Clonidine

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Clonidine hydrochloride oral tablets (Alembic label), prescribing information, label version effective 30 September 2026. Set ID 88a8db46-0fc9-48cd-b7cc-ac9c9cdea100.

The label approves clonidine hydrochloride tablets for hypertension, alone or with other antihypertensives. Clonidine stimulates alpha-adrenoreceptors in the brain stem, reducing sympathetic outflow and lowering peripheral and renal vascular resistance, heart rate and blood pressure; the pulse slows in most patients without altering the normal hemodynamic response to exercise. It acutely stimulates growth hormone release without chronic elevation on long-term use. Oral bioavailability is 70% to 80%, peak levels come in about 1 to 3 hours, and elimination half-life is 12 to 16 hours, up to 41 hours in severe renal impairment. The most frequent adverse effects, which appear dose-related, are dry mouth (about 40 in 100 patients), drowsiness (about 33), dizziness (about 16), and constipation and sedation (about 10 each). Less frequent reports, not all causally linked, include agitation, anxiety, insomnia, nervousness, vivid dreams or nightmares, erectile dysfunction, loss of libido and gynecomastia. Clonidine may potentiate the CNS depression of alcohol, barbiturates or other sedating drugs, and patients are cautioned about driving. The label warns that sudden cessation has caused nervousness, agitation, headache and tremor with a rapid rise in blood pressure and raised plasma catecholamines, more likely after higher doses or with continued beta-blocker treatment, and that rare hypertensive encephalopathy, stroke and death have followed withdrawal. In overdose, hypertension may come first and be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness and reduced reflexes, with conduction defects, apnea, coma and seizures after large overdoses; as little as 0.1 mg has caused toxicity in children, and there is no specific antidote.

Participants / model

Adults with hypertension; label PK participants; patients taking clonidine and overdose cases

Treatment

Clonidine hydrochloride oral tablets (Alembic label)

Follow-up

Label version effective 30 September 2026

Study design

FDA prescribing information

Funding

not stated in the source

Label-level statements. The page does not reproduce label dosing, the label's schedule for stopping clonidine, or onset timing. The less frequent adverse reactions carry no rates and no established causality.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. ONYDA XR (clonidine hydrochloride) extended-release oral suspension, prescribing information, label version effective 11 April 2025. Set ID 4a15c850-9da5-4bdc-a34d-7f740a6149b7.

The label approves ONYDA XR for ADHD in children 6 and older, as monotherapy or as an add-on to CNS stimulant medication. Among patients who completed 5 weeks of a controlled fixed-dose pediatric monotherapy study of clonidine extended-release tablets cited in the label, somnolence was reported by 31% and 38% across the two fixed doses versus 4% on placebo.

Participants / model

Children 6 and older with ADHD

Treatment

ONYDA XR extended-release oral suspension

Follow-up

Label version effective 11 April 2025

Study design

FDA prescribing information

Funding

not stated in the source

The stimulant add-on approval is for pediatric ADHD, not for adult stimulant comedown.

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application records for clonidine, including CATAPRES-TTS (NDA 018891), DURACLON (NDA 020615), ONYDA XR (NDA 217645) and generic clonidine hydrochloride (ANDA 070923). Dates read from the openFDA Drugs@FDA records.

openFDA Drugs@FDA records include CATAPRES-TTS (transdermal system), NDA 018891, approved 10 October 1984; DURACLON, NDA 020615, approved 2 October 1996; ONYDA XR, NDA 217645, approved 24 May 2024; and generic clonidine hydrochloride, the earliest among the records returned being ANDA 070923 on 4 September 1987. The original CATAPRES tablet application was not among the records returned.

Participants / model

Not a clinical population

Treatment

Drug applications

Follow-up

Approvals from 1984 to 2024 in the records returned

Study design

FDA application records

Funding

not stated in the source

The original CATAPRES tablet application was not returned, so the first U.S. approval date for tablets is not established. The generic date is the earliest among the records returned.

Chemical identity record

National Library of Medicine. PubChem compound records CID 2803 (clonidine) and CID 20179 (clonidine hydrochloride).

Clonidine free base: C9H9Cl2N3, 230.09 g/mol, CAS 4205-90-7. Clonidine hydrochloride, the salt in US tablets and ONYDA XR: CID 20179, C9H10Cl3N3, 266.6 g/mol, CAS 4205-91-8; the tablet label gives 266.56 and states the tablet strength as the hydrochloride, with a free-base equivalent.

Participants / model

Chemical identity, not a clinical population

Treatment

Defined molecule and salt

Follow-up

Not applicable

Study design

NLM chemical record

Funding

not stated in the source

Identity record only; it says nothing about efficacy or safety.

Systematic review and meta-analysis

Gowing L et al. Cochrane Database Syst Rev. 2016;2016(5):CD002024. PMID 27140827.

