---
canonical_name: 40 Hz Ultrasound
alternate_names: 40 Hz Transcranial Ultrasound Stimulation, 40 Hz Pulsed Ultrasound, Gamma-Frequency Ultrasound, 40 Hz Transcranial Focused Ultrasound, 40 Hz TUS, Gamma-Entrainment Ultrasound
canonical_topic: 40 Hz Ultrasound for Health & Longevity
short_topic_lc: 40_hz_ultrasound
creation_date: 2026-0704-0049
creator_ai_fullname: Opus 4.8
---

# 40 Hz Ultrasound for Health & Longevity

Evidence Review created on 07/04/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** 40 Hz Transcranial Ultrasound Stimulation, 40 Hz Pulsed Ultrasound, Gamma-Frequency Ultrasound, 40 Hz Transcranial Focused Ultrasound, 40 Hz TUS, Gamma-Entrainment Ultrasound

## Motivation

40 Hz ultrasound is an experimental way of sending gentle, focused sound waves — pitched far above the range of human hearing — through the skull and switching them on and off forty times each second. The aim is to nudge the brain's own electrical rhythms toward a fast "gamma" beat of about forty cycles per second, a pattern tied to attention and memory that tends to weaken with age and in Alzheimer's disease. Because sound waves can be aimed at deep structures without surgery, researchers see this as a possible non-invasive tool for protecting the aging brain.

Interest grew after work showing that flickering light and clicking sound at 40 Hz could clear sticky protein deposits and preserve memory in mice. Adapting that same rhythm to ultrasound raised the prospect of reaching regions that light and sound cannot, such as the memory-forming hippocampus deep inside the brain.

This review examines what is currently known about 40 Hz ultrasound for brain health and longevity: how it is thought to work, what the early animal and human evidence shows, its possible benefits and risks, and the many open questions that remain.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section collects high-level, directly relevant overviews of 40 Hz ultrasound and its parent field of 40 Hz gamma-frequency brain stimulation.

* [Research Worth Sharing, April 2026 Edition](https://peterattiamd.com/research-worth-sharing-april-2026/) - Peter Attia

  This roundup includes a dedicated discussion of 40 Hz light-and-sound stimulation as a low-risk approach to Alzheimer's disease, explaining the gamma-entrainment rationale that underpins the ultrasound variant. It is a useful expert framing of why driving the brain at 40 Hz is being pursued and how a device maker is testing it clinically.

* [Focus Toolkit: Tools to Improve Your Focus & Concentration](https://www.hubermanlab.com/episode/focus-toolkit-tools-to-improve-your-focus-and-concentration) - Andrew Huberman

  In this episode, Andrew Huberman reviews 40 Hz auditory stimulation (binaural beats) as a tool that some studies link to improved focus, offering accessible context on how gamma-range rhythms are thought to influence attention and neuromodulator release. It is helpful background on the broader 40 Hz gamma-entrainment idea that ultrasound seeks to deliver more deeply and focally.

* [Gamma oscillations and application of 40-Hz audiovisual stimulation to improve brain function](https://pubmed.ncbi.nlm.nih.gov/36374520/) - Chen et al., 2022

  This narrative review explains what gamma oscillations (fast brain waves near forty cycles per second linked to attention and memory) are and how driving them at 40 Hz is being explored for brain health. It gives the conceptual foundation shared by every 40 Hz method, including ultrasound.

* [Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice](https://pubmed.ncbi.nlm.nih.gov/34872618/) - Park et al., 2021

  This is the landmark study that first applied transcranial ultrasound stimulation (TUS — sending sound waves through the skull to influence brain activity) pulsed at 40 Hz in an Alzheimer's mouse model, reporting reduced amyloid-β (Aβ, the sticky protein that clumps into plaques in Alzheimer's disease) and stronger gamma rhythms without microbleeds. It defines the specific intervention this review addresses.

* [Ultrasound-Induced Synchronized Neural Activities at 40 Hz and 200 Hz Entrained Corresponded Oscillations and Improve Alzheimer's Disease Memory](https://pubmed.ncbi.nlm.nih.gov/40202152/) - Chen et al., 2025

  This more recent study shows that 40 Hz ultrasound aimed at the deep hippocampus improved memory and boosted gamma and ripple rhythms in Alzheimer's-model mice, with effects lasting several days. It illustrates the deep-targeting advantage that distinguishes ultrasound from light and sound.

Note: Directly relevant, in-depth content specific to 40 Hz ultrasound (or 40 Hz gamma entrainment) could not be found from Rhonda Patrick, Chris Kresser, or Life Extension Magazine at the time of writing; the list therefore draws on the two priority experts who have covered the topic (Peter Attia, Andrew Huberman) plus the primary and review literature that defines it.

## Grokipedia

No dedicated Grokipedia article exists for 40 Hz ultrasound (or 40 Hz transcranial ultrasound stimulation). A direct search of grokipedia.com returned only broad, unrelated pages on ultrasound and on 40 Hz binaural beats, none of which is a primary page for this intervention.

## Examine

No Examine article exists for 40 Hz ultrasound. Examine.com focuses on dietary supplements, foods, and nutrition-related interventions, and does not cover energy-based brain-stimulation devices such as this one.

## ConsumerLab

No ConsumerLab article exists for 40 Hz ultrasound. ConsumerLab independently tests dietary supplements and similar consumer products and does not review brain-stimulation devices or procedures.

## Systematic Reviews

The following systematic reviews and meta-analyses cover transcranial ultrasound neuromodulation and 40 Hz gamma stimulation, the fields most directly relevant to 40 Hz ultrasound; no systematic review examines the 40 Hz ultrasound variant on its own.

* [Human Studies of Transcranial Ultrasound neuromodulation: A systematic review of effectiveness and safety](https://pubmed.ncbi.nlm.nih.gov/35533835/) - Sarica et al., 2022

  This review of 35 human studies (677 participants) found that transcranial ultrasound stimulation can change brain excitability, connectivity, and behavior, with only mild adverse events in about 3–4% of participants and no serious harms. It is the key human-safety and effectiveness reference for the broader technique that 40 Hz ultrasound belongs to.

* [The Effects and Safety of Gamma Rhythm Stimulation on Cognitive Function in Alzheimer's Disease: A Systematic Review and Meta-Analysis](https://pubmed.ncbi.nlm.nih.gov/40855942/) - Wu et al., 2025

  Pooling eight randomized controlled trials (RCTs — studies that randomly assign participants to treatment or a dummy control) of 40 Hz gamma stimulation in Alzheimer's disease, this meta-analysis reported benefits on cognitive tests with a standardized mean difference (SMD — a measure of effect size) for the Mini-Mental State Examination (MMSE, a common bedside test of thinking) of 3.09 (95% confidence interval [CI — the range in which the true value likely lies] 2.37–3.82) and no rise in adverse events. Most included trials used light and sound rather than ultrasound, so it evidences the 40 Hz concept rather than the ultrasound delivery method itself.

* [The effectiveness and safety of low-intensity transcranial ultrasound stimulation: A systematic review of human and animal studies](https://pubmed.ncbi.nlm.nih.gov/38061596/) - Qin et al., 2024

  This review of 11 human and 44 animal studies found low-intensity transcranial ultrasound modulated brain circuits across neurological and psychiatric conditions, suppressed inflammation, and favored new neuron growth, with only mild, reversible side effects. It summarizes the safety and biological plausibility that support 40 Hz ultrasound.

* [Effect of Low Intensity Transcranial Ultrasound Stimulation on Neuromodulation in Animals and Humans: An Updated Systematic Review](https://pubmed.ncbi.nlm.nih.gov/33935626/) - Kim et al., 2021

  Reviewing 26 studies, this paper showed low-intensity ultrasound can reach both surface and deep brain structures to change motor and cognitive behavior, while highlighting that stimulation parameters differ widely and remain unstandardized. It underscores the deep-targeting rationale and the parameter-uncertainty that also apply to 40 Hz protocols.

