Cognitive decline / neurodegen / TBI
Neuronal/synaptic loss with strong bioenergetic component.
Decision support, not prescription. You decide.
Candidate agents
9 agents · tap to expand▶ExenatideLeadEmergingA GLP-1 receptor agonist that was a serious, well-studied disease-modifying candidate for Parkinson's disease, but its definitive phase 3 trial was negative, so it is not a supported neuroprotective therapy.expand
A GLP-1 receptor agonist that was a serious, well-studied disease-modifying candidate for Parkinson's disease, but its definitive phase 3 trial was negative, so it is not a supported neuroprotective therapy.
▸Full clinical story
Neuronal GLP-1 signaling improves insulin signaling, mitochondrial/bioenergetic function, and dampens neuroinflammation, directly engaging the bioenergetic lever thought to drive dopaminergic and synaptic loss. Preclinical Parkinson's models showed neuroprotection and neurotrophic effects, which motivated the clinical program.
A single-centre phase 2 RCT (n=62) reported that weekly exenatide improved off-medication MDS-UPDRS III motor scores versus placebo, an effect that persisted after a 12-week washout. However, the definitive multicentre phase 3 Exenatide-PD3 trial (n=194, 96 weeks) found NO difference from placebo on off-medication motor progression (adjusted effect 0.92, 95% CI -1.56 to 3.39, p=0.47). Graded none: despite a plausible mechanism and the early phase 2 signal, the confirmatory RCT showed no disease-modifying benefit.
Anecdotal community signal only: some Parkinson's patients and biohackers use exenatide or semaglutide off-label hoping for neuroprotection, largely driven by the 2017 phase 2 result and GLP-1 diabetes-cohort epidemiology. Reports are subjective and heavily confounded by metabolic effects and weight loss; this is not evidence of benefit.
Trials used extended-release exenatide 2 mg subcutaneously once weekly. This is trial context, not a validated neuroprotective protocol.
Nausea and GI intolerance, and clinically meaningful weight and muscle loss, which is a real concern in frail, older, or underweight Parkinson's patients; pancreatitis risk; hypoglycemia if combined with insulin or sulfonylureas. Sarcopenia can worsen mobility in neurodegeneration.
Mechanistically attractive and safe, but the confirmatory phase 3 trial was negative for Parkinson's disease modification. Not supported as a neuroprotective therapy outside of research; the GLP-1 neuroprotection question is now open at best.
- Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. ↗
- Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson's disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial. ↗
▶SemaglutideEmergingAn oral GLP-1 receptor agonist tested as a disease-modifying therapy in early Alzheimer's disease; the large confirmatory phase 3 program has read out negative, so cognitive-protection claims are not supported.expand
An oral GLP-1 receptor agonist tested as a disease-modifying therapy in early Alzheimer's disease; the large confirmatory phase 3 program has read out negative, so cognitive-protection claims are not supported.
▸Full clinical story
GLP-1 signaling is proposed to reduce neuroinflammation, improve neuronal insulin signaling and mitochondrial bioenergetics, and potentially lower cortical tau accumulation, addressing the neuroenergetic and inflammatory components of Alzheimer's pathology.
A mechanistic RCT (ISAP) was designed to test whether oral semaglutide reduces tau PET signal and neuroinflammation in amyloid-positive adults, but it is only a protocol/biomarker study, not an efficacy trial. The two large phase 3 trials EVOKE and EVOKE+ (combined n=3808 randomised, amyloid-confirmed early Alzheimer's) found NO slowing of clinical progression (CDR-SB) at 104 weeks (estimated differences -0.08, p=0.57 and 0.10, p=0.46) and were discontinued for negative outcome. Graded none: despite mechanism and supportive epidemiology, the definitive confirmatory efficacy trials in Alzheimer's were negative.
Anecdotal community signal only: semaglutide is used very widely off-label for weight and metabolic goals, and some patients and clinicians hoped for cognitive protection based on diabetes/obesity cohort signals. There is no demonstrated cognitive benefit; any perceived effect is unproven.
Alzheimer's trials titrated oral semaglutide to 14 mg once daily; subcutaneous formulations are used for metabolic indications. This is trial context, not a cognitive protocol.
GI intolerance and appetite suppression driving weight and lean-mass loss, which raises sarcopenia and frailty risk in older adults with cognitive impairment; gallbladder disease and pancreatitis; hypoglycemia when combined with insulin/sulfonylureas.
Despite strong epidemiology and a plausible mechanism, the definitive Alzheimer's trials were negative. Not a cognitive therapy; its role in neurodegeneration is now essentially closed pending different agents or subgroups.
- Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults. ↗
- Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials. ↗
▶SemaxEmergingA Russian synthetic ACTH(4-10) heptapeptide marketed as a nootropic/neuroprotective agent; it has a single low-quality human study in ischemic stroke but is essentially unstudied for dementia, Parkinson's, or TBI in the Western literature.expand
A Russian synthetic ACTH(4-10) heptapeptide marketed as a nootropic/neuroprotective agent; it has a single low-quality human study in ischemic stroke but is essentially unstudied for dementia, Parkinson's, or TBI in the Western literature.
