What is the evidence for using clonidine (clonidine) in the treatment of post-traumatic stress disorder (PTSD)?

Clonidine for PTSD Treatment

Clonidine may be considered for treatment of PTSD-associated nightmares, though it has limited high-quality evidence supporting its use. 1

Mechanism of Action and Rationale

Clonidine is an α2-adrenergic receptor agonist that suppresses sympathetic nervous system outflow throughout the brain. Its use in PTSD is based on the following pathophysiological rationale:

• Elevated norepinephrine levels in cerebrospinal fluid and urine are found in patients with PTSD 1
• CSF norepinephrine concentration correlates with PTSD symptom severity 1
• Consistently elevated CNS noradrenergic activity may contribute to disruption of normal REM sleep and arousal symptoms 1
• Clonidine alters REM/NREM sleep in a dose-dependent manner 1

Evidence for Effectiveness

The evidence for clonidine in PTSD is primarily focused on nightmare reduction:

• Two Level 4 case series demonstrated efficacy of 0.2 to 0.6 mg clonidine (in divided doses) to reduce nightmares in 11/13 Cambodian refugees 1
• A one-year prospective pilot study of combination clonidine-imipramine therapy (average clonidine dose 0.2 mg/day) showed decreased nightmare frequency in 7 of 9 refugees with PTSD 1
• A 2-week pilot study of 4 female civilians with severe PTSD showed that clonidine (0.1 mg twice daily) reduced nightmare frequency and improved sleep quality 1
• A recent systematic review (2024) found that many studies reported improved sleep quality, nightmare reduction, and improvement of PTSD symptoms with clonidine, though the quality of evidence was rated from very low to low 2

Dosing and Administration

• Typical dosage range: 0.1-0.6 mg/day 1
• Often administered in divided doses 1
• Median dose across studies: 0.15 mg/day (range: 0.1-0.5 mg/day) 2
• Low-dose clonidine increases REM sleep and decreases non-REM sleep, while medium-dose clonidine decreases REM sleep and increases N2 sleep 1

Side Effects and Monitoring

• Monitor for orthostatic hypotension, which is the most commonly reported side effect 1
• Blood pressure should be monitored, especially when increasing doses 1
• Generally well-tolerated in studies with few reported adverse effects 1

Comparative Effectiveness

• Prazosin has stronger evidence (Level A recommendation) for PTSD-associated nightmares compared to clonidine (Level C recommendation) 1
• Meta-analysis of two studies comparing clonidine to alpha-blockers (prazosin or terazosin) showed no significant difference, potentially suggesting non-inferiority 2
• Clonidine shares the therapeutic rationale and potential for postural hypotension with prazosin but has not been investigated with the same rigor 1

Clinical Applications

• Despite limited high-quality evidence, clonidine has been described as "a mainstay of PTSD treatment for severely traumatized refugees for over 20 years" 1
• May be particularly useful for patients with prominent hyperarousal symptoms 3
• Can improve subjective sleep latency and restorative qualities of sleep 3
• Case reports suggest rapid effectiveness in controlling nightmares when restarted after discontinuation 4

Important Caveats

• No randomized placebo-controlled trials of clonidine for nightmares or other aspects of PTSD have been reported 1
• The paucity of hard data relegates clonidine to a lower level recommendation compared to prazosin 1
• Future research, including well-powered RCTs, is needed to better establish efficacy and identify the most suitable treatment groups 2
• Consider clonidine particularly in patients with comorbid conditions where its other properties may be beneficial (e.g., hypertension, opioid withdrawal symptoms) 1, 5