There was moderate-quality evidence that alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) reduced the likelihood of severe opioid withdrawal versus placebo (RR 0.32, 95% CI 0.18 to 0.57; 3 studies, 148 participants) and raised treatment completion (RR 1.95, 95% CI 1.34 to 2.84). Compared with tapering methadone, efficacy did not differ significantly, but hypotensive or other adverse effects were more likely (RR 1.92, 95% CI 1.19 to 3.10). Lofexidine had a better safety profile than clonidine.

Participants / model

People dependent on heroin or methadone; 26 randomized trials with 1,728 participants

Treatment

Alpha2-adrenergic agonists, mostly oral

Follow-up

Pooled randomized trials

Study design

Cochrane systematic review and meta-analysis

Funding

not stated in the source

This is opioid withdrawal evidence, not stimulant comedown evidence.

PubMed search record

PubMed search run on 9 October 2026: clonidine[tiab] AND (amphetamine*[tiab] OR methamphetamine[tiab] OR cocaine[tiab] OR stimulant*[tiab] OR psychostimulant*[tiab]) AND (withdrawal[tiab] OR comedown[tiab] OR crash[tiab] OR abstinence[tiab]) AND humans[mh]. 28 records returned. A second search, clonidine[tiab] AND (wired[tiab] OR comedown[tiab] OR come-down[tiab]), returned 0 records.

The first search returned 28 records. None tested clonidine for stimulant withdrawal or comedown. They covered opioid withdrawal and detoxification trials, addiction pharmacology reviews, hypertension pharmacology, ADHD adherence and treatment debates, smoking cessation, anesthesia, and drug-induced hepatotoxicity papers, animal behavior papers, a cocaine-dependence case series in which clonidine was used only for opioid detoxification and the authors note there is no approved medication for cocaine withdrawal, a catatonia case, and the detoxification case report above. The second search returned 0 records. The stimulant comedown and wired-but-tired uses have no study behind them in these records.

Participants / model

Records returned, not a population

Treatment

Not applicable

Follow-up

Searches run on 9 October 2026

Study design

Literature search

Funding

not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists. The link opens the first search.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. ONYDA XR (clonidine hydrochloride) extended-release oral suspension, prescribing information, label version effective 11 April 2025. Set ID 4a15c850-9da5-4bdc-a34d-7f740a6149b7.

The label approves ONYDA XR for ADHD in children 6 and older, as monotherapy or as an add-on to CNS stimulant medication. Among patients who completed 5 weeks of a controlled fixed-dose pediatric monotherapy study of clonidine extended-release tablets cited in the label, somnolence was reported by 31% and 38% across the two fixed doses versus 4% on placebo.

Participants / model

Children 6 and older with ADHD

Treatment

ONYDA XR extended-release oral suspension

Follow-up

Label version effective 11 April 2025

Study design

FDA prescribing information

Funding

not stated in the source

The stimulant add-on approval is for pediatric ADHD, not for adult stimulant comedown.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Clonidine hydrochloride oral tablets (Alembic label), prescribing information, label version effective 30 September 2026. Set ID 88a8db46-0fc9-48cd-b7cc-ac9c9cdea100.

The label approves clonidine hydrochloride tablets for hypertension, alone or with other antihypertensives. Clonidine stimulates alpha-adrenoreceptors in the brain stem, reducing sympathetic outflow and lowering peripheral and renal vascular resistance, heart rate and blood pressure; the pulse slows in most patients without altering the normal hemodynamic response to exercise. It acutely stimulates growth hormone release without chronic elevation on long-term use. Oral bioavailability is 70% to 80%, peak levels come in about 1 to 3 hours, and elimination half-life is 12 to 16 hours, up to 41 hours in severe renal impairment. The most frequent adverse effects, which appear dose-related, are dry mouth (about 40 in 100 patients), drowsiness (about 33), dizziness (about 16), and constipation and sedation (about 10 each). Less frequent reports, not all causally linked, include agitation, anxiety, insomnia, nervousness, vivid dreams or nightmares, erectile dysfunction, loss of libido and gynecomastia. Clonidine may potentiate the CNS depression of alcohol, barbiturates or other sedating drugs, and patients are cautioned about driving. The label warns that sudden cessation has caused nervousness, agitation, headache and tremor with a rapid rise in blood pressure and raised plasma catecholamines, more likely after higher doses or with continued beta-blocker treatment, and that rare hypertensive encephalopathy, stroke and death have followed withdrawal. In overdose, hypertension may come first and be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness and reduced reflexes, with conduction defects, apnea, coma and seizures after large overdoses; as little as 0.1 mg has caused toxicity in children, and there is no specific antidote.

