the sympathetic nervous system.[1] Clonidine can also bind imidazoline I1 receptors in brainstem regions involved in cardiovascular responses.[1] Through these actions clonidine lowers arterial blood pressure, heart rate, and total peripheral resistance.[58][59] α2 adrenoceptor activation decreases noradrenergic arousal signaling in the ascending reticular activating system, can modify prefrontal cortical network activity relevant to attention, and suppresses nociceptive signaling in the dorsal horn of the spinal cord.[73][74][59]

α2 adrenoceptors are Gi/Go-coupled G protein-coupled receptors that signal through heterotrimeric G proteins made up of a Gαi/o subunit protein and a paired Gβγ subunit complex (i.e., the β and γ subunits).[58][73] After receptor activation, Gαi/o and Gβγ can separate, and both components contribute to inhibition of neuronal activity and neurotransmitter release.[73][58] Gαi/o inhibits adenylyl cyclase, which decreases the expression of cyclic adenosine monophosphate (cAMP) and ceases protein kinase A (PKA)-dependent phosphorylation of amino acid residues involved in neuronal excitability and synaptic signaling.[58][73] In parallel, Gβγ can increase K+ conductance through G protein-coupled inwardly rectifying potassium channels (GIRKs), an effect that reduces neuronal firing through membrane hyperpolarization.[58][73]

In noradrenergic presynaptic neurons in the sympathetic nervous system, α2 adrenoceptors act as inhibitory autoreceptors that inhibit action potential-evoked neurotransmitter release.[73][58] After presynaptic α2 adrenoceptor activation by clonidine, the released Gβγ dimer can inhibit voltage-gated Ca2+ channels (including P/Q-type and N-type channels), which reduces Ca2+ entry during presynaptic depolarization and lowers vesicular neurotransmitter release.[73] Gβγ signaling can also increase K+ conductance (including via GIRKs) to oppose presynaptic depolarization and further limit voltage-gated Ca2+ channel activation.[73][58] In addition, Gβγ can bind proteins within the SNARE complex (e.g., SNAP-25), which can suppress synaptic vesicle fusion downstream of Ca2+ entry.[73] These mechanisms reduce the release of norepinephrine and other neurotransmitters from affected nerve terminals.[73][58]

Clonidine lowers arterial blood pressure primarily by reducing sympathetic nervous system activity and increasing vagus nerve activity to the heart.[58][59] In the medulla oblongata, activation of α2 adrenoceptors reduces the firing of neurons that are responsible for sympathetic nerve signaling to the heart, kidneys, and peripheral vasculature and can slow heart rate by increasing vagal tone.[58][59] At postganglionic nerve fibers, presynaptic α2 adrenoceptors function as inhibitory autoreceptors that suppress nerve-evoked release of norepinephrine and other signaling compounds (including adenosine triphosphate and neuropeptide Y).[58] These central and peripheral actions are associated with decreased plasma norepinephrine and reduced urinary catecholamine excretion, and with reductions in plasma renin and urinary aldosterone reported alongside decreases in total peripheral resistance and heart rate.[58][59] With intravenous administration, clonidine may cause a short-lived increase in blood pressure attributed to α2 adrenoceptor-mediated vasoconstriction in vascular smooth muscle, followed by a more sustained hypotensive response once clonidine crosses the blood brain barrier and binds to its receptor sites in the medulla oblongata; this biphasic pattern is generally less evident with oral or transdermal routes of administration due to dilution of the drug before reaching circulation.[58]

In the prefrontal cortex, α2A is the predominant α2 adrenoceptor subtype, and clonidine’s attention- and working memory-related effects are attributed to postsynaptic α2A activation.[24][74] Across the brain more generally, α2A and α2C adrenoceptors are widely distributed, while α2B is primarily expressed in the thalamus.[25][1][74] α2A adrenoceptors on dendritic spines of prefrontal pyramidal neurons can close hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) to promote attentional control and working memory.[74] The mechanism behind this behavioral effect has been described as the consequence of improved signal-to-noise ratio in the prefrontal cortex, which can facilitate focused attention on relevant stimuli and improved cognitive control of behavior.[24][74]