* [Transcranial ultrasound stimulation parameters for neurological diseases: a systematic review](https://pubmed.ncbi.nlm.nih.gov/40470501/) - Wang et al., 2025

  Analyzing 35 studies, this review linked specific ultrasound parameters — fundamental frequency, pulse repetition frequency, and mechanical index — to physiological responses, and noted that low-frequency, low-intensity protocols are being aimed at neurodegenerative disease. Because 40 Hz is a pulse-repetition setting, this parameter-focused review is directly relevant to how such protocols are designed.

## Mechanism of Action

40 Hz ultrasound combines two ideas: ultrasound as a way to physically influence brain cells, and 40 Hz as a rhythm chosen to restore gamma brain waves.

* **Ultrasound as a mechanical signal.** Ultrasound is a pressure (sound) wave above the range of human hearing. For brain stimulation, a carrier frequency of roughly 200–650 kilohertz is used because it passes through the skull reasonably well. At low intensity it does not heat or destroy tissue; instead, the mechanical push of the wave is thought to act on mechanosensitive ion channels — pore-like proteins such as Piezo1 and certain TRP channels (mechanically-activated gates) that open when a cell membrane is deformed — changing a neuron's electrical excitability. This is called acoustic (or mechanical) neuromodulation.

* **40 Hz as a rhythm.** The ultrasound is delivered in short bursts repeated 40 times per second (a pulse-repetition or amplitude-modulation frequency of 40 Hz). The goal is "gamma entrainment": coaxing populations of neurons to fire together at about 40 Hz, the gamma rhythm that supports attention and memory and that is weakened in Alzheimer's disease.

* **Downstream biological effects.** Evidence from the wider 40 Hz gamma field (mostly light and sound) suggests that restoring gamma activity mobilizes microglia (the brain's resident immune cells) to engulf and clear amyloid-β, and prompts certain neurons to release the signaling molecule VIP (vasoactive intestinal peptide), which increases flow through the glymphatic system (the brain's fluid-based waste-clearance network) to wash out amyloid. In an Alzheimer's mouse study, 40 Hz ultrasound also lowered inflammatory signaling through NF-κB (a master switch that turns on inflammation) and RIPK1 (a protein that can trigger cell death and inflammation), reducing pro-inflammatory messengers.

The explanation is appropriately concise but sufficient for a non-specialist: sound-wave energy is pulsed at a brain-wave rhythm to both stimulate cells directly and restore a memory-supporting oscillation, with knock-on effects on plaque clearance and inflammation.

Competing mechanistic explanations exist and are genuinely unsettled:

* **Direct versus indirect action.** Some researchers argue that measured effects of transcranial ultrasound reflect true, direct neuromodulation of the targeted region. Others present evidence that ultrasound can activate the hearing pathway (an "auditory confound") or startle responses, so that part of the effect may be indirect. This critique is treated here as a claim to be tested, not a settled fact; careful sham-controlled and deafened-animal studies are needed to separate the two.

* **Entrainment versus general stimulation.** It is also debated whether benefits come specifically from 40 Hz entrainment of gamma rhythms or from a more general stimulation of microglia and blood-flow responses that would occur at other frequencies too.

40 Hz ultrasound is not a pharmacological compound, so drug-style properties such as half-life, selectivity, tissue distribution, and hepatic metabolism do not apply; the relevant "dose" parameters are acoustic (carrier frequency, intensity, pulse pattern, duration, and target).

## Historical Context & Evolution

* **Original intended use.** Ultrasound entered medicine first as diagnostic imaging in the 1940s–1950s and then as high-intensity focused ultrasound (HIFU — concentrated ultrasound used to heat and destroy tissue), which today ablates targets for essential tremor and is used experimentally to transiently open the blood–brain barrier. These uses are about imaging or destroying tissue, not gently modulating it.

* **Why it came to be considered for brain optimization.** Low-intensity ultrasound was revived as a neuromodulation tool from roughly 2008–2010, when investigators showed that weak, non-destructive ultrasound could reversibly excite or suppress neural activity and reach deep structures that surface techniques cannot. In parallel, work beginning with a 2016 study established that driving the brain at 40 Hz with flickering light and sound reduced Alzheimer's-type pathology and preserved memory in mice — the "gamma entrainment using sensory stimulation" (GENUS) paradigm. Combining these two threads, researchers reasoned that ultrasound pulsed at 40 Hz might deliver gamma entrainment to deep regions such as the hippocampus non-invasively.

* **What the historical research actually found.** The first dedicated demonstration (2021) reported that two weeks of daily 40 Hz ultrasound in an Alzheimer's mouse model reduced insoluble amyloid-β and plaque counts, increased gamma power, normalized cross-frequency coupling, and did not cause microbleeding. Subsequent work extended this to deep hippocampal targeting with lasting memory gains and to awake, wearable delivery with anti-inflammatory molecular changes. These are described here as findings in their own right, not merely as claims about them.

* **Evolution of scientific opinion.** Opinion is still forming rather than settled. Early enthusiasm for ultrasound neuromodulation has been tempered by the auditory-confound debate and by wide variation in stimulation parameters, and the 40 Hz gamma field itself has produced both encouraging clinical signals and some null results. What has changed is that human safety data for ultrasound neuromodulation have accumulated and clinical trials of 40 Hz stimulation (mostly sensory) are now underway; what remains open is whether the ultrasound version confers a real, translatable benefit in people. The current picture should not be read as a final verdict in either direction.

## Expected Benefits

The benefits below are framed for risk-aware, proactive adults interested in protecting long-term brain health, not as established population-level outcomes. A dedicated search of clinical, preclinical, and expert sources was performed to compile the complete benefit profile. It is important to state up front that, for the specific 40 Hz ultrasound modality, essentially all direct evidence is preclinical (animal) or mechanistic; human clinical benefit has been shown for related 40 Hz sensory stimulation, not for the ultrasound version. Grades therefore reflect the ultrasound-specific evidence.

### Low 🟩

#### Reduction of Amyloid-β Plaque Burden

40 Hz ultrasound aims to enlist microglia and glymphatic clearance to remove amyloid-β, the protein that accumulates as plaques in Alzheimer's disease. Across three independent Alzheimer's mouse studies, ultrasound pulsed at 40 Hz reduced insoluble amyloid-β and plaque counts in targeted cortex and hippocampus, an effect consistent with the broader 40 Hz gamma literature. The evidence basis is small-animal studies only; whether skull attenuation and larger human brains allow a comparable effect is unproven, and no human trial of 40 Hz ultrasound has measured amyloid.

**Magnitude:** In 5×FAD Alzheimer's-model mice, two weeks of daily 40 Hz ultrasound reduced insoluble amyloid-β42 in the targeted cortex and lowered hippocampal plaque counts relative to sham; no human effect size has been established.

#### Enhancement of Gamma Oscillations and Memory in Alzheimer's Models

Because the pulsing rhythm is meant to entrain gamma activity, treated animals showed increased gamma-band power, better coordination between brain rhythms, and improved performance on memory tasks. The evidence basis is animal electrophysiology and behavior, supported by human studies showing that ultrasound can measurably change cortical activity; the memory findings themselves come from mice, and human cognitive benefit from 40 Hz ultrasound has not been tested.

**Magnitude:** In Alzheimer's-model mice, 40 Hz ultrasound raised gamma-band power and improved memory-task performance, with gains persisting up to about five days after stimulation; human magnitude is unknown.