▸Full clinical story
Semax raises BDNF and other neurotrophins and modulates central monoamines, with the rationale being neurotrophic support of synaptic survival and functional recovery after ischemic or traumatic injury.
One clinical study of 110 ischemic stroke patients reported that adding Semax raised plasma BDNF, accelerated functional recovery, and improved Barthel index and motor outcomes; rodent work supports nootropic/neuroprotective activity. Graded preclinical for this condition: the only human data are in ischemic stroke (adjacent, not the target neurodegenerative or TBI conditions) and are low-quality, single-region, and methodologically limited, while Alzheimer's, Parkinson's, and TBI are supported only by mechanism and animal work with no RCTs.
Anecdotal community signal only: Semax is used intranasally within the nootropic community for focus, mental recovery, and post-concussion symptoms, with users reporting subjective cognitive and mood benefit and faster recovery. Widely discussed but entirely uncontrolled.
Intranasal administration; the stroke study used courses of 6000 mcg/day, while nootropic use is often cited around 300-600 mcg/day intranasally. This is context, not a protocol.
Not FDA-approved; gray-market sourcing raises purity and sterility concerns; scant long-term safety data; mildly stimulating and can affect sleep/anxiety.
A plausible neurotrophic mechanism with a genuine but low-quality, regionally isolated human signal in stroke and no direct data in the target conditions. Experimental; nowhere near guideline-grade for cognitive decline.
▶DihexaPreclinicalAn orally active small-molecule angiotensin IV analog designed to drive synaptogenesis; preclinical only, but sold in gray-market nootropics well ahead of any human data.expand
An orally active small-molecule angiotensin IV analog designed to drive synaptogenesis; preclinical only, but sold in gray-market nootropics well ahead of any human data.
▸Full clinical story
Dihexa potentiates hepatocyte growth factor/c-Met signaling to promote the formation of new functional synapses, directly targeting the synaptic-connection loss underlying Alzheimer's and Parkinson's cognitive decline.
Preclinical only: reviewed animal work reports metabolic stability, blood-brain-barrier penetration, and pro-cognitive, synaptogenic effects in Alzheimer's and Parkinson's models. There are no human trials. Grade preclinical.
Anecdotal community signal only: dihexa is sold as a research chemical and taken orally or transdermally by nootropic users for cognitive enhancement, who report subjective focus and memory gains. The community itself frequently raises concern that a growth-factor-potentiating compound could promote unchecked cell growth. Entirely uncontrolled.
Community anecdotes cite roughly 5-45 mg orally; these figures are unvalidated. Context, not a protocol.
As an HGF/c-Met pathway agonist it carries a theoretical oncogenic and angiogenic risk; there are no human safety data and no toxicology to bound long-term use; unregulated sourcing compounds the risk.
A compelling synaptogenic mechanism with zero human evidence and real theoretical safety concerns. Research-only; not appropriate for clinical use.
▶ElamipretidePreclinicalA mitochondria-targeted peptide (SS-31) aimed squarely at the bioenergetic component of vascular cognitive impairment; strictly preclinical for cognition, and the most directly relevant study was negative.expand
A mitochondria-targeted peptide (SS-31) aimed squarely at the bioenergetic component of vascular cognitive impairment; strictly preclinical for cognition, and the most directly relevant study was negative.
▸Full clinical story
Elamipretide binds cardiolipin on the inner mitochondrial membrane, stabilizing electron-transport-chain function and reducing mitochondrial reactive oxygen species. This directly targets the mitochondrial oxidative-stress lever implicated in cerebrovascular aging and vascular cognitive impairment.
In an aged, hypertensive mouse model, SS-31 did NOT significantly reduce cerebral microhemorrhage burden linked to vascular cognitive impairment (the study's main translational value was a machine-learning imaging pipeline). Elamipretide's human trials have been in mitochondrial myopathy and cardiac disease, not cognition. Grade preclinical, and this specific cognitive-vascular result was negative.
Anecdotal community signal only, and minimal: a few longevity/mitochondrial-health enthusiasts discuss elamipretide, but access is limited and it is not a commonly used off-label cognitive peptide.
Non-CNS trials have used subcutaneous elamipretide around 40 mg/day; no cognitive dosing is established. Context only.
Injection-site reactions are the main reported issue in trials; blood-brain-barrier penetration for CNS targets is uncertain, and neither CNS efficacy nor CNS safety is established.
A strong mechanistic fit for the bioenergetic lever, but no human cognitive evidence and a negative preclinical vascular readout. Early experimental; not clinically actionable for cognitive decline.