Sedation is attributed to clonidine's activity on noradrenergic neurons of the locus coeruleus and thalamus.[25][1] Somatodendritic α2 adrenoceptors reduce locus coeruleus firing, and presynaptic α2 adrenoceptors reduce norepinephrine release along noradrenergic pathways, in turn lowering noradrenergic modulation of arousal in the ascending reticular activating system.[73] α2 adrenoceptors are also expressed on axon terminals that release several other neurotransmitters (i.e., serotonin, dopamine, acetylcholine, GABA, and glutamate), and their activation can suppress release at these synapses as well.[73]

Clonidine produces analgesic effects in part through α2 adrenoceptors in the dorsal horn of the spinal cord.[59][73] In primary nociceptive neurons, α2A and α2C adrenoceptors are present on axon terminals and can be co-localized with neuropeptides involved in nociceptive signaling (e.g., substance P and calcitonin gene-related peptide), and clonidine inhibits their release in preclinical models.[73] Activation of α2 adrenoceptors in the spinal cord reduces excitatory input to dorsal horn neurons and decreases dorsal horn neuron firing, thereby inhibiting nociceptive signaling.[59][73]

The discovery of imidazoline receptors has prompted investigation of I1 receptor contributions to Clonidine's cardiovascular effects.[1][58] I1 receptors are widely distributed, including in the central nervous system, and I1 activation has been implicated in clonidine's sympatholytic effect.[1][58] One proposed model is that I1 receptor activation in the brainstem facilitates endogenous catecholamine signaling that then activates α2 adrenoceptors to reduce sympathetic activity and blood pressure, but the magnitude of I1 receptors in clonidine’s hypotensive effects remains unsettled.[58]

Growth hormone test

Clonidine stimulates release of GHRH hormone from the hypothalamus, which in turn stimulates pituitary release of growth hormone.[75] This effect has been used as part of a "growth hormone test," which can assist with diagnosing growth hormone deficiency in children.[76]

Pharmacokinetics

After being ingested, clonidine is absorbed into the blood stream rapidly with an overall bioavailability around 70–80%.[77] Peak concentrations in human plasma occur within 60–90 minutes for the "immediate release" (IR) version of the drug, which is shorter than the "extended release" (ER/XR) version.[78] Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6;[79][78] to compare, the optimal log P to allow a drug that is active in the human central nervous system to penetrate the blood brain barrier is 2.0.[80] Less than half of the absorbed portion of an orally administered dose will be metabolized by the liver into inactive metabolites, with roughly the other half being excreted unchanged by the kidneys.[78] About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces.[78] Work with liver microsomes shows in the liver clonidine is primarily metabolized by CYP2D6 (66%), CYP1A2 (10–20%), and CYP3A (0–20%) with negligible contributions from the less abundant enzymes CYP3A5, CYP1A1, and CYP3A4.[81] 4-hydroxyclonidine, the main metabolite of clonidine, is also an α2A agonist but is non lipophilic and is not believed to contribute to the effects of clonidine since it does not cross the blood–brain barrier.[82][83]

Measurements of the half-life of clonidine vary widely, between 6 and 23 hours, with the half-life being greatly affected by and prolonged in the setting of poor kidney function.[78] Variations in half-life may be partially attributable to CYP2D6 genetics.[81] Some research has suggested the half-life of clonidine is dose dependent and approximately doubles upon chronic dosing,[84] while other work contradicts this.[85] Following a 0.3 mg oral dose, a small study of five patients by Dollery et al. (1976) found half-lives ranging between 6.3 and 23.4 hours (mean 12.7).[86] A similar N=5 study by Davies et al. (1977) found a narrower range of half-lives, between 6.7 and 13 hours (mean 8.6),[77] while an N=8 study by Keraäen et al. that included younger patients found a somewhat shorter mean half-life of 7.5 hours.[87]

History

Clonidine was introduced in 1966.[88] It was first used as a hypertension treatment under the trade name of Catapres.[89]

Society and culture

Brand names

As of June 2017, clonidine is marketed under many brand names worldwide: Arkamin, Aruclonin, Atensina, Catapin, Catapres, Catapresan, Catapressan, Chianda, Chlofazoline, Chlophazolin, Clonid-Ophtal, Clonidin, Clonidina, Clonidinã, Clonidine, Clonidine hydrochloride, Clonidinhydrochlorid, Clonidini, Clonidinum, Clonigen, Clonistada, Clonnirit, Clophelinum, Dixarit, Duraclon, Edolglau, Haemiton, Hypodine, Hypolax, Iporel, Isoglaucon, Jenloga, Kapvay, Klofelino, Kochaniin, Lonid, Melzin, Menograine, Normopresan, Paracefan, Pinsanidine, Run Rui, and Winpress.[90] It is marketed as a combination drug with chlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination with bendroflumethiazide as Pertenso.[90]