#### Reduction of Neuroinflammation

Chronic low-grade brain inflammation is a feature of aging and neurodegeneration, and 40 Hz ultrasound appears to dampen it. A preclinical study using awake, wearable delivery reported reduced inflammatory signaling (through the RIPK1 and NF-κB pathways) and lower levels of pro-inflammatory messengers, alongside increased plaque-clearing microglial activity. This rests on a single mechanistic animal study, so it is promising but not yet corroborated in humans.

**Magnitude:** In a preclinical study, 40 Hz ultrasound lowered pro-inflammatory signaling molecules (including IL-6, IL-1β, and TNF-α) in Alzheimer's-model mice; no human data exist.

### Speculative 🟨

#### Enhanced Glymphatic Waste Clearance

By restoring gamma activity, 40 Hz stimulation may increase flow through the glymphatic system, helping the brain flush metabolic waste and misfolded proteins — a process closely tied to sleep and to long-term brain resilience. This mechanism has been shown for 40 Hz light and sound and is a plausible route for ultrasound, but it has not been directly demonstrated for the ultrasound modality, and the basis is mechanistic and inferential only.

#### General Cognitive and Longevity Support in Healthy Adults

The most aspirational use — using 40 Hz ultrasound preventively in healthy, aging adults to preserve memory, focus, and brain structure — is entirely unproven. All human cognitive signals to date come from related sensory stimulation in people who already have cognitive impairment; there is no controlled evidence that 40 Hz ultrasound benefits healthy adults, and any expectation rests on extrapolation from animal and mechanistic data.

## Benefit-Modifying Factors

* **Skull thickness and density:** Because the effect depends on ultrasound reaching its target, a thicker or denser skull absorbs and scatters more energy, potentially reducing the delivered dose. This is a physical modifier unique to ultrasound and tends to matter more in older adults, in whom skull density and shape vary.

* **Baseline gamma deficit and amyloid load:** Individuals whose gamma rhythms are already weakened and whose amyloid burden is higher may, in principle, have more room to benefit — mirroring the pattern seen in impaired versus healthy animals — whereas healthy adults with intact rhythms may see little measurable change.

* **Genetic risk profile (e.g., APOE4):** Carriers of APOE4 (a gene variant that raises Alzheimer's risk and is linked to greater amyloid accumulation) might have more pathology available to clear, but could also differ in vascular fragility; whether this raises or lowers net benefit is untested.

* **Sex differences:** Preclinical work has used both sexes, and one awake-delivery study used only female mice; microglial and inflammatory responses can differ by sex, so responses in men and women may not be identical. Human sex-specific data are absent.

* **Age:** The target population skews older, where the potential upside (more pathology to address) coexists with reduced ultrasound transmission and greater biological variability, making individual responses harder to predict.

## Potential Risks & Side Effects

Risks are framed for the proactive adult considering this experimental intervention. A dedicated search of human ultrasound-neuromodulation safety reviews and device-safety literature was performed. The overall human safety record of low-intensity ultrasound neuromodulation is reassuring, but the 40 Hz ultrasound protocol specifically has not been studied in people, so some risks remain theoretical.

### Medium 🟥 🟥

#### Transient Mild Sensory and Neurological Effects

The most consistently reported effects of transcranial ultrasound in people are mild and short-lived: headache, warmth or tingling at the scalp, transient mood or attention changes, neck discomfort, sleepiness, and occasional nausea. The proposed mechanisms are local scalp heating, acoustic sensation, and short-term shifts in brain excitability. Across pooled human studies these were self-limited and non-serious, but they define the realistic near-term side-effect profile; the 40 Hz pulsing pattern has not been separately characterized for these effects.

**Magnitude:** Across pooled human transcranial ultrasound studies (~677 participants), mild adverse events were reported in roughly 3–4% of participants, with no serious events.

### Low 🟥

#### Local Thermal Heating and Skull Bioeffects

Ultrasound deposits energy that can warm tissue, particularly at the skull–brain interface where absorption is highest. At the low intensities used for neuromodulation this is generally kept within accepted safety limits, but longer sessions, higher intensities, or poor targeting could raise local temperature. The relevant safeguards are the thermal and mechanical safety indices used in diagnostic ultrasound.

**Magnitude:** Not quantified in available studies.

#### Off-Target or Unintended Neuromodulation

Ultrasound beams can be distorted by the skull, producing standing waves or hitting regions other than the intended target, which could transiently alter unintended circuits. The consequence is usually a temporary, unwanted change in perception, mood, or motor function rather than lasting harm, and it is mitigated by acoustic simulation and neuronavigation.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Blood-Brain Barrier Disruption and Microhemorrhage

At higher intensities, or when combined with injected microbubble contrast agents, ultrasound can open the blood-brain barrier (BBB — the protective lining of the brain's blood vessels), which in rare cases could allow small bleeds. The dedicated 40 Hz ultrasound study that looked for this found no increase in microbleeding, so at low neuromodulation intensities the risk appears low; it is flagged as speculative because it is intensity-dependent and unmeasured over long-term repeated use.

#### Seizure Provocation

Any technique that drives synchronized brain activity raises a theoretical concern about triggering seizures, especially in susceptible individuals. Reassuringly, 40 Hz sensory stimulation has been reported as safe even in people with epilepsy, and no seizures have been attributed to 40 Hz ultrasound; the concern is retained as speculative pending direct human data.

#### Unknown Long-Term and Cumulative Effects

Because no one has used 40 Hz ultrasound in humans over months or years, the cumulative effects of repeated deep-brain stimulation — on tissue, vasculature, or unintended adaptation of brain circuits — are simply unknown. This uncertainty is inherent to any early-stage energy-based intervention.

## Risk-Modifying Factors

* **Cerebral amyloid angiopathy and bleeding tendency:** Individuals with amyloid deposits in blood-vessel walls, prior brain hemorrhage, or use of anticoagulants may face a higher theoretical risk if the blood-brain barrier is perturbed, and would warrant extra caution.

* **Genetic risk (e.g., APOE4):** APOE4 carriers can have more vascular amyloid, which is relevant to the theoretical microhemorrhage concern, though no ultrasound-specific genetic risk has been established.

* **Seizure threshold:** A personal or family history of seizures, or use of medications that lower seizure threshold, could increase susceptibility to the (so far unobserved) seizure risk of rhythmic stimulation.

* **Skull anatomy and implants:** Skull defects, craniotomy sites, thin or unusually dense skull regions, and implanted hardware change how ultrasound propagates and can create hot spots or unpredictable targeting.

* **Sex and age:** Preclinical inflammatory responses can differ by sex, and older adults have more variable skull transmission and vascular fragility; human risk data stratified by sex and age do not yet exist.

## Key Interactions & Contraindications

* **Other brain-stimulation methods:** Combining 40 Hz ultrasound with transcranial magnetic stimulation, transcranial direct-current stimulation, or 40 Hz light/sound could have additive or unpredictable effects on excitability. Severity: caution. Consequence: unintended over-stimulation. Mitigating action: avoid stacking neuromodulation methods without supervision and separate sessions in time.

* **Seizure-threshold-lowering prescription drugs:** Agents such as bupropion (an antidepressant), tramadol (a pain medication), and some antipsychotics can lower the seizure threshold. Severity: caution. Consequence: theoretical increased seizure susceptibility during rhythmic stimulation. Mitigating action: review medications and consider extra caution or avoidance in those on multiple such drugs.

* **Sedatives and anesthetics:** Sedating drugs and general anesthesia alter the brain's response to ultrasound (animal work shows anesthesia changes the effect substantially). Severity: monitor. Consequence: unreliable or blunted response. Mitigating action: standardize the arousal state; avoid pairing with sedation outside research.