Participants / model

Adults with hypertension; label PK participants; patients taking clonidine and overdose cases

Treatment

Clonidine hydrochloride oral tablets (Alembic label)

Follow-up

Label version effective 30 September 2026

Study design

FDA prescribing information

Funding

not stated in the source

Label-level statements. The page does not reproduce label dosing, the label's schedule for stopping clonidine, or onset timing. The less frequent adverse reactions carry no rates and no established causality.

Randomized controlled trial

Hoehn-Saric R et al. Arch Gen Psychiatry. 1981;38(11):1278-82. PMID 7305609.

Clonidine was superior to placebo in patients who tolerated it, but 17% of patients became worse. Its main effect was fewer anxiety attacks and fewer psychic symptoms; somatic symptoms were least affected.

Participants / model

23 adults with generalized anxiety disorder (9) or panic disorder (14)

Treatment

Oral clonidine hydrochloride or placebo

Follow-up

4 weeks

Study design

Double-blind placebo-controlled crossover study

Funding

not stated in the source

Small study in patients with anxiety disorders, not stimulant users.

Human study

Carskadon MA et al. Sleep. 1989;12(4):338-44. PMID 2762688.

A single morning dose made subjects significantly sleepier than placebo when trying to stay awake, with a tendency to microsleeps, and during a 3-hour nap reduced REM and stage 1 sleep and increased stage 2 sleep. The authors describe profound sedation when awake and marked REM suppression when asleep.

Participants / model

18 healthy men aged 18 to 21

Treatment

Single oral clonidine 0.25 to 0.3 mg or placebo, in the morning

Follow-up

Single dose with a 3-hour nap

Study design

Placebo-controlled study with polysomnography

Funding

not stated in the source

Healthy young men given one dose; it describes sedation and sleep architecture, not stimulant comedown.

Randomized controlled trial

Gentili A et al. Eur J Clin Pharmacol. 1996;50(6):463-5. PMID 8858272.

A single dose of clonidine at night completely suppressed REM sleep in one subject and reduced it in the other seven.

Participants / model

8 healthy men

Treatment

Single oral clonidine 0.1 mg or placebo, at night

Follow-up

Single night

Study design

Double-blind randomized placebo-controlled crossover trial with nocturnal polysomnography

Funding

not stated in the source

Very small study in healthy men.

Randomized controlled trial

Kostis JB et al. Psychopharmacology (Berl). 1990;102(2):163-70. PMID 2274600.

Treatment had significant effects on overnight polysomnography: total sleep time and sleep maintenance fell, REM latency rose and REM percentage fell. The abstract does not attribute each change to a specific drug. Mood effects were seen with each drug, and nocturnal penile tumescence fell in both younger and older men.

Participants / model

Hypertensive men: 24 aged 31 to 59 in the three-drug crossover; 23 aged 60 to 78 in a separate propranolol-versus-placebo study

Treatment

Oral propranolol 20 to 80 mg twice daily, clonidine 0.1 to 0.3 mg twice daily, or placebo, 3 months each

Follow-up

3 months per treatment

Study design

Placebo-controlled crossover trial

Funding

not stated in the source

The sleep changes are not attributed to a specific drug in the abstract.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Clonidine hydrochloride oral tablets (Alembic label), prescribing information, label version effective 30 September 2026. Set ID 88a8db46-0fc9-48cd-b7cc-ac9c9cdea100.

The label approves clonidine hydrochloride tablets for hypertension, alone or with other antihypertensives. Clonidine stimulates alpha-adrenoreceptors in the brain stem, reducing sympathetic outflow and lowering peripheral and renal vascular resistance, heart rate and blood pressure; the pulse slows in most patients without altering the normal hemodynamic response to exercise. It acutely stimulates growth hormone release without chronic elevation on long-term use. Oral bioavailability is 70% to 80%, peak levels come in about 1 to 3 hours, and elimination half-life is 12 to 16 hours, up to 41 hours in severe renal impairment. The most frequent adverse effects, which appear dose-related, are dry mouth (about 40 in 100 patients), drowsiness (about 33), dizziness (about 16), and constipation and sedation (about 10 each). Less frequent reports, not all causally linked, include agitation, anxiety, insomnia, nervousness, vivid dreams or nightmares, erectile dysfunction, loss of libido and gynecomastia. Clonidine may potentiate the CNS depression of alcohol, barbiturates or other sedating drugs, and patients are cautioned about driving. The label warns that sudden cessation has caused nervousness, agitation, headache and tremor with a rapid rise in blood pressure and raised plasma catecholamines, more likely after higher doses or with continued beta-blocker treatment, and that rare hypertensive encephalopathy, stroke and death have followed withdrawal. In overdose, hypertension may come first and be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness and reduced reflexes, with conduction defects, apnea, coma and seizures after large overdoses; as little as 0.1 mg has caused toxicity in children, and there is no specific antidote.