Research

Borderline personality disorder

A systematic review of psychopharmacology in borderline personality disorder identified clonidine as a promising adjunctive therapy targeting noradrenergic dysregulation, especially in comorbid PTSD cases. However, it emphasized the limitations of small sample sizes and called for larger placebo-controlled trials.[91]

Notes

  1. ↑ Psychostimulants are a subset of the stimulant drug class that are defined by their ability to alter the function of the dopamine transporter, a mode of action that distinguishes them from other stimulants such as caffeine.[20]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Stahl's essential psychopharmacology: neuroscientific basis and practical applications (5th ed.). Cambridge: Cambridge University Press. 2021. pp. 482–83. ISBN 978-1-108-97529-2. "Clonidine is a relatively nonselective agonist at α2 receptors, with actions on α2A, α2B, and α2C receptors. In addition, clonidine has actions on imidazoline receptors, thought to be responsible for some of clonidine’s sedating and hypotensive actions. Although the actions of clonidine at α2A receptors exhibit therapeutic potential for ADHD, its actions at other receptors may increase side effects. Clonidine is approved for the treatment of hypertension, but only the controlled release version of clonidine is approved for treatment of ADHD. ... Unlike clonidine, guanfacine is 15–60 times more selective for α2A receptors than for α2B and α2C receptors. Additionally, guanfacine is 10 times weaker than clonidine at inducing sedation and lowering blood pressure, yet it is 25 times more potent in enhancing prefrontal cortical function." 
  2. ↑ "Chapter 12:Adrenergic Agonists and Antagonists". Goodman and Gilman's The Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education / Medical. 2017. ISBN 978-1-259-58473-2. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 "Clonidine, Clonidine Hydrochloride Monograph for Professionals". 10 June 2024. https://www.drugs.com/monograph/clonidine-clonidine-hydrochloride.html. 
  4. ↑ "Xylazine–a review of its pharmacology and use in veterinary medicine". Journal of Veterinary Pharmacology and Therapeutics 11 (4): 295–313. December 1988. doi:10.1111/j.1365-2885.1988.tb00189.x. PMID 3062194. 
  5. ↑ 5.0 5.1 British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 144. ISBN 978-0-85711-338-2. 
  6. ↑ "Clonidine: clinical pharmacology and therapeutic use in pain management". Current Clinical Pharmacology 6 (4): 280–287. November 2011. doi:10.2174/157488411798375886. PMID 21827389. 
  7. ↑ "A historical perspective: development of clonidine". Best Practice & Research Clinical Anaesthesiology 14 (2): 237–246. June 2000. doi:10.1053/bean.2000.0079. 
  8. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 550. ISBN 978-3-527-60749-5. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA550. Retrieved 12 September 2020. 
  9. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  10. ↑ "Clonidine Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Clonidine. 
  11. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Catapres FDA label
  12. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Kapvay FDA label
  13. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Duraclon FDA label
  14. ↑ 14.0 14.1 "Revisiting resistant hypertension: a comprehensive review" (in en). Internal Medicine Journal 53 (10): 1739–1751. 2023. doi:10.1111/imj.16189. PMID 37493367. 
  15. ↑ "Efficacy of pharmacological and interventional treatment for resistant hypertension: a network meta-analysis" (in en). Cardiovascular Research 120 (1): 108–119. 27 February 2024. doi:10.1093/cvr/cvad165. PMID 37890022. https://academic.oup.com/cardiovascres/article/120/1/108/7331230. "Compared with placebo/sham, a significant reduction in office sBP could also be accomplished with clonidine". 