* **Ultrasound contrast agents (microbubbles):** Over-the-counter products are not a concern, but injected microbubble contrast agents dramatically increase ultrasound's ability to open the blood-brain barrier. Severity: absolute caution. Consequence: unintended barrier opening and possible bleeding. Mitigating action: do not combine neuromodulation ultrasound with contrast agents.

* **Supplements and drugs affecting bleeding:** Supplements or drugs that thin the blood or affect vessel integrity (e.g., high-dose fish oil, ginkgo, prescription anticoagulants) are a theoretical additive concern only if the blood-brain barrier is perturbed. Severity: caution. Consequence: theoretical bleeding risk. Mitigating action: disclose all blood-thinning agents before any procedure.

* **Populations who should avoid or use only under strict supervision:** People with intracranial metal or implanted devices (aneurysm clips, shunts, deep-brain-stimulation hardware, cochlear implants), an active or uncontrolled seizure disorder, a recent intracranial hemorrhage (e.g., within roughly 90 days) or known cerebral amyloid angiopathy, skull defects or recent craniotomy, and pregnant individuals should avoid 40 Hz ultrasound outside carefully controlled research.

## Risk Mitigation Strategies

* **Stay within established acoustic safety limits:** Keep the thermal index and mechanical index within the ranges accepted for diagnostic and neuromodulation ultrasound (well below tissue-ablation thresholds), which directly limits the risk of thermal heating and mechanical injury.

* **Screen for implants and bleeding risk first:** Use imaging (magnetic resonance imaging or computed tomography) and a medical history to exclude intracranial metal, prior hemorrhage, and cerebral amyloid angiopathy before exposure, preventing device heating, mistargeting, and bleeding complications.

* **Use neuronavigation and acoustic simulation:** Model how the individual's skull bends the beam and target with image guidance so energy reaches the intended region, mitigating off-target neuromodulation and hot spots.

* **Start low and titrate:** Begin with the lowest effective intensity and shorter exposures (as in preclinical protocols of roughly 1–2 hours of pulsed delivery at spatial-peak intensities kept low) and increase only if well tolerated, reducing the chance of thermal or excitability side effects.

* **Exclude microbubble contrast and control arousal state:** Never pair neuromodulation ultrasound with injected contrast agents, and standardize wakefulness and medication status, preventing unintended blood-brain-barrier opening and unpredictable responses.

* **Monitor during and after sessions:** Watch for headache, scalp warmth, mood or attention changes, and any sign of a seizure, and stop if they occur, so that transient effects are caught early before they escalate.

## Therapeutic Protocol

There is no validated human protocol for 40 Hz ultrasound; what follows describes parameters used by leading research groups and how they compare with the sensory 40 Hz approach.

* **Core acoustic parameters:** Research protocols use a carrier frequency of roughly 500 kilohertz, delivered in tone bursts repeated at a 40 Hz pulse-repetition frequency (the feature that makes it "40 Hz"), at low spatial-peak intensities intended to modulate rather than heat or ablate tissue. These parameters are still being optimized.

* **Session length and course:** Preclinical protocols applied roughly 1–2 hours of daily pulsed stimulation for about two weeks; one awake, wearable study identified a 14-day regimen at an acoustic intensity of about 2.14 W/cm² as optimal in mice. Human dosing has not been established.

* **Competing approaches, presented without ranking one as default:** The main alternative delivering the same 40 Hz rhythm is non-invasive sensory stimulation (flickering light and clicking sound), popularized through the GENUS research program at MIT and commercialized by the spin-off company Cognito Therapeutics — a commercial developer whose financial interest in a positive result should be weighed when reading its clinical data. Ultrasound's proposed advantage is deep, focal targeting; sensory stimulation's advantage is a longer human track record and simpler delivery. A third route, transcranial magnetic or alternating-current stimulation at 40 Hz, is also under study.

* **Best time of day:** Optimal timing is unknown. Because gamma-driven waste clearance is linked to rest and sleep, some hypothesize that eyes-closed or pre-sleep sessions (as used in sensory protocols) may be favorable, but this has not been tested for ultrasound.

* **Genetic considerations:** No pharmacogenetic guidance exists; variants such as APOE4 may influence the underlying pathology but have no established bearing on protocol choice.

* **Sex-based considerations:** Preclinical responses can differ by sex, and at least one protocol was validated only in females, so optimal settings may ultimately differ between men and women.

* **Age-related considerations:** Older adults' denser, more variable skulls attenuate ultrasound more, so effective protocols may require individualized targeting and dosimetry, especially at the older end of the target range.

* **Baseline biomarkers:** Baseline gamma activity (measurable by an electroencephalogram) and amyloid status may help identify who is most likely to respond and provide a reference for tracking change.

* **Pre-existing conditions:** Stage of cognitive impairment, vascular health, and seizure history should shape whether and how any protocol is applied.

## Discontinuation & Cycling

* **Lifelong versus short-term:** 40 Hz ultrasound is not a drug and is applied as defined courses rather than continuously; research to date has used fixed multi-week regimens rather than indefinite use.

* **Withdrawal effects:** No withdrawal syndrome or dependence has been described; stopping simply ends the stimulation.

* **Tapering:** No tapering is required, as there is no physiological dependence to unwind.

* **Cycling and maintenance:** Whether repeated cycles maintain benefit is unresolved. In animals the gains persisted only days after a course, which implies that ongoing or periodically repeated sessions would likely be needed to sustain any effect rather than a single course providing lasting change.

* **Practical framing:** Given the transience of preclinical effects, a realistic model is periodic maintenance sessions, but the ideal interval, and whether tolerance develops, are unknown.

## Sourcing and Quality

* **Research-grade versus consumer devices:** Genuine 40 Hz transcranial ultrasound requires calibrated, research-grade focused-ultrasound transducers and drive electronics used in laboratory and clinical settings; it is not available as a validated consumer product.

* **Avoid mislabeled consumer gadgets:** Many direct-to-consumer "40 Hz" wellness devices deliver light, sound, or vibration — not ultrasound — and some audio products labeled "40 Hz" (such as binaural-beat apps) are unrelated to transcranial ultrasound. Buyers should verify the actual energy type and not assume equivalence.

* **What to look for:** Where ultrasound neuromodulation is offered in a study or clinic, key quality signals are documented acoustic output (carrier frequency, intensity, thermal and mechanical indices), transducer calibration, image-based neuronavigation, and oversight by qualified investigators.

* **Regulatory reality:** No 40 Hz therapeutic ultrasound device is cleared for brain health or longevity; access is essentially limited to research protocols using established laboratory or clinical ultrasound systems.

## Practical Considerations

* **Time to effect:** In animal studies, changes in brain rhythms and pathology emerged over about two weeks of daily sessions; the time course in humans is unknown, and no rapid, perceptible effect should be expected.

* **Common pitfalls:** The biggest mistakes are confusing 40 Hz sensory or audio gadgets with actual ultrasound, assuming mouse results translate directly to people, and overlooking the auditory-confound debate that complicates interpretation of ultrasound effects.

* **Regulatory status:** The intervention is investigational. Low-intensity ultrasound neuromodulation is not approved for cognitive or longevity indications; high-intensity focused ultrasound is separately approved for uses such as essential-tremor ablation and is being trialed for blood-brain-barrier opening, which are different applications.

* **Cost and accessibility:** Access is currently confined to research settings, and image-guided ultrasound systems are expensive and require specialized expertise, so 40 Hz ultrasound is difficult to obtain outside a trial.

## Interaction with Foundational Habits

* **Sleep:** The interaction is plausibly direct and potentiating. Gamma activity and glymphatic waste clearance are tightly linked to sleep, and 40 Hz sensory stimulation has been reported to improve sleep and daily function in Alzheimer's patients; the practical implication is that adequate sleep may complement any waste-clearance benefit, and eyes-closed or pre-sleep timing is a reasonable hypothesis to test.