Participants / model

Adults with hypertension; label PK participants; patients taking clonidine and overdose cases

Treatment

Clonidine hydrochloride oral tablets (Alembic label)

Follow-up

Label version effective 30 September 2026

Study design

FDA prescribing information

Funding

not stated in the source

Label-level statements. The page does not reproduce label dosing, the label's schedule for stopping clonidine, or onset timing. The less frequent adverse reactions carry no rates and no established causality.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Clonidine hydrochloride oral tablets (Alembic label), prescribing information, label version effective 30 September 2026. Set ID 88a8db46-0fc9-48cd-b7cc-ac9c9cdea100.

The label approves clonidine hydrochloride tablets for hypertension, alone or with other antihypertensives. Clonidine stimulates alpha-adrenoreceptors in the brain stem, reducing sympathetic outflow and lowering peripheral and renal vascular resistance, heart rate and blood pressure; the pulse slows in most patients without altering the normal hemodynamic response to exercise. It acutely stimulates growth hormone release without chronic elevation on long-term use. Oral bioavailability is 70% to 80%, peak levels come in about 1 to 3 hours, and elimination half-life is 12 to 16 hours, up to 41 hours in severe renal impairment. The most frequent adverse effects, which appear dose-related, are dry mouth (about 40 in 100 patients), drowsiness (about 33), dizziness (about 16), and constipation and sedation (about 10 each). Less frequent reports, not all causally linked, include agitation, anxiety, insomnia, nervousness, vivid dreams or nightmares, erectile dysfunction, loss of libido and gynecomastia. Clonidine may potentiate the CNS depression of alcohol, barbiturates or other sedating drugs, and patients are cautioned about driving. The label warns that sudden cessation has caused nervousness, agitation, headache and tremor with a rapid rise in blood pressure and raised plasma catecholamines, more likely after higher doses or with continued beta-blocker treatment, and that rare hypertensive encephalopathy, stroke and death have followed withdrawal. In overdose, hypertension may come first and be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness and reduced reflexes, with conduction defects, apnea, coma and seizures after large overdoses; as little as 0.1 mg has caused toxicity in children, and there is no specific antidote.

Participants / model

Adults with hypertension; label PK participants; patients taking clonidine and overdose cases

Treatment

Clonidine hydrochloride oral tablets (Alembic label)

Follow-up

Label version effective 30 September 2026

Study design

FDA prescribing information

Funding

not stated in the source

Label-level statements. The page does not reproduce label dosing, the label's schedule for stopping clonidine, or onset timing. The less frequent adverse reactions carry no rates and no established causality.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. ONYDA XR (clonidine hydrochloride) extended-release oral suspension, prescribing information, label version effective 11 April 2025. Set ID 4a15c850-9da5-4bdc-a34d-7f740a6149b7.

The label approves ONYDA XR for ADHD in children 6 and older, as monotherapy or as an add-on to CNS stimulant medication. Among patients who completed 5 weeks of a controlled fixed-dose pediatric monotherapy study of clonidine extended-release tablets cited in the label, somnolence was reported by 31% and 38% across the two fixed doses versus 4% on placebo.

Participants / model

Children 6 and older with ADHD

Treatment

ONYDA XR extended-release oral suspension

Follow-up

Label version effective 11 April 2025

Study design

FDA prescribing information

Funding

not stated in the source

The stimulant add-on approval is for pediatric ADHD, not for adult stimulant comedown.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Clonidine hydrochloride oral tablets (Alembic label), prescribing information, label version effective 30 September 2026. Set ID 88a8db46-0fc9-48cd-b7cc-ac9c9cdea100.

The label approves clonidine hydrochloride tablets for hypertension, alone or with other antihypertensives. Clonidine stimulates alpha-adrenoreceptors in the brain stem, reducing sympathetic outflow and lowering peripheral and renal vascular resistance, heart rate and blood pressure; the pulse slows in most patients without altering the normal hemodynamic response to exercise. It acutely stimulates growth hormone release without chronic elevation on long-term use. Oral bioavailability is 70% to 80%, peak levels come in about 1 to 3 hours, and elimination half-life is 12 to 16 hours, up to 41 hours in severe renal impairment. The most frequent adverse effects, which appear dose-related, are dry mouth (about 40 in 100 patients), drowsiness (about 33), dizziness (about 16), and constipation and sedation (about 10 each). Less frequent reports, not all causally linked, include agitation, anxiety, insomnia, nervousness, vivid dreams or nightmares, erectile dysfunction, loss of libido and gynecomastia. Clonidine may potentiate the CNS depression of alcohol, barbiturates or other sedating drugs, and patients are cautioned about driving. The label warns that sudden cessation has caused nervousness, agitation, headache and tremor with a rapid rise in blood pressure and raised plasma catecholamines, more likely after higher doses or with continued beta-blocker treatment, and that rare hypertensive encephalopathy, stroke and death have followed withdrawal. In overdose, hypertension may come first and be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness and reduced reflexes, with conduction defects, apnea, coma and seizures after large overdoses; as little as 0.1 mg has caused toxicity in children, and there is no specific antidote.