  16. ↑ 16.0 16.1 "Not first-line antihypertensive agents, but still effective — The efficacy and safety of imidazoline receptor agonists: A network meta-analysis". Pharmacology Research & Perspectives 12 (3). June 2024. doi:10.1002/prp2.1215. PMID 38807350. "In summary, both imidazoline receptor agonists, clonidine and moxonidine, were significantly more effective than placebo in all cases.". 
  17. ↑ "Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children". Canadian Journal of Cardiology 36 (5): 596–624. 2020. doi:10.1016/j.cjca.2020.02.086. PMID 32389335. 
  18. ↑ "Transdermal Clonidine for Hypertension: An Underutilized Ally in the Modern Era" (in en). High Blood Pressure & Cardiovascular Prevention. 5 December 2025. doi:10.1007/s40292-025-00770-5. PMID 41345378. https://doi.org/10.1007/s40292-025-00770-5. 
  19. ↑ 19.0 19.1 "Adrenoceptors and Hypertension". Handbook of Experimental Pharmacology 285: 297–332. 2024. doi:10.1007/164_2024_719. ISBN 978-3-031-66775-6. PMID 38890192. "These agents attenuate noradrenaline release centrally (brainstem) reducing the output of vasoconstrictor signals to the peripheral SNS leading to hypotension and bradycardia. The classical example in this class is clonidine. This class of agents are used only in exceptional clinical cases and circumstances, mainly due to the limiting side effects of sedation, dry mouth, rebound effects after stopping, and depression. ... Clonidine may be used in resistant hypertension and hypertensive crisis particularly in patients in intensive care with concomitant agitation.". 
  20. ↑ "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". Nestler, Hyman & Malenka's Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (4th ed.). McGraw Hill. 2020. ISBN 9781260456905. "The psychostimulants, cocaine, amphetamine, and methylphenidate, are indirect DA agonists that interact with DA transporters. ... Cognitive control is impaired in several disorders, including attention deficit hyperactivity disorder (ADHD), which is treated with psychostimulants, a term used to describe indirect DA agonists such as methylphenidate and amphetamines that block DAT or cause reverse transport of DA." 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 "Nonstimulant medications for the treatment of attention-deficit/hyperactivity disorder in children and adolescents". Pediatric Annals 54 (1): e27–e33. January 2025. doi:10.3928/19382359-20241007-07. PMID 39760346. "Clonidine IR may be given at bedtime to help with sleep, but this will not help with ADHD symptoms during the day. Therefore, clonidine ER is preferred to clonidine IR for treating ADHD.  ... Adding clonidine ER to a stimulant as an augmentation strategy has been shown to significantly improve ADHD symptoms for children who had only a partial response to stimulants.". 
  22. ↑ 22.0 22.1 "An updated overview on the genetics and pharmacological treatment of attention-deficit/hyperactivity disorder". Discover Mental Health 3 (1): 2. 2023. doi:10.1007/s44192-022-00030-1. PMID 37861876. 
  23. ↑ 23.0 23.1 "The Australian evidence-based clinical practice guideline for attention deficit hyperactivity disorder" (in EN). Australian & New Zealand Journal of Psychiatry 57 (8): 1101–1116. 1 August 2023. doi:10.1177/00048674231166329. PMID 37254562. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 24.6 24.7 24.8 "Evidence-based pharmacological treatment options for ADHD in children and adolescents". Pharmacology & Therapeutics 230. January 2022. doi:10.1016/j.pharmthera.2021.107940. PMID 34710792. "In the prefrontal cortex, postsynaptic alpha-2 agonism leads to enhanced noradrenergic neurotransmission. This, in turn, strengthens the regulatory role of the prefrontal cortex, which is responsible for top-down guidance of attention, thought and working memory. ... While sharing the same mechanism of action, clonidine and guanfacine differ regarding their potency, with guanfacine being approximately ten times less potent than clonidine. The documented higher specificity of guanfacine to alpha-2A receptors may mediate differences between the two agents regarding the adverse effects profile, e.g., less sedative effects of guanfacine ... When sleep disturbances are present, clonidine and guanfacine may be considered.". 