* **Nutrition:** The interaction is indirect. There is no known nutrient depletion or food timing requirement, but a brain-supportive dietary pattern (adequate omega-3 fats, low processed-food intake, good glycemic control) supports the same amyloid-clearance and anti-inflammatory pathways 40 Hz stimulation targets, making the two potentially complementary.

* **Exercise:** The interaction is indirect and potentiating. Aerobic exercise raises brain-derived neurotrophic factor and supports vascular and glymphatic health, overlapping with the mechanisms proposed for 40 Hz ultrasound; there is no evidence that stimulation blunts exercise adaptations, and the two plausibly reinforce each other.

* **Stress management:** The interaction is indirect. Chronic stress and elevated cortisol impair memory circuits and promote inflammation, working against the goals of gamma stimulation; stress-reduction practices are therefore a sensible complement, though no direct interaction with ultrasound has been demonstrated.

## Monitoring Protocol & Defining Success

Because 40 Hz ultrasound targets brain health, meaningful monitoring combines objective brain and blood markers with cognitive and qualitative tracking. Before starting, a baseline should be established across cognitive testing, brain-rhythm measurement, and blood-based markers so that any change can be judged against a personal reference point.

Ongoing monitoring cadence: establish a baseline, then reassess at roughly 4–8 weeks after beginning a course, and thereafter every 6–12 months, with brain-rhythm and cognitive checks repeated around each treatment course.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
|-----------|--------------------------|-----------------|---------------|
| EEG 40 Hz gamma response | Robust, reproducible 40 Hz steady-state response | Confirms the brain is actually entraining to the stimulation | Measured by electroencephalography (EEG, a recording of the brain's electrical waves); best interpreted against the personal baseline |
| Cognitive composite (e.g., MoCA) | 26–30 (MoCA) | Tracks memory and thinking over time | MoCA = Montreal Cognitive Assessment, a short pen-and-paper thinking test; use the same test and time of day |
| Plasma p-tau217 | Low / stable (assay-specific) | Blood marker tracking Alzheimer's-type pathology | p-tau217 = a phosphorylated form of the tau protein; interpret trends, not single values; fasting not required |
| Plasma Aβ42/40 ratio | Higher / stable (assay-specific) | Reflects amyloid-β burden | A lower ratio signals more amyloid; assay-dependent, so use one lab consistently |
| Neurofilament light (NfL) | Low for age (assay-specific) | General marker of nerve-cell injury | NfL = neurofilament light, released when neurons are damaged; rises with age |
| hs-CRP | < 1.0 mg/L | Tracks systemic inflammation | hs-CRP = high-sensitivity C-reactive protein, a blood marker of inflammation; conventional labs often flag only > 3.0 mg/L, so the functional target is stricter |
| Homocysteine | < 7–8 µmol/L | Elevated levels are linked to brain atrophy | Conventional labs may accept up to ~15 µmol/L; the functional target is lower; best paired with B-vitamin status |
| Vitamin D (25-OH) | 40–60 ng/mL | Supports brain and immune health | Conventional "sufficient" starts at 30 ng/mL; measure away from recent high-dose supplementation |

Qualitative markers to track:

* Subjective memory and word-finding
* Mental clarity and focus
* Mood and motivation
* Sleep quality and daytime energy

## Emerging Research

The field around 40 Hz ultrasound is early and fast-moving, and honest emerging research includes work that could strengthen the case as well as work that could weaken it.

* **Preclinical proof-of-concept (supportive):** The foundational animal studies continue to accumulate, including deep hippocampal targeting with lasting memory gains ([Chen et al., 2025](https://pubmed.ncbi.nlm.nih.gov/40202152/)) and awake, wearable delivery with anti-inflammatory molecular effects ([Yi et al., 2026](https://pubmed.ncbi.nlm.nih.gov/42016382/), DOI [10.34133/research.1244](https://doi.org/10.34133/research.1244)), building on the original demonstration ([Park et al., 2021](https://pubmed.ncbi.nlm.nih.gov/34872618/)).

* **Human ultrasound-for-cognition trials (translational):** A randomized study of low-intensity focused ultrasound in mild cognitive impairment and mild Alzheimer's disease is recruiting ([NCT05417555](https://clinicaltrials.gov/study/NCT05417555), University of California Los Angeles, 144 participants), and a completed study tested transcranial focused ultrasound to enhance cognition in healthy volunteers ([NCT06829368](https://clinicaltrials.gov/study/NCT06829368), University of Nottingham, 24 participants, primary endpoint cognitive performance). These will help establish whether ultrasound neuromodulation affects human cognition at all.

* **Human 40 Hz stimulation trials (concept validation):** Trials of the 40 Hz rhythm delivered by sensory means test the frequency concept that ultrasound seeks to deliver more deeply, including combined 40 Hz audio-visual stimulation with cognitive games ([NCT06595511](https://clinicaltrials.gov/study/NCT06595511), Istanbul Medipol University, 30 participants) and sensory-evoked cortical gamma oscillation in Alzheimer's disease ([NCT05206305](https://clinicaltrials.gov/study/NCT05206305), University of Tennessee Medical Center, 20 participants). Positive results would bolster the rationale; null results would undercut it.

* **Standardization and dosimetry (future direction):** A major open question is how to standardize acoustic parameters and account for skull effects; parameter-focused reviews ([Wang et al., 2025](https://pubmed.ncbi.nlm.nih.gov/40470501/)) argue that dose-response frameworks and better targeting are prerequisites for clinical translation.

* **Resolving the auditory-confound debate (could weaken the case):** Future sham-controlled and deafened-animal studies aimed at separating direct neuromodulation from indirect hearing-pathway activation could substantially revise how much of the observed effect is attributed to ultrasound itself.

* **Combination and preventive use (could strengthen the case):** Whether pairing deep ultrasound with sensory 40 Hz stimulation, or applying it preventively in healthy aging, adds benefit is an untested but frequently proposed direction.

## Conclusion

40 Hz ultrasound is an early-stage, non-invasive idea: gentle sound-wave energy aimed through the skull and pulsed forty times a second to nudge the brain's fast "gamma" rhythm, with the hope of clearing sticky plaques, calming inflammation, and supporting memory as the brain ages. Its distinctive promise is reaching deep memory regions that flickering light and sound cannot.

The honest state of the evidence is that the direct proof for this specific method is almost entirely from mice. In those studies the approach lowered plaque, strengthened brain rhythms, improved memory, and did so without obvious harm. Human data exist for the broader family of low-intensity ultrasound, which appears generally safe with only mild, passing side effects, and for the 40 Hz rhythm delivered through light and sound, where early results in people with memory loss are encouraging. Some of that clinical work comes from a company selling a device, which is worth keeping in mind.

What is missing is any test of 40 Hz ultrasound in people, along with agreed settings, deep-targeting accuracy, and answers to a real debate about how much of the effect is genuine. Benefits in healthy adults remain unproven. The picture is one of genuine scientific interest paired with large, unresolved uncertainty, and it should not be read as settled in either direction.

**[Top](#top) - [Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol)**


---
canonical_name: 5-Amino-1MQ
alternate_names: 5-Amino-1-methylquinolinium, 5-AMQ, 5A1MQ, 5-Amino-1-methylquinoline
canonical_topic: 5-Amino-1MQ for Health & Longevity
short_topic_lc: 5_amino_1mq
creation_date: 2026-0715-0250
creator_ai_fullname: Opus 4.8
---

# 5-Amino-1MQ for Health & Longevity

Evidence Review created on 07/15/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** 5-Amino-1-methylquinolinium, 5-AMQ, 5A1MQ, 5-Amino-1-methylquinoline

## Motivation

5-Amino-1MQ is a small molecule that blocks an enzyme which becomes overactive in fat tissue and in aging muscle. By quieting this enzyme, cells hold onto more of two ingredients they use to make energy and to keep their internal "housekeeping" running — one of which is a molecule called NAD⁺ that naturally declines with age. In laboratory animals, this shift pushed the body to burn stored fat rather than store it, without the animals eating less.