Participants / model

Adults with hypertension; label PK participants; patients taking clonidine and overdose cases

Treatment

Clonidine hydrochloride oral tablets (Alembic label)

Follow-up

Label version effective 30 September 2026

Study design

FDA prescribing information

Funding

not stated in the source

Label-level statements. The page does not reproduce label dosing, the label's schedule for stopping clonidine, or onset timing. The less frequent adverse reactions carry no rates and no established causality.

Case report

Hughes PL et al. Mayo Clin Proc. 1985;60(1):47-9. PMID 2856945.

Clonidine masked the clinical signs of sedative withdrawal during detoxification of a patient dependent on sedatives, opiates and amphetamines. The authors urge caution with clonidine in mixed-drug detoxification.

Participants / model

One patient with sedative, opiate and amphetamine dependence

Treatment

Clonidine during detoxification

Follow-up

Single case

Study design

Case report

Funding

not stated in the source

A single case; it flags a possible harm and does not measure how often it happens.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Clonidine hydrochloride oral tablets (Alembic label), prescribing information, label version effective 30 September 2026. Set ID 88a8db46-0fc9-48cd-b7cc-ac9c9cdea100.

The label approves clonidine hydrochloride tablets for hypertension, alone or with other antihypertensives. Clonidine stimulates alpha-adrenoreceptors in the brain stem, reducing sympathetic outflow and lowering peripheral and renal vascular resistance, heart rate and blood pressure; the pulse slows in most patients without altering the normal hemodynamic response to exercise. It acutely stimulates growth hormone release without chronic elevation on long-term use. Oral bioavailability is 70% to 80%, peak levels come in about 1 to 3 hours, and elimination half-life is 12 to 16 hours, up to 41 hours in severe renal impairment. The most frequent adverse effects, which appear dose-related, are dry mouth (about 40 in 100 patients), drowsiness (about 33), dizziness (about 16), and constipation and sedation (about 10 each). Less frequent reports, not all causally linked, include agitation, anxiety, insomnia, nervousness, vivid dreams or nightmares, erectile dysfunction, loss of libido and gynecomastia. Clonidine may potentiate the CNS depression of alcohol, barbiturates or other sedating drugs, and patients are cautioned about driving. The label warns that sudden cessation has caused nervousness, agitation, headache and tremor with a rapid rise in blood pressure and raised plasma catecholamines, more likely after higher doses or with continued beta-blocker treatment, and that rare hypertensive encephalopathy, stroke and death have followed withdrawal. In overdose, hypertension may come first and be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness and reduced reflexes, with conduction defects, apnea, coma and seizures after large overdoses; as little as 0.1 mg has caused toxicity in children, and there is no specific antidote.

Participants / model

Adults with hypertension; label PK participants; patients taking clonidine and overdose cases

Treatment

Clonidine hydrochloride oral tablets (Alembic label)

Follow-up

Label version effective 30 September 2026

Study design

FDA prescribing information

Funding

not stated in the source

Label-level statements. The page does not reproduce label dosing, the label's schedule for stopping clonidine, or onset timing. The less frequent adverse reactions carry no rates and no established causality.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. ONYDA XR (clonidine hydrochloride) extended-release oral suspension, prescribing information, label version effective 11 April 2025. Set ID 4a15c850-9da5-4bdc-a34d-7f740a6149b7.

The label approves ONYDA XR for ADHD in children 6 and older, as monotherapy or as an add-on to CNS stimulant medication. Among patients who completed 5 weeks of a controlled fixed-dose pediatric monotherapy study of clonidine extended-release tablets cited in the label, somnolence was reported by 31% and 38% across the two fixed doses versus 4% on placebo.

Participants / model

Children 6 and older with ADHD

Treatment

ONYDA XR extended-release oral suspension

Follow-up

Label version effective 11 April 2025

Study design

FDA prescribing information

Funding

not stated in the source

The stimulant add-on approval is for pediatric ADHD, not for adult stimulant comedown.

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application records for clonidine, including CATAPRES-TTS (NDA 018891), DURACLON (NDA 020615), ONYDA XR (NDA 217645) and generic clonidine hydrochloride (ANDA 070923). Dates read from the openFDA Drugs@FDA records.

openFDA Drugs@FDA records include CATAPRES-TTS (transdermal system), NDA 018891, approved 10 October 1984; DURACLON, NDA 020615, approved 2 October 1996; ONYDA XR, NDA 217645, approved 24 May 2024; and generic clonidine hydrochloride, the earliest among the records returned being ANDA 070923 on 4 September 1987. The original CATAPRES tablet application was not among the records returned.