  25. ↑ 25.00 25.01 25.02 25.03 25.04 25.05 25.06 25.07 25.08 25.09 25.10 25.11 25.12 "The role of alpha-2 agonists for attention deficit hyperactivity disorder in children". Neurology International 15 (2): 697–707. June 2023. doi:10.3390/neurolint15020043. PMID 37218982. "Clonidine stimulates Alpha-2A, Alpha-2B, and Alpha2C, whereas guanfacine stimulates the Alpha-2A receptors in the prefrontal cortex. ... The most prominent side effect of both drugs is sedation and orthostatic hypotension. Sudden discontinuation of these drugs could also result in rebound hypertension. However, it has milder side effects than clonidine due to the longer duration of action of guanfacine. ... Although Clonidine has efficacy in reducing ADHD symptomatology, it is not favored for long-term treatment due to the risk of hypotension and a less favorable pharmacokinetic profile [40]. Switching patients from Clonidine IR to Guanfacine XR is one option for managing ADHD symptomatology". 
  26. ↑ "Guanfacine's mechanism of action in treating prefrontal cortical disorders: Successful translation across species". Neurobiology of Learning and Memory 176. 2020. doi:10.1016/j.nlm.2020.107327. PMID 33075480. "Historically, the α2-AR agonist, clonidine, was tested in ADHD, where it was thought that the powerful sedative effects of this nonselective agonist were helping to make patients less active (Hunt, Capper, & O'Connell, 1990). It is now known that the therapeutic effects are independent of, and indeed in spite of, these sedative side effects, with the development of guanfacine’s use in ADHD based on understanding its prefrontal enhancement in monkeys (Arnsten and Contant, 1992, Arnsten et al., 1996), and the recognition that ADHD is a PFC disorder.". 
  27. ↑ "Chapter 15: Reinforcement and Addiction". Nestler, Hyman & Malenka's Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (4th ed.). McGraw Hill. 2020. ISBN 9781260456905. "The reinforcing effects of cocaine and amphetamines require an intact mesolimbic dopamine system. ... Dopamine levels are increased in the NAc during self-administration of cocaine or amphetamines, as mentioned previously, and blockade of dopaminergic transmission in the NAc—for example, in response to intra-NAc injections of dopamine receptor antagonists or of the toxin 6-hydroxydopamine (Chapter 6)—dramatically reduces drug reinforcement. ... While physical dependence and withdrawal occur dramatically with some drugs of abuse (opiates, ethanol), these phenomena are not useful in the diagnosis of an addiction because they do not occur as robustly with other drugs of abuse (cocaine, amphetamine) and can occur with many drugs that are not abused (propranolol, clonidine)." 
  28. ↑ 28.00 28.01 28.02 28.03 28.04 28.05 28.06 28.07 28.08 28.09 "Clonidine". Prescriber's Guide: Stahl's Essential Psychopharmacology (8th ed.). Cambridge, United Kingdom: Cambridge University Press. April 2024. pp. 179–84. ISBN 9781009464772. 
  29. ↑ "A systematic review of the effectiveness of sleep hygiene in children with ADHD". Psychology, Health & Medicine 25 (4): 497–518. 20 April 2020. doi:10.1080/13548506.2020.1732431. PMID 32204604. 
  30. ↑ 30.0 30.1 30.2 30.3 30.4 30.5 30.6 30.7 "What is the place of clonidine in anesthesia? Systematic review and meta-analyses of randomized controlled trials". Journal of Clinical Anesthesia 38: 140–153. May 2017. doi:10.1016/j.jclinane.2017.02.003. PMID 28372656. 
  31. ↑ 31.00 31.01 31.02 31.03 31.04 31.05 31.06 31.07 31.08 31.09 31.10 31.11 31.12 31.13 31.14 31.15 31.16 31.17 31.18 31.19 Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd. 2025. ISBN 978-0-6458137-6-0. 