Interest grew after obese mice given the compound lost fat, handled blood sugar better, and developed less fatty liver, while separate work in old mice suggested it helped injured muscle recover. These findings, combined with the broader excitement around raising NAD⁺, moved 5-Amino-1MQ from the laboratory into the wider longevity and body-composition scene, where it is sold as a capsule despite having never been tested in a human study.

This review examines what is actually known about 5-Amino-1MQ: how it works, what the animal and cell evidence shows for fat loss, metabolic health, and muscle, what risks and unknowns remain, and how far the current science does — and does not — reach.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section lists high-level overviews and foundational sources that discuss 5-Amino-1MQ or its core mechanism — inhibition of NNMT (nicotinamide N-methyltransferase), an enzyme that consumes the NAD⁺ precursor nicotinamide — in substantial depth.

* [5-Amino 1MQ: Benefits, Dosage & Side Effects](https://jaycampbell.com/blog/5-amino-1mq-the-body-recomposition-peptide/) - Jay Campbell

  A widely read practitioner-facing overview from the body-optimization community that summarizes the mechanism, the animal evidence, and typical real-world dosing, while illustrating the promotional framing readers are likely to encounter.

* [Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice](https://pubmed.ncbi.nlm.nih.gov/29155147/) - Neelakantan et al., 2018

  The foundational primary paper that first characterized 5-Amino-1MQ, establishing its selectivity, cell permeability, and ability to reverse diet-induced obesity in mice — the origin of essentially every benefit claim made for the compound.

* [Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome](https://pubmed.ncbi.nlm.nih.gov/38919254/) - Sun et al., 2024

  A narrative review that explains why NNMT sits at the crossroads of the NAD⁺ and methylation systems and how inhibiting it may influence obesity, diabetes, and lipid handling, giving useful context for the metabolic rationale.

* [Emerging opportunities for nicotinamide N-methyltransferase (NNMT) inhibitor clinical translation](https://pubmed.ncbi.nlm.nih.gov/42067476/) - Puleo et al., 2026

  A recent review assessing how close NNMT inhibitors are to human use, candidly discussing the bioavailability and unknown-safety hurdles that separate promising animal data from validated therapeutics.

* [Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation](https://pubmed.ncbi.nlm.nih.gov/33453420/) - Roberti et al., 2021

  A mechanistic overview linking NNMT activity to both energy metabolism and gene regulation, helpful for understanding why a single enzyme influences fat, muscle, and aging biology at once.

Note: No content from the priority experts (Rhonda Patrick, Peter Attia, Andrew Huberman, Chris Kresser, Life Extension) could be found addressing this specific compound or its mechanism; the list is therefore drawn from the most relevant practitioner and academic sources available.

## Grokipedia

[5-Amino-1MQ](https://grokipedia.com/page/5-Amino-1MQ)

A dedicated encyclopedia entry summarizing the compound's chemistry, its NNMT-inhibition mechanism, pharmacokinetics, and reported metabolic and aged-muscle effects; it offers a broad orientation to the topic while carrying the optimistic framing typical of sources on this compound.

## Examine

No Examine article exists for 5-Amino-1MQ. Examine.com focuses on dietary supplements and nutraceuticals with human evidence and does not currently cover 5-Amino-1MQ, an unapproved research compound with no human data.

## ConsumerLab

No ConsumerLab article exists for 5-Amino-1MQ. ConsumerLab tests commercially marketed vitamins and supplements and does not cover 5-Amino-1MQ, which is sold as an unregulated research compound rather than a mainstream supplement.

## Systematic Reviews

No systematic reviews or meta-analyses for 5-Amino-1MQ were found on PubMed as of 07/15/2026.

## Mechanism of Action

5-Amino-1MQ (5-amino-1-methylquinolinium) is a selective small-molecule inhibitor of **nicotinamide N-methyltransferase (NNMT)** — an enzyme (a protein that speeds up a chemical reaction) that attaches a methyl group (a small carbon-hydrogen tag) to nicotinamide, a building block of NAD⁺.

The primary mechanism follows from what NNMT normally does:

* **The reaction NNMT catalyzes:** NNMT takes nicotinamide (a form of vitamin B3 and a precursor to **NAD⁺**, nicotinamide adenine dinucleotide — a coenzyme cells use for energy production and DNA repair) and tags it with a methyl group donated by **SAM** (S-adenosylmethionine, the body's universal methyl donor). This produces **1-MNA** (1-methylnicotinamide, an excreted by-product) and **SAH** (S-adenosylhomocysteine).

* **What inhibition does:** By blocking NNMT, 5-Amino-1MQ prevents nicotinamide and SAM from being consumed in this reaction. In cultured fat cells this raised intracellular NAD⁺ and SAM, lowered 1-MNA, and suppressed the making of new fat (lipogenesis).

* **Downstream effects:** Higher NAD⁺ can support **sirtuin-1 (SIRT1**, an NAD⁺-dependent enzyme that regulates metabolism and stress resistance), while higher SAM can shift the methylation of genes toward a more metabolically active state (for example, favoring **PGC-1α**, a master regulator of mitochondrial and fat-burning genes). NNMT is over-expressed in fat tissue in obesity and in skeletal muscle with aging, which is why inhibiting it is proposed to be beneficial specifically in those tissues.

Competing mechanistic view: the NAD⁺-raising effect of NNMT inhibition is modest and tissue-specific, and some researchers argue that most of 5-Amino-1MQ's metabolic effect comes from preserving SAM and re-tuning gene methylation rather than from NAD⁺ elevation itself. Both explanations remain under investigation, and neither has been confirmed in humans.

Key pharmacological properties (from rodent data; no human pharmacology exists):

* **Selectivity:** High — it does not meaningfully inhibit structurally related methyltransferases or NAD⁺-salvage enzymes.

* **Half-life:** Approximately 3.8 hours after intravenous and 6.9 hours after oral dosing in rats.

* **Tissue distribution:** Distributes to metabolically active tissues including adipose (fat), skeletal muscle, and liver after subcutaneous dosing.

* **Metabolism and elimination:** As a small cationic molecule it is recovered in plasma and urine, indicating substantial renal (kidney) elimination; the specific metabolizing enzymes (e.g., **CYP**, cytochrome P450 liver enzymes) have not been characterized. Oral bioavailability in rats was about 38%.

## Historical Context & Evolution

5-Amino-1MQ was not repurposed from an older drug; it was purpose-built. In 2017–2018, researchers at the University of Texas set out to design small, selective, membrane-permeable inhibitors of NNMT as a new mechanism-of-action approach to obesity and type 2 diabetes. Among the methylquinolinium scaffolds they screened, the 5-amino substitution combined high potency with good cell permeability, making it the lead compound.

The reason it came to be considered for health optimization is that NNMT sits at the junction of two systems the longevity field already cared about: the NAD⁺ salvage pathway (energy and repair) and the SAM methyl-donor cycle (gene regulation). When early mouse studies showed fat loss without appetite suppression, and a 2019 study suggested benefits for aged muscle regeneration, the compound was rapidly adopted by the body-composition and longevity communities and sold online, well ahead of any human testing.

