Chronic stress is not merely a psychological burden; it is a physiological driver of systemic decay, manifesting as HPA axis dysregulation, sleep fragmentation, and persistent fatigue Impact of stress on health (2021). While individual medicinal mushrooms like Reishi or Lion’s Mane have long been staples of the “biohacker” cabinet, high-quality human clinical data on synergistic blends has remained sparse. A new randomized, double-blind, placebo-controlled trial published in Brain and Behavior Hisamuddin et al., 2026 (DOI: 10.1002/brb3.71193) by researchers from Nexus Wise and various Malaysian universities, evaluates a proprietary five-mushroom extract (Restake) designed to act as a comprehensive adaptogen.
The study followed 50 adults over 12 weeks, measuring the impact of a 500 mg/day dose of a blend containing Lion’s Mane, Cordyceps, Reishi, Shiitake, and Maitake. The results demonstrate significant physiological shifts: a 5.5% reduction in serum cortisol and an 8.1% drop in ACTH, indicating a direct “dampening” effect on the body’s primary stress pathways. Beyond hormonal markers, the supplement group showed a 33.5% improvement in anxiety (HAM-A) and a notable 11.1% improvement in overall sleep quality (PSQI).
The “Big Idea” here is the restoration of the HPA axis set-point. By leveraging a high concentration of fungal β-1,3/1,6-glucans (>30%), the blend appears to address the “Inflammaging” component of fatigue. It significantly reduced C-reactive protein (CRP) levels, suggesting that the perceived “burnout” of the participants was at least partially driven by low-grade systemic inflammation Inflammation and fatigue (2022). While the sample size is modest, the convergence of subjective psychometric scores and objective endocrine biomarkers provides a compelling case for fungal poly-pharmacy in managing modern stress phenotypes.
Source:
- Open Access Paper: Adaptogenic Effects of Mushroom Blend Supplementationon Stress, Fatigue, and Sleep: A Randomised, Double-Blind,and Placebo-Controlled Trial
- Impact Evaluation The impact score (CiteScore 2024) for Brain and Behavior is 4.8, evaluated against a typical high-end range of 0–60+ for top general science or clinical journals; therefore, this is a Medium impact journal.
Part 2: Biohacker Analysis
Study Design Specifications
- Type: Human Randomized, Double-Blind, Placebo-Controlled Trial (Phase II-style).
- Subjects: 50 healthy adults (40% male, 60% female), aged 22–55.
- Control Group: n=25 (Placebo: beta-cyclodextrin and arabic gum).
- Treatment Group: n=25 (Restake: 500 mg mushroom blend extract).
- Duration: 12 weeks with data points at Baseline, 6 weeks, and 12 weeks.
Mechanistic Deep Dive
The study highlights three primary longevity-relevant pathways:
- HPA Axis Modulation: The reduction in ACTH and Cortisol suggests the blend acts as a “molecular thermostat,” preventing the neurotoxic effects of chronic glucocorticoid exposure Cortisol and brain aging (2018).
- Anti-Inflammatory (NF-κB Inhibition): The significant reduction in CRP (-6.3% vs. +4.9% in placebo) is likely mediated by β-glucan interaction with Dectin-1 receptors, which modulates innate immune signaling and reduces pro-inflammatory cytokine output β-glucans and immune modulation (2005).
- Neuroplasticity: The researchers hypothesize that Hericium erinaceus (Lion’s Mane) components (erinacines/hericenones) stimulate Nerve Growth Factor (NGF) and BDNF, providing a structural basis for the observed 16.8% reduction in depressive symptoms Lion’s Mane and BDNF (2019).
Novelty
This is the first human trial to validate a five-fold mushroom synergistic extract specifically for the stress-fatigue-sleep triad. It identifies Norepinephrine (NE) as a fatigue biomarker that increased (+10.4%) in the treatment group, suggesting an improvement in sympathetic “tone” or alertness without the concomitant rise in cortisol—a rare “relaxed-alert” physiological state.
Critical Limitations
- Dosing Ambiguity: The “proprietary blend” ratio is not fully disclosed in the main text, making it difficult to determine which specific mushroom is doing the heavy lifting.
- Sample Size: N=50 is sufficient for statistical significance but lacks the power to identify rare side effects or genotype-specific responses.
- Morning Melatonin: Melatonin was measured in the morning. This is a significant methodological flaw; peak melatonin occurs at night. The observed “trend” toward increased melatonin is low-confidence data Melatonin rhythm (2014).
- Data Gaps: Missing data on gut microbiome changes, despite the paper suggesting gut-modulation as a mechanism for sleep improvement.
Part 3: Claims Verification
| Claim | Evidence Level | Verification/Search Result |
|---|---|---|
| Mushroom β-glucans reduce cortisol/stress | Level B | Supported by RCTs in athletes and cancer patients Richter et al. (2015). |
| Lion’s Mane improves anxiety/depression | Level B | Validated in smaller RCTs Docherty et al. (2023). |
| Reishi improves sleep quality | Level D/B | Strong animal data; human data is mostly “Level B” but mixed quality Li et al. (2024). |
| β-glucans reduce CRP (inflammation) | Level A | Meta-analyses confirm fiber/glucan impact on CRP Meta-analysis (2025). |
| Mushroom extracts increase morning Melatonin | Level E | Translational Gap. Morning sampling is an unreliable proxy for pineal output. |
Safety Check: Mushroom extracts are generally GRAS (Generally Recognized as Safe). However, Cordyceps may have mild anti-platelet effects. Contraindications: Potential interaction with immunosuppressants (due to immune-stimulating glucans). [Safety Data: Low Toxicity Profile].