  32. ↑ 32.0 32.1 "Caudal epidural blocks in paediatric patients: a review and practical considerations". British Journal of Anaesthesia 122 (4): 509–517. 2019. doi:10.1016/j.bja.2018.11.030. PMID 30857607. "Clonidine is the most common adjunctive drug for single-injection caudal blocks. Various mechanisms have been proposed to account for its favourable effect. Chief among them is presumably that clonidine binds to alpha-2 receptors in the dorsal horn of the spinal cord.". 
  33. ↑ "Effect of perioperative systemic alpha-2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials". Anesthesiology 116 (6): 1312–1322. June 2012. doi:10.1097/ALN.0b013e31825681cb. PMID 22546966. 
  34. ↑ "Effect of preoperative administration of systemic alpha-2 agonists on postoperative pain: a systematic review and meta-analysis". Anesthesia and Pain Medicine 15 (2): 157–166. April 2020. doi:10.17085/apm.2020.15.2.157. PMID 33329808. 
  35. ↑ "Elevated Norepinephrine may be a Unifying Etiological Factor in the Abuse of a Broad Range of Substances: Alcohol, Nicotine, Marijuana, Heroin, Cocaine, and Caffeine". Substance Abuse 7: 171–183. October 2013. doi:10.4137/SART.S13019. PMID 24151426. 
  36. ↑ Drugs of Abuse (2nd ed.). Los Angeles: Practice Management Information. 1997. 
  37. ↑ "Clonidine for smoking cessation". The Cochrane Database of Systematic Reviews 2008 (3). 2004. doi:10.1002/14651858.CD000058.pub2. PMID 15266422. 
  38. ↑ "Role of Clonidine in Neonatal Abstinence Syndrome: A Systematic Review". The Annals of Pharmacotherapy 50 (4): 301–310. April 2016. doi:10.1177/1060028015626438. PMID 26783353. 
  39. ↑ "Pharmacological Treatments for Neonatal Abstinence Syndrome: A Systematic Review and Network Meta-analysis". JAMA Pediatrics 173 (3): 234–243. March 2019. doi:10.1001/jamapediatrics.2018.5044. PMID 30667476. 
  40. ↑ "Two cases of acute dexmedetomidine withdrawal syndrome following prolonged infusion in the intensive care unit: Report of cases and review of the literature". Human & Experimental Toxicology 32 (1): 107–110. January 2013. doi:10.1177/0960327112454896. PMID 23111887. Bibcode: 2013HETox..32..107K. 
  41. ↑ 41.0 41.1 "Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results". The Journal of Clinical Endocrinology and Metabolism 88 (6): 2656–2666. June 2003. doi:10.1210/jc.2002-030005. PMID 12788870. 
  42. ↑ "The drug treatment of post-traumatic stress disorder". Journal of Affective Disorders 13 (2): 203–213. September–October 1987. doi:10.1016/0165-0327(87)90024-3. PMID 2960712. 
  43. ↑ "Pharmacotherapy for post-traumatic stress disorder". The Psychiatric Clinics of North America 17 (2): 409–423. June 1994. doi:10.1016/S0193-953X(18)30122-9. PMID 7937367. 
  44. ↑ "Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder". Biological Psychiatry 46 (9): 1192–1204. November 1999. doi:10.1016/S0006-3223(99)00219-X. PMID 10560025. 
  45. ↑ "Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder". Depression and Anxiety 25 (3): 260–271. 2008. doi:10.1002/da.20292. PMID 17354267. 
  46. ↑ "Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin". Journal of Psychiatric Practice 13 (2): 72–78. March 2007. doi:10.1097/01.pra.0000265763.79753.c1. PMID 17414682. 
  47. ↑ "Neuropsychiatric consequences of cardiovascular medications". Dialogues in Clinical Neuroscience 9 (1): 29–45. 2007. doi:10.31887/DCNS.2007.9.1/jchuffman. PMID 17506224. 
  48. ↑ "Post-traumatic stress disorder and its treatment in children and adolescents". Current Psychiatry Reports 10 (2): 104–108. April 2008. doi:10.1007/s11920-008-0019-0. PMID 18474199. 
  49. ↑ "Clonidine in mania". Drug Development Research 3 (1): 101–105. 1983. doi:10.1002/ddr.430030112. 
  50. ↑ "Treatment and Management of RLS". WebMD LLC. https://www.medscape.org/viewarticle/522010_6. 
