What is the most evidence-based supplement for anxiety and restlessness?

Most Evidence-Based Supplement for Anxiety and Restlessness

Ashwagandha (Withania somnifera) root extract is the most evidence-based supplement for anxiety and restlessness, with multiple high-quality randomized controlled trials demonstrating significant reductions in both anxiety and stress symptoms. 1

Evidence Supporting Ashwagandha

Meta-Analysis Findings

• A 2022 systematic review and meta-analysis of 12 randomized controlled trials (n=1,002 participants) demonstrated that Ashwagandha supplementation significantly reduced anxiety (SMD: -1.55,95% CI: -2.37, -0.74; p=0.005) and stress levels (SMD: -1.75; 95% CI: -2.29, -1.22; p=0.005) compared to placebo 1
• The dose-response analysis indicated favorable effects on anxiety up to 12,000 mg/day and optimal stress reduction at 300-600 mg/day 1

Specific Clinical Trial Results

• A 2023 randomized, double-blind, placebo-controlled trial (n=54) using 500 mg Ashwagandha root extract (standardized to 2.5% withanolides, providing 12.5 mg withanolides/day) for 60 days showed significant improvements in Perceived Stress Scale (PSS), Generalized Anxiety Disorder-7 (GAD-7), and quality of life scores 2

• This same study demonstrated objective improvements in multitasking, concentration, and decision-making time on neuropsychological testing, along with reduced morning salivary cortisol and increased urinary serotonin 2

• A 2019 dose-ranging study (n=58) found significant PSS score reductions with both 250 mg/day (P<0.05) and 600 mg/day (P<0.001) of Ashwagandha extract, with corresponding reductions in serum cortisol levels 3

• A 2025 study using a new formulation (Zenroot™, 125 mg containing 1.5% withanolides) for 84 days showed significant improvements in PSS, Beck Anxiety Inventory (BAI), and Pittsburgh Sleep Quality Index (PSQI) scores, along with objective improvements in skin conductance response and heart rate variability 4

Recommended Dosing Protocol

Start with 300-600 mg/day of high-concentration full-spectrum Ashwagandha root extract standardized to contain at least 2.5% withanolides, divided into two doses (morning and evening). 5, 2

• The extract should be taken consistently for a minimum of 60 days to achieve maximal benefit 5, 2
• Lower doses (125-250 mg/day) may be effective for mild symptoms, while moderate to severe anxiety may require 500-600 mg/day 3, 4

Safety Profile

Ashwagandha demonstrates excellent tolerability across multiple trials:

• Adverse effects were mild and comparable to placebo groups 5
• No serious adverse events were reported in any of the reviewed trials 5, 3, 2
• Biochemical and hematological parameters remained within normal ranges throughout treatment periods 2

Perioperative Considerations

For patients undergoing surgery, Ashwagandha should be continued perioperatively as there is no clinical evidence suggesting it potentiates anesthetic effects or causes perioperative complications. 6

Alternative Supplements with Weaker Evidence

While Ashwagandha has the strongest evidence base, other supplements have limited support:

Lavender

• May be continued perioperatively and has shown efficacy for anxiety treatment, including preoperatively 6
• However, the evidence base is less robust than for Ashwagandha

Passionflower

• Demonstrates anxiolytic effects with a good safety profile in perioperative settings 6
• Can be continued through surgical procedures 6

Melatonin

• A Cochrane review concluded preoperative melatonin reduces anxiety compared to placebo and may be as effective as midazolam 6
• However, its primary indication is sleep regulation rather than daytime anxiety management

Supplements with Insufficient Evidence

The Society for Integrative Oncology-ASCO guideline explicitly states there is inconclusive evidence for melatonin and other natural products/supplements to improve anxiety symptoms, regardless of when in the course of care they are provided. 6

Critical Warnings

Avoid these supplements for anxiety:

• Lemon balm: Hold 2 weeks before surgery due to potential additive CNS depression with sedatives 6
• Kava: Not mentioned in recent guidelines but historically associated with hepatotoxicity
• St. John's Wort: Not recommended due to extensive drug interactions (though not specifically mentioned in provided evidence)

Mechanism of Action

Ashwagandha's anxiolytic effects are mediated through:

• Reduction in serum cortisol levels (demonstrated reduction P=0.0006 vs placebo) 5
• Increased serotonin production (shown via increased urinary serotonin) 2
• Modulation of the hypothalamic-pituitary-adrenal (HPA) axis 5
• Enhancement of GABAergic neurotransmission (based on adaptogenic properties) 5

Integration with Conventional Treatment

Ashwagandha should be viewed as a complementary intervention, not a replacement for evidence-based psychological therapies or pharmacotherapy when clinically indicated. 6

• For moderate to severe anxiety, cognitive behavioral therapy (CBT) remains the gold standard psychological intervention 7, 8
• SSRIs (escitalopram, sertraline) or SNRIs (venlafaxine, duloxetine) are first-line pharmacological options when medication is warranted 7, 8
• Ashwagandha can be safely combined with these treatments, though patients should inform their healthcare providers of all supplements being taken 2

Common Pitfalls to Avoid

• Do not expect immediate results: Full therapeutic benefit requires 8-12 weeks of consistent supplementation 5, 2
• Ensure proper standardization: Use only extracts standardized to withanolide content (minimum 2.5%) to ensure consistent dosing 2
• Avoid underdosing: Doses below 250 mg/day may be subtherapeutic for moderate anxiety 3
• Do not discontinue abruptly if combined with SSRIs: While Ashwagandha itself has no discontinuation syndrome, patients on combination therapy should taper SSRIs appropriately 7