Participants / model

Not a clinical population

Treatment

Drug applications

Follow-up

Approvals from 1984 to 2024 in the records returned

Study design

FDA application records

Funding

not stated in the source

The original CATAPRES tablet application was not returned, so the first U.S. approval date for tablets is not established. The generic date is the earliest among the records returned.

Systematic review and meta-analysis

Gowing L et al. Cochrane Database Syst Rev. 2016;2016(5):CD002024. PMID 27140827.

There was moderate-quality evidence that alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) reduced the likelihood of severe opioid withdrawal versus placebo (RR 0.32, 95% CI 0.18 to 0.57; 3 studies, 148 participants) and raised treatment completion (RR 1.95, 95% CI 1.34 to 2.84). Compared with tapering methadone, efficacy did not differ significantly, but hypotensive or other adverse effects were more likely (RR 1.92, 95% CI 1.19 to 3.10). Lofexidine had a better safety profile than clonidine.

Participants / model

People dependent on heroin or methadone; 26 randomized trials with 1,728 participants

Treatment

Alpha2-adrenergic agonists, mostly oral

Follow-up

Pooled randomized trials

Study design

Cochrane systematic review and meta-analysis

Funding

not stated in the source

This is opioid withdrawal evidence, not stimulant comedown evidence.

Randomized controlled trial

Hoehn-Saric R et al. Arch Gen Psychiatry. 1981;38(11):1278-82. PMID 7305609.

Clonidine was superior to placebo in patients who tolerated it, but 17% of patients became worse. Its main effect was fewer anxiety attacks and fewer psychic symptoms; somatic symptoms were least affected.

Participants / model

23 adults with generalized anxiety disorder (9) or panic disorder (14)

Treatment

Oral clonidine hydrochloride or placebo

Follow-up

4 weeks

Study design

Double-blind placebo-controlled crossover study

Funding

not stated in the source

Small study in patients with anxiety disorders, not stimulant users.

Human study

Carskadon MA et al. Sleep. 1989;12(4):338-44. PMID 2762688.

A single morning dose made subjects significantly sleepier than placebo when trying to stay awake, with a tendency to microsleeps, and during a 3-hour nap reduced REM and stage 1 sleep and increased stage 2 sleep. The authors describe profound sedation when awake and marked REM suppression when asleep.

Participants / model

18 healthy men aged 18 to 21

Treatment

Single oral clonidine 0.25 to 0.3 mg or placebo, in the morning

Follow-up

Single dose with a 3-hour nap

Study design

Placebo-controlled study with polysomnography

Funding

not stated in the source

Healthy young men given one dose; it describes sedation and sleep architecture, not stimulant comedown.

PubMed search record

PubMed search run on 9 October 2026: clonidine[tiab] AND (amphetamine*[tiab] OR methamphetamine[tiab] OR cocaine[tiab] OR stimulant*[tiab] OR psychostimulant*[tiab]) AND (withdrawal[tiab] OR comedown[tiab] OR crash[tiab] OR abstinence[tiab]) AND humans[mh]. 28 records returned. A second search, clonidine[tiab] AND (wired[tiab] OR comedown[tiab] OR come-down[tiab]), returned 0 records.

The first search returned 28 records. None tested clonidine for stimulant withdrawal or comedown. They covered opioid withdrawal and detoxification trials, addiction pharmacology reviews, hypertension pharmacology, ADHD adherence and treatment debates, smoking cessation, anesthesia, and drug-induced hepatotoxicity papers, animal behavior papers, a cocaine-dependence case series in which clonidine was used only for opioid detoxification and the authors note there is no approved medication for cocaine withdrawal, a catatonia case, and the detoxification case report above. The second search returned 0 records. The stimulant comedown and wired-but-tired uses have no study behind them in these records.

Participants / model

Records returned, not a population

Treatment

Not applicable

Follow-up

Searches run on 9 October 2026

Study design

Literature search

Funding

not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists. The link opens the first search.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. Clonidine hydrochloride oral tablets (Alembic label), prescribing information, label version effective 30 September 2026. Set ID 88a8db46-0fc9-48cd-b7cc-ac9c9cdea100.