The scientific findings themselves are consistent in direction: across independent mouse studies, NNMT inhibition reduced adiposity, improved glucose handling, and reduced fatty liver. What has changed over time is sober recognition of the gap between animals and humans. Recent reviews emphasize that bioavailability, durable target engagement, and long-term safety in people remain unestablished, and that no clinical trial of 5-Amino-1MQ has been registered or reported. The evolution here is not a reversal but a maturing of caution: the mechanism remains promising, while the human evidence remains absent.

## Expected Benefits

A dedicated search of clinical databases, PubMed, and expert sources was performed to compile the benefit profile. A critical caveat frames every item below: **no human studies of 5-Amino-1MQ exist.** All efficacy evidence is from rodent or cell-culture work. A second caveat concerns who produced that evidence: the pivotal efficacy studies (Neelakantan et al., 2018; Babula et al., 2024) originate with the compound's developers at the University of Texas Medical Branch and the spin-out company Ridgeline Therapeutics, parties with a direct financial interest in its adoption — a conflict of interest to weigh when reading the animal results below. This ceilings the achievable evidence grade at "Low," and benefits that depend on human-specific claims (such as body recomposition in trained athletes) are "Speculative."

### Low 🟩

#### Reduction in Fat Mass and Body Weight

In diet-induced obese mice, 5-Amino-1MQ and closely related NNMT inhibitors reduced body weight, white fat mass, and fat-cell size, with a proposed mechanism of preserved SAM and NAD⁺ shifting fat cells away from making and storing fat and toward burning it. The evidence basis is several independent mouse studies plus supporting cell-culture data showing suppressed lipogenesis; notably, weight loss occurred without reduced food intake. The main limitation is that no human data confirm the effect or its size.

**Magnitude:** No human quantification exists; in obese mice, once-daily dosing over ~28 days dose-dependently limited body-weight and fat-mass gain and lowered total cholesterol versus vehicle-treated controls.

#### Improved Insulin Sensitivity and Glucose Control

NNMT inhibition improved oral glucose tolerance and insulin sensitivity and lowered elevated insulin in obese mice, consistent with reduced fat mass and improved liver metabolism. The proposed mechanism combines less fat accumulation with restored NAD⁺/SIRT1 signaling in metabolic tissues. The evidence is animal-only, and it is unknown whether lean or metabolically healthy humans — the likely users — would see any glucose benefit at all.

**Magnitude:** No human data; in obese mice, treatment improved oral glucose tolerance and insulin sensitivity and suppressed high fasting insulin relative to controls.

#### Reduced Liver Fat (Hepatic Steatosis)

In obese mice, 5-Amino-1MQ attenuated fatty-liver changes and immune-cell infiltration, reduced liver weight, size, and triglyceride content, and normalized the liver enzymes ALT (alanine transaminase) and AST (aspartate transaminase) — markers that rise with liver stress. The mechanism is thought to be reduced whole-body and hepatic fat storage. Evidence is confined to one well-characterized mouse study; human relevance is unproven.

**Magnitude:** No human data; in obese mice, liver triglycerides, liver weight/size, and ALT/AST were reduced toward normal versus controls.

#### Aged Skeletal Muscle Regeneration and Strength

In 24-month-old mice (roughly equivalent to advanced human age), NNMT inhibition after muscle injury increased muscle stem-cell (satellite-cell) activity, produced larger regenerating muscle fibers, and improved contractile strength, with a proposed mechanism of restored NAD⁺ balance reactivating aged, senescent stem cells. The evidence basis is a single controlled aged-mouse study supported by matching cell-culture results. Limitations are substantial: it is one study, in an injury model, and it does not test whether healthy humans gain muscle.

**Magnitude:** No human data; in injured aged mice, regenerating fiber cross-sectional area was roughly 2-fold larger and peak contractile torque about 70% higher than in untreated controls.

### Speculative 🟨

#### Cellular NAD⁺ Restoration and Longevity

The broadest claim made for 5-Amino-1MQ is that, by preventing NAD⁺ from being drained, it counters the age-related decline of this molecule and thereby supports "healthy aging." Mechanistically this is plausible — NNMT inhibition does raise NAD⁺ in some tissues — but there are no lifespan, healthspan, or aging-biomarker studies of 5-Amino-1MQ in any species, so the longevity framing rests on mechanism and extrapolation from the wider NAD⁺ field rather than on direct evidence.

#### Cognitive and Neuronal Energy Support

Marketing materials frequently claim improvements in focus, memory, and mental energy via enhanced neuronal NAD⁺. This is speculative: it is based on the general role of NAD⁺ in brain energy metabolism rather than on any study measuring cognition, mood, or brain endpoints with 5-Amino-1MQ. No controlled or anecdotal clinical data support a cognitive benefit.

## Benefit-Modifying Factors

Because human data are absent, the following are reasoned from the compound's biology and the populations most likely to respond.

* **Baseline adiposity and metabolic status:** Every documented benefit occurred in obese or metabolically stressed animals with elevated tissue NNMT. Lean, metabolically healthy users — common in the longevity audience — may have little baseline NNMT over-expression to inhibit and could therefore see smaller or negligible effects.

* **Age:** The muscle-regeneration signal appeared specifically in aged animals, where NNMT rises and stem-cell function declines. Older adults at the upper end of the target range may in principle be the most likely to benefit for muscle endpoints, whereas younger users may gain less.

* **Baseline NAD⁺ status:** Individuals with already-adequate NAD⁺ (e.g., from a nutrient-rich diet or NAD⁺ precursor use) may experience a smaller relative rise and blunted downstream effect.

* **Genetic variation in NNMT and methylation enzymes:** Because every documented benefit tracks with elevated tissue NNMT, common variants that raise baseline NNMT expression could enlarge the pool of over-active enzyme available to inhibit and, in principle, increase the benefit; conversely, variants in methylation-cycle enzymes such as **MTHFR** (methylenetetrahydrofolate reductase, an enzyme in folate/methyl metabolism) or **COMT** (catechol-O-methyltransferase, which uses the methyl donor SAM to break down certain neurotransmitters) could alter how the spared SAM is used. Both possibilities are mechanistically reasoned and unstudied for this compound.

* **Sex-based differences:** The pivotal rodent studies used predominantly male animals. Sex differences in fat distribution, NNMT expression, and methylation biology are plausible but have not been characterized for this compound.

* **Pre-existing conditions:** Fatty liver, insulin resistance, or early type 2 diabetes are the conditions the animal benefits map onto; people without these may have less to gain metabolically.

## Potential Risks & Side Effects

A dedicated search of drug-reference and toxicology sources was performed. The defining feature of the risk profile is absence of data: there are no published human safety studies, no formal toxicology package in the public domain, and no post-marketing surveillance. Animal studies reported no obvious adverse effects at the doses tested, but those were short, small, and not designed to detect subtle or long-term harm. Consequently, one risk is graded "Low" (unregulated product quality, where general evidence is strong) and the remainder are "Speculative."

### Low 🟥

#### Unregulated Product Quality and Contamination

5-Amino-1MQ is sold as a research compound and gray-market "peptide," outside pharmaceutical manufacturing standards. The risk is not from the molecule's known pharmacology but from what is actually in the capsule: independent testing of gray-market metabolic and "longevity" products has repeatedly found under- or over-dosing, wrong compounds, and contaminants. The consequence ranges from no effect to unexpected toxicity, and the user has no reliable way to verify identity or purity.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Loss of 1-Methylnicotinamide (1-MNA) Signaling

NNMT's product, 1-MNA, is not merely waste — some research attributes anti-inflammatory and blood-vessel-protective actions to it. Chronically suppressing NNMT lowers 1-MNA, so it is theoretically possible that long-term use removes a beneficial signal. No study has measured whether this matters in living animals or humans.

#### Systemic Methylation Shifts from SAM Elevation

By sparing SAM, sustained NNMT inhibition could raise methyl-donor availability body-wide, potentially altering the methylation of DNA and other targets beyond the intended metabolic genes. Whether this produces unwanted epigenetic changes over months or years is unknown and untested.