  51. ↑ "Rosacea: a common, yet commonly overlooked, condition". American Family Physician 66 (3): 435–440. August 2002. PMID 12182520. http://www.aafp.org/afp/2002/0801/p435.html. Retrieved 12 February 2012. 
  52. ↑ "Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy". Pain 153 (9): 1815–1823. September 2012. doi:10.1016/j.pain.2012.04.014. PMID 22683276. 
  53. ↑ "Clonidine Oral Uses". WebMD. http://www.webmd.com/drugs/drug-11754-Clonidine.aspx?drugid=11754&drugname=Clonidine. 
  54. ↑ "Clonidine". Drugs.com. https://www.drugs.com/clonidine.html. 
  55. ↑ "What about clonidine for diarrhoea? A systematic review and meta-analysis of its effect in humans". Therapeutic Advances in Gastroenterology 9 (3): 282–301. May 2016. doi:10.1177/1756283X15625586. PMID 27134659. 
  56. ↑ "Current pharmacotherapeutic approaches for the treatment of Tourette syndrome". Drugs of Today 50 (2): 159–179. February 2014. doi:10.1358/dot.2014.50.2.2097801. PMID 24619591. 
  57. ↑ "Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives". Brain Sciences 8 (3): 47. March 2018. doi:10.3390/brainsci8030047. PMID 29547576. 
  58. ↑ 58.00 58.01 58.02 58.03 58.04 58.05 58.06 58.07 58.08 58.09 58.10 58.11 58.12 58.13 58.14 58.15 58.16 58.17 58.18 58.19 "Adrenergic agonists and antagonists". Goodman & Gilman's The Pharmacological Basis of Therapeutics (14th ed.). New York: McGraw-Hill. 2022. ISBN 978-1-264-25807-9. 
  59. ↑ 59.00 59.01 59.02 59.03 59.04 59.05 59.06 59.07 59.08 59.09 59.10 59.11 "Review of clinical pharmacokinetics and pharmacodynamics of clonidine as an adjunct to opioids in palliative care". Basic & Clinical Pharmacology & Toxicology 134 (4): 485–497. April 2024. doi:10.1111/bcpt.13979. PMID 38275186. 
  60. ↑ "Clonidine poisoning in children: a recent experience". Journal of Paediatrics and Child Health 40 (12): 678–680. December 2004. doi:10.1111/j.1440-1754.2004.00491.x. PMID 15569283. 
  61. ↑ 61.0 61.1 61.2 61.3 61.4 61.5 "APO-CLONIDINE clonidine hydrochloride 100 micrograms tablet bottle: Product information". https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent=&id=CP-2016-PI-02864-1. 
  62. ↑ "Catapres 150 Tablets Catapres Ampoules" (PDF). TGA eBusiness Services. Boehringer Ingelheim Pty Limited. 28 February 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-02400-3. 
  63. ↑ "Clonidine". Drugs and Lactation Database (LactMed). National Library of Medicine (US). 2006. https://www.ncbi.nlm.nih.gov/books/NBK501628/. Retrieved 5 January 2019. 
  64. ↑ "Clonidine". Prescription Marketed Drugs. www.drugsdb.eu. http://drugsdb.eu/drug.php?d=Clonidine&m=Physicians%20Total%20Care,%20Inc.&id=b65742b7-5db5-41cf-bf69-41700cdd2c59.xml. 
  65. ↑ 65.00 65.01 65.02 65.03 65.04 65.05 65.06 65.07 65.08 65.09 65.10 "S18616, a highly potent, spiroimidazoline agonist at alpha(2)-adrenoceptors: I. Receptor profile, antinociceptive and hypothermic actions in comparison with dexmedetomidine and clonidine". The Journal of Pharmacology and Experimental Therapeutics 295 (3): 1192–1205. December 2000. doi:10.1016/S0022-3565(24)39022-6. PMID 11082457. 
  66. ↑ "Characterization of 5-hydroxytryptamine1B receptors in rat spinal cord via [125I]iodocyanopindolol binding and inhibition of [3H]-5-hydroxytryptamine release". The Journal of Pharmacology and Experimental Therapeutics 260 (2): 614–626. February 1992. doi:10.1016/S0022-3565(25)11341-4. PMID 1738111. 
  67. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  68. ↑ 68.0 68.1 68.2 "Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding". Biochemical Pharmacology 55 (7): 1035–1043. April 1998. doi:10.1016/s0006-2952(97)00631-x. PMID 9605427. 
  69. ↑ "Sodium-dependent isomerization of dopamine D-2 receptors characterized using [125I]epidepride, a high-affinity substituted benzamide ligand". The Journal of Pharmacology and Experimental Therapeutics 252 (3): 1108–1116. March 1990. doi:10.1016/S0022-3565(25)20168-9. PMID 2138666. 