The label approves clonidine hydrochloride tablets for hypertension, alone or with other antihypertensives. Clonidine stimulates alpha-adrenoreceptors in the brain stem, reducing sympathetic outflow and lowering peripheral and renal vascular resistance, heart rate and blood pressure; the pulse slows in most patients without altering the normal hemodynamic response to exercise. It acutely stimulates growth hormone release without chronic elevation on long-term use. Oral bioavailability is 70% to 80%, peak levels come in about 1 to 3 hours, and elimination half-life is 12 to 16 hours, up to 41 hours in severe renal impairment. The most frequent adverse effects, which appear dose-related, are dry mouth (about 40 in 100 patients), drowsiness (about 33), dizziness (about 16), and constipation and sedation (about 10 each). Less frequent reports, not all causally linked, include agitation, anxiety, insomnia, nervousness, vivid dreams or nightmares, erectile dysfunction, loss of libido and gynecomastia. Clonidine may potentiate the CNS depression of alcohol, barbiturates or other sedating drugs, and patients are cautioned about driving. The label warns that sudden cessation has caused nervousness, agitation, headache and tremor with a rapid rise in blood pressure and raised plasma catecholamines, more likely after higher doses or with continued beta-blocker treatment, and that rare hypertensive encephalopathy, stroke and death have followed withdrawal. In overdose, hypertension may come first and be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness and reduced reflexes, with conduction defects, apnea, coma and seizures after large overdoses; as little as 0.1 mg has caused toxicity in children, and there is no specific antidote.

Participants / model

Adults with hypertension; label PK participants; patients taking clonidine and overdose cases

Treatment

Clonidine hydrochloride oral tablets (Alembic label)

Follow-up

Label version effective 30 September 2026

Study design

FDA prescribing information

Funding

not stated in the source

Label-level statements. The page does not reproduce label dosing, the label's schedule for stopping clonidine, or onset timing. The less frequent adverse reactions carry no rates and no established causality.

FDA prescribing information

DailyMed, U.S. National Library of Medicine. ONYDA XR (clonidine hydrochloride) extended-release oral suspension, prescribing information, label version effective 11 April 2025. Set ID 4a15c850-9da5-4bdc-a34d-7f740a6149b7.

The label approves ONYDA XR for ADHD in children 6 and older, as monotherapy or as an add-on to CNS stimulant medication. Among patients who completed 5 weeks of a controlled fixed-dose pediatric monotherapy study of clonidine extended-release tablets cited in the label, somnolence was reported by 31% and 38% across the two fixed doses versus 4% on placebo.

Participants / model

Children 6 and older with ADHD

Treatment

ONYDA XR extended-release oral suspension

Follow-up

Label version effective 11 April 2025

Study design

FDA prescribing information

Funding

not stated in the source

The stimulant add-on approval is for pediatric ADHD, not for adult stimulant comedown.

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application records for clonidine, including CATAPRES-TTS (NDA 018891), DURACLON (NDA 020615), ONYDA XR (NDA 217645) and generic clonidine hydrochloride (ANDA 070923). Dates read from the openFDA Drugs@FDA records.

openFDA Drugs@FDA records include CATAPRES-TTS (transdermal system), NDA 018891, approved 10 October 1984; DURACLON, NDA 020615, approved 2 October 1996; ONYDA XR, NDA 217645, approved 24 May 2024; and generic clonidine hydrochloride, the earliest among the records returned being ANDA 070923 on 4 September 1987. The original CATAPRES tablet application was not among the records returned.

Participants / model

Not a clinical population

Treatment

Drug applications

Follow-up

Approvals from 1984 to 2024 in the records returned

Study design

FDA application records

Funding

not stated in the source

The original CATAPRES tablet application was not returned, so the first U.S. approval date for tablets is not established. The generic date is the earliest among the records returned.

Systematic review and meta-analysis

Gowing L et al. Cochrane Database Syst Rev. 2016;2016(5):CD002024. PMID 27140827.

There was moderate-quality evidence that alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) reduced the likelihood of severe opioid withdrawal versus placebo (RR 0.32, 95% CI 0.18 to 0.57; 3 studies, 148 participants) and raised treatment completion (RR 1.95, 95% CI 1.34 to 2.84). Compared with tapering methadone, efficacy did not differ significantly, but hypotensive or other adverse effects were more likely (RR 1.92, 95% CI 1.19 to 3.10). Lofexidine had a better safety profile than clonidine.

Participants / model

People dependent on heroin or methadone; 26 randomized trials with 1,728 participants

Treatment

Alpha2-adrenergic agonists, mostly oral

Follow-up

Pooled randomized trials

Study design

Cochrane systematic review and meta-analysis

Funding

not stated in the source

This is opioid withdrawal evidence, not stimulant comedown evidence.

Randomized controlled trial

Hoehn-Saric R et al. Arch Gen Psychiatry. 1981;38(11):1278-82. PMID 7305609.

Clonidine was superior to placebo in patients who tolerated it, but 17% of patients became worse. Its main effect was fewer anxiety attacks and fewer psychic symptoms; somatic symptoms were least affected.

Participants / model

23 adults with generalized anxiety disorder (9) or panic disorder (14)

Treatment

Oral clonidine hydrochloride or placebo

Follow-up

4 weeks

Study design

Double-blind placebo-controlled crossover study

Funding

not stated in the source

Small study in patients with anxiety disorders, not stimulant users.