▶HumaninPreclinicalA mitochondria-derived peptide studied as an endogenous neuroprotective factor and a mitochondrial-stress biomarker in Alzheimer's disease; a preclinical/biomarker-stage concept, not a therapy.expand
A mitochondria-derived peptide studied as an endogenous neuroprotective factor and a mitochondrial-stress biomarker in Alzheimer's disease; a preclinical/biomarker-stage concept, not a therapy.
▸Full clinical story
Humanin protects neurons from amyloid-beta toxicity and oxidative stress and supports mitochondrial function, tying directly to the bioenergetic lever. Brain expression declines with aging, which is proposed to raise neurodegeneration risk.
Preclinical Alzheimer's models show humanin protects against amyloid-beta and oxidative injury; human data are biomarker-level. In a randomized exercise trial (ADEX, n=95), neuron-derived extracellular-vesicle humanin rose with exercise, especially in APOE e4 carriers. There is no therapeutic RCT of exogenous humanin, and circulating levels move bidirectionally in AD. Grade preclinical.
Anecdotal community signal only, and very limited: humanin is occasionally mentioned alongside MOTS-c in longevity/mitochondrial-peptide circles, but there is little real-world off-label clinical use.
No established human therapeutic dose; potent analogs (e.g., HNG) are used in animal work. Context only.
No clinical safety data for exogenous administration; sourcing and purity unknown; the biomarker itself is hard to interpret because levels both rise (compensatory) and fall in Alzheimer's across studies.
A biologically interesting neuroprotective peptide and candidate biomarker with preclinical support, but not a usable therapeutic. Track it as mechanism/biomarker, not treatment.
▶PACAPPreclinicalAn endogenous neuropeptide with neuroprotective activity in Alzheimer's models; preclinical, of mechanistic interest for the neuronal-loss lever but not clinically usable.expand
An endogenous neuropeptide with neuroprotective activity in Alzheimer's models; preclinical, of mechanistic interest for the neuronal-loss lever but not clinically usable.
▸Full clinical story
PACAP activates PAC1/VPAC receptors to promote neuronal survival, reduce amyloid-beta accumulation, and limit neuronal loss, and its levels and receptors are altered in Alzheimer's brain, suggesting a role in disease pathophysiology.
Preclinical and review-level evidence shows neuroprotection and reduced amyloid-beta in Alzheimer's models, with altered PACAP levels/receptors in human AD tissue serving as a biomarker signal. There are no therapeutic trials. Grade preclinical.
Anecdotal community signal only, and minimal: PACAP is not a widely used off-label peptide, largely because of delivery and stability challenges; interest is mostly academic.
No established human therapeutic dose; the native peptide has a short half-life and poor stability. Context only.
PACAP is a validated migraine trigger and potent vasodilator, so systemic exposure could provoke headache/migraine; poor blood-brain-barrier penetration and rapid degradation limit delivery; no clinical safety data.
An endogenous neuroprotective peptide with genuine preclinical support but major delivery hurdles, a migraine-trigger liability, and no human therapeutic data. Early-stage mechanism, not a treatment.
▶EpitalonPreclinicalPromotes neurogenic gene/protein expression in human stem cells, hinting at a neuro-supportive role that is entirely preclinical.expand
Promotes neurogenic gene/protein expression in human stem cells, hinting at a neuro-supportive role that is entirely preclinical.
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Epigenetically (likely via histone binding) upregulates neuronal differentiation markers such as Nestin, GAP43, beta-Tubulin III and Doublecortin.
A single in-vitro study in human gingival mesenchymal stem cells showed 1.6-1.8 fold marker increases; no animal cognition or human data.
No verifiable community threads located.
No human cognitive dosing established.
Cell-culture evidence only; do not infer clinical neuroprotection. Research-use-only.
A plausible epigenetic-neurogenesis signal in vitro, but far from any cognitive clinical claim.
▶PE-22-28PreclinicalSame TREK-1 mechanism drives rapid hippocampal neurogenesis and synaptogenesis in rodents - a neuroplasticity signal, not a proven cognitive benefit.expand
Same TREK-1 mechanism drives rapid hippocampal neurogenesis and synaptogenesis in rodents - a neuroplasticity signal, not a proven cognitive benefit.
▸Full clinical story
TREK-1 blockade enhances hippocampal CREB phosphorylation and neurogenesis and promotes synaptogenesis on cortical neurons.
Preclinical only: 4-day PE-22-28/analog treatment induced neurogenesis and enhanced synaptogenesis in mouse neurons (PMID 28955242; foundational spadin data PMID 20405001). No human cognitive outcomes measured.
No credible community reports of cognitive effects; forum discussion is limited and informational.
No human dose established; rodent parenteral dosing only.
Same as for mood: avoid in bipolar disorder and in cardiac arrhythmia / potassium-channel-drug users; no human safety data.
Promising preclinical neuroplasticity signal, but no human evidence for cognitive benefit - strictly experimental.
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