  70. ↑ "1,3-Di(2-[5-3Htolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs"]. Proceedings of the National Academy of Sciences of the United States of America 83 (22): 8784–8788. November 1986. doi:10.1073/pnas.83.22.8784. PMID 2877462. Bibcode: 1986PNAS...83.8784W. 
  71. ↑ "Ligand-Receptor Binding and Tissue Response". Pharmacology. Elsevier. 2009. p. 65. ISBN 978-0-12-369521-5. https://archive.org/details/pharmacologyprim00kena_186. 
  72. ↑ "Characterization of I2 imidazoline and sigma binding sites in the rat and human stomach". The Journal of Pharmacology and Experimental Therapeutics 285 (1): 170–177. April 1998. doi:10.1016/S0022-3565(24)37390-2. PMID 9536007. 
  73. ↑ 73.00 73.01 73.02 73.03 73.04 73.05 73.06 73.07 73.08 73.09 73.10 73.11 73.12 73.13 73.14 "Presynaptic adrenoceptors". Handbook of Experimental Pharmacology 285: 185–245. 2024. doi:10.1007/164_2024_714. ISBN 978-3-031-66776-3. PMID 38755350. 
  74. ↑ 74.0 74.1 74.2 74.3 74.4 "Current pharmacological treatments for attention-deficit/hyperactivity disorder". Current Topics in Behavioral Neurosciences 57: 19–50. 2022. doi:10.1007/7854_2022_330. PMID 35507282. 
  75. ↑ "Growth hormone-releasing hormone: clinical studies and therapeutic aspects". Neuroendocrinology 53 (Suppl 1): 37–40. 1991. doi:10.1159/000125793. PMID 1901390. 
  76. ↑ "Growth Hormone Test". Cincinnati Children's Hospital Medical Center. https://www.cincinnatichildrens.org/health/g/growth-hormone. 
  77. ↑ 77.0 77.1 "Pharmacokinetics and concentration-effect relationships of intervenous and oral clonidine". Clinical Pharmacology and Therapeutics 21 (5): 593–601. May 1977. doi:10.1002/cpt1977215593. PMID 870272. 
  78. ↑ 78.0 78.1 78.2 78.3 78.4 "alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role". Anaesthesia 54 (2): 146–165. February 1999. doi:10.1046/j.1365-2044.1999.00659.x. PMID 10215710. 
  79. ↑ Foye's principles of medicinal chemistry (6th ed.). Philadelphia: Lippincott Williams & Wilkins. 2008. p. 403. ISBN 978-0-7817-6879-5. https://archive.org/details/foyesprinciplesm00lemk. 
  80. ↑ "Medicinal chemical properties of successful central nervous system drugs". NeuroRx 2 (4): 541–553. October 2005. doi:10.1602/neurorx.2.4.541. PMID 16489364. 
  81. ↑ 81.0 81.1 Cite error: Invalid <ref> tag; no text was provided for refs named cypmetabolism
  82. ↑ "Antinociceptive activity of clonidine in the mouse, rat and dog". Life Sciences 31 (11): 1123–1132. September 1982. doi:10.1016/0024-3205(82)90086-8. PMID 6128647. 
  83. ↑ "Alpha adrenoceptor modulation of the jaw-opening reflex". Neuropharmacology 26 (7A): 649–655. July 1987. doi:10.1016/0028-3908(87)90224-3. PMID 2819761. 
  84. ↑ "Clonidine kinetics in man--evidence for dose dependency and changed pharmacokinetics during chronic therapy". British Journal of Clinical Pharmacology 12 (5): 653–658. November 1981. doi:10.1111/j.1365-2125.1981.tb01284.x. PMID 7332729. 
  85. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named clinp
  86. ↑ "Clinical pharmacology and pharmacokinetics of clonidine". Clinical Pharmacology and Therapeutics 19 (1): 11–17. January 1976. doi:10.1002/cpt197619111. PMID 1245090. 
  87. ↑ "Pharmacokinetics and side-effects of clonidine". European Journal of Clinical Pharmacology 13 (2): 97–101. May 1978. doi:10.1007/BF00609752. PMID 658114. 
  88. ↑ "A historical perspective: development of clonidine". Best Practice & Research Clinical Anaesthesiology 14 (2): 237–246. June 2000. doi:10.1053/bean.2000.0079. 
  89. ↑ "Clonidine: Drug Uses, Dosage & Side Effects - Drugs.com". Drugs.com. https://www.drugs.com/clonidine.html. 
  90. ↑ 90.0 90.1 "Clonidine brand names". Drugs.com. https://www.drugs.com/international/clonidine.html. 
  91. ↑ "Pharmacotherapy for borderline personality disorder--current evidence and recent trends". Current Psychiatry Reports 17 (1): 534. January 2015. doi:10.1007/s11920-014-0534-0. PMID 25413640. 
  • Alpha-2 agonists in ADHD



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