Human study

Carskadon MA et al. Sleep. 1989;12(4):338-44. PMID 2762688.

A single morning dose made subjects significantly sleepier than placebo when trying to stay awake, with a tendency to microsleeps, and during a 3-hour nap reduced REM and stage 1 sleep and increased stage 2 sleep. The authors describe profound sedation when awake and marked REM suppression when asleep.

Participants / model

18 healthy men aged 18 to 21

Treatment

Single oral clonidine 0.25 to 0.3 mg or placebo, in the morning

Follow-up

Single dose with a 3-hour nap

Study design

Placebo-controlled study with polysomnography

Funding

not stated in the source

Healthy young men given one dose; it describes sedation and sleep architecture, not stimulant comedown.

Randomized controlled trial

Gentili A et al. Eur J Clin Pharmacol. 1996;50(6):463-5. PMID 8858272.

A single dose of clonidine at night completely suppressed REM sleep in one subject and reduced it in the other seven.

Participants / model

8 healthy men

Treatment

Single oral clonidine 0.1 mg or placebo, at night

Follow-up

Single night

Study design

Double-blind randomized placebo-controlled crossover trial with nocturnal polysomnography

Funding

not stated in the source

Very small study in healthy men.

Randomized controlled trial

Kostis JB et al. Psychopharmacology (Berl). 1990;102(2):163-70. PMID 2274600.

Treatment had significant effects on overnight polysomnography: total sleep time and sleep maintenance fell, REM latency rose and REM percentage fell. The abstract does not attribute each change to a specific drug. Mood effects were seen with each drug, and nocturnal penile tumescence fell in both younger and older men.

Participants / model

Hypertensive men: 24 aged 31 to 59 in the three-drug crossover; 23 aged 60 to 78 in a separate propranolol-versus-placebo study

Treatment

Oral propranolol 20 to 80 mg twice daily, clonidine 0.1 to 0.3 mg twice daily, or placebo, 3 months each

Follow-up

3 months per treatment

Study design

Placebo-controlled crossover trial

Funding

not stated in the source

The sleep changes are not attributed to a specific drug in the abstract.

Case report

Hughes PL et al. Mayo Clin Proc. 1985;60(1):47-9. PMID 2856945.

Clonidine masked the clinical signs of sedative withdrawal during detoxification of a patient dependent on sedatives, opiates and amphetamines. The authors urge caution with clonidine in mixed-drug detoxification.

Participants / model

One patient with sedative, opiate and amphetamine dependence

Treatment

Clonidine during detoxification

Follow-up

Single case

Study design

Case report

Funding

not stated in the source

A single case; it flags a possible harm and does not measure how often it happens.

PubMed search record

PubMed search run on 9 October 2026: clonidine[tiab] AND (amphetamine*[tiab] OR methamphetamine[tiab] OR cocaine[tiab] OR stimulant*[tiab] OR psychostimulant*[tiab]) AND (withdrawal[tiab] OR comedown[tiab] OR crash[tiab] OR abstinence[tiab]) AND humans[mh]. 28 records returned. A second search, clonidine[tiab] AND (wired[tiab] OR comedown[tiab] OR come-down[tiab]), returned 0 records.

The first search returned 28 records. None tested clonidine for stimulant withdrawal or comedown. They covered opioid withdrawal and detoxification trials, addiction pharmacology reviews, hypertension pharmacology, ADHD adherence and treatment debates, smoking cessation, anesthesia, and drug-induced hepatotoxicity papers, animal behavior papers, a cocaine-dependence case series in which clonidine was used only for opioid detoxification and the authors note there is no approved medication for cocaine withdrawal, a catatonia case, and the detoxification case report above. The second search returned 0 records. The stimulant comedown and wired-but-tired uses have no study behind them in these records.

Participants / model

Records returned, not a population

Treatment

Not applicable

Follow-up

Searches run on 9 October 2026

Study design

Literature search

Funding

not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists. The link opens the first search.

Chemical identity record

National Library of Medicine. PubChem compound records CID 2803 (clonidine) and CID 20179 (clonidine hydrochloride).

Clonidine free base: C9H9Cl2N3, 230.09 g/mol, CAS 4205-90-7. Clonidine hydrochloride, the salt in US tablets and ONYDA XR: CID 20179, C9H10Cl3N3, 266.6 g/mol, CAS 4205-91-8; the tablet label gives 266.56 and states the tablet strength as the hydrochloride, with a free-base equivalent.

Participants / model

Chemical identity, not a clinical population

Treatment

Defined molecule and salt

Follow-up

Not applicable

Study design

NLM chemical record

Funding

not stated in the source

Identity record only; it says nothing about efficacy or safety.