#### Reduced Xenobiotic Clearance

NNMT also methylates certain foreign compounds and drugs as part of their processing. Inhibiting it could, in principle, slow the clearance of such substances and change their effects or toxicity. No interaction study has examined this for 5-Amino-1MQ.

#### Unknown Long-Term, Fertility, and Pregnancy Safety

There are no reproductive, developmental, carcinogenicity, or chronic-toxicity studies. Because the compound alters fundamental energy and methylation pathways active in every cell, the absence of long-term data is a meaningful unknown rather than a reassurance.

## Risk-Modifying Factors

* **Pre-existing liver or kidney impairment:** Rodent data indicate substantial renal elimination and hepatic tissue exposure; impaired kidney or liver function could alter clearance and exposure in unpredictable ways, and no dosing adjustment data exist.

* **Genetic variation in methylation enzymes:** Variants such as **MTHFR** (methylenetetrahydrofolate reductase, an enzyme in folate/methyl metabolism) or **COMT** (catechol-O-methyltransferase, which uses SAM to break down certain neurotransmitters) could interact with a SAM-sparing intervention, but this is theoretical and unstudied.

* **Sex differences:** Safety was assessed almost entirely in male animals; risks specific to females, including any hormonal or reproductive effects, are uncharacterized.

* **Baseline biomarkers:** Individuals with elevated homocysteine or abnormal liver enzymes at baseline have no data to guide whether NNMT inhibition helps, harms, or is neutral for those markers.

* **Age and polypharmacy:** Older users are more likely to take multiple medications, increasing the chance of the theoretical drug-clearance interactions noted above.

## Key Interactions & Contraindications

No formal human interaction studies exist; the following are mechanism-based and precautionary.

* **NAD⁺ precursors and vitamin B3 forms (supplements):** Nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), niacin, and nicotinamide act on the same NAD⁺ system. Severity: caution/additive. Consequence: overlapping or additive effects on NAD⁺ metabolism with unknown net result; effects have not been studied in combination.

* **Methyl-donor supplements (supplements):** SAMe, betaine (trimethylglycine), and high-dose folate/methylcobalamin also influence the methylation cycle. Severity: caution. Consequence: unpredictable additive shifts in methylation balance.

* **Prescription drugs cleared by methyltransferase pathways (prescription):** Agents whose metabolism depends on methyltransferase activity — for example thiopurines such as azathioprine and mercaptopurine (metabolized by thiopurine S-methyltransferase, TPMT, an enzyme that inactivates thiopurine drugs) or levodopa (a substrate of COMT) — could theoretically be affected if a SAM-sparing agent alters methyl-donor availability. Severity: caution/monitor. Consequence: altered drug levels; no specific pairs have been characterized.

* **Over-the-counter agents (OTC):** No specific OTC interactions are documented; standard caution applies given the absence of data.

* **Other longevity interventions:** Combining with other experimental metabolic compounds compounds the uncertainty; no combination has safety data.

* **Populations who should avoid it:** Pregnant or breastfeeding individuals (no reproductive data); people with active cancer or under cancer surveillance (NNMT and methylation biology intersect with tumor metabolism, and effects are unstudied in this setting); those with significant liver or kidney disease; and anyone unwilling to accept an intervention with zero human safety data. Because no severity thresholds (e.g., specific enzyme or function cut-offs) have been established for this compound, avoidance is framed categorically.

## Risk Mitigation Strategies

* **Third-party purity and identity testing:** Because the dominant near-term risk is product quality, obtain a batch-specific certificate of analysis (identity, purity, and contaminant screening from an independent laboratory) before use. This mitigates the contamination and mislabeling risk.

* **Conservative, single-agent dosing:** Avoid stacking with other NAD⁺ boosters or methyl-donor supplements initially, so that any effect or adverse event can be attributed and the additive-interaction risk is minimized.

* **Baseline and follow-up laboratory monitoring:** Check liver enzymes (ALT/AST), a metabolic panel, fasting glucose and insulin, a lipid panel, and homocysteine before starting and periodically thereafter, to detect any adverse shift early given the compound's effects on liver and methylation pathways.

* **Time-limited trials rather than open-ended use:** Given the absence of long-term safety data, limiting use to defined, short evaluation periods (e.g., 8–12 weeks) with reassessment reduces cumulative exposure to unknown long-term risks.

* **Medical supervision for at-risk individuals:** Anyone with liver, kidney, hormonal, or oncologic history should involve a clinician, mitigating the risk of an unmonitored interaction or contraindication.

## Therapeutic Protocol

There is no validated human protocol; no clinical trial has established a safe or effective dose. What follows describes how the compound is used in practice by community practitioners, explicitly flagged as unvalidated.

* **Commonly used form and dose:** 5-Amino-1MQ is most often sold and used as an **oral capsule**, typically labeled at 50 mg once daily, sometimes with a range of 50–150 mg reported anecdotally. These figures derive from vendor labeling and community practice, not from dose-finding studies.

* **Practitioner framing:** Body-composition practitioners (for example, sources such as Jay Campbell's writing) position it as a daily oral agent taken for a period of weeks; some clinics pair it with NAD⁺ therapy. No expert consensus or clinic-standardized protocol exists.

* **Competing approaches:** The main alternative "approach" to raising NAD⁺ is supplementation with NAD⁺ precursors (NR, NMN, niacin) or intravenous NAD⁺, which have at least some human data. Neither is presented here as the default; 5-Amino-1MQ is distinguished by acting on the enzyme that consumes NAD⁺ rather than by adding precursor.

* **Best time of day:** Not established. It is commonly taken in the morning; there is no chronobiology data to support any particular timing.

* **Half-life and dose splitting:** With a rodent half-life of roughly 4–7 hours, once-daily oral dosing is the norm in practice, though the short half-life is a theoretical argument for split dosing that has not been tested.

* **Genetic considerations:** Variants in methylation-related enzymes (MTHFR, COMT) could in theory influence response to a SAM-sparing agent, but no pharmacogenetic data exist to guide dosing.

* **Sex-based considerations:** Dosing has not been studied by sex; pivotal animal work used mostly males, so no sex-specific guidance can be given.

* **Age considerations:** Older adults are the group with the clearest theoretical rationale (higher tissue NNMT, muscle findings in aged animals), but there is no age-adjusted dosing evidence.

* **Baseline biomarkers and conditions:** Response is expected to be greatest in those with metabolic dysfunction; individuals who are already lean and metabolically healthy have no evidence of benefit and no tailored protocol.

## Discontinuation & Cycling

* **Lifelong vs. short-term:** There is no evidence to support indefinite use. Given the absent long-term safety data, use is best regarded as short-term and experimental rather than lifelong.

* **Withdrawal effects:** None are documented. As a metabolic enzyme inhibitor with a short half-life, no physical dependence or withdrawal syndrome is expected, but this has not been studied.

* **Tapering:** No tapering protocol is described or biologically indicated; the compound clears within roughly a day.

* **Cycling:** Whether cycling preserves any effect or reduces risk is unknown. Some practitioners cycle it (e.g., weeks on, weeks off) on general principles, but no data show this maintains efficacy or improves safety.

## Sourcing and Quality

* **Regulatory status of supply:** 5-Amino-1MQ is not an approved drug or a recognized dietary supplement. It is sold as a "research chemical" or gray-market "peptide," so no regulator verifies its identity, dose, or purity.

* **What to look for:** Prioritize vendors that provide a recent, batch-specific certificate of analysis from an independent laboratory documenting compound identity, purity (often marketed as ≥98–99%), and screening for heavy metals, solvents, and microbial contaminants. Absence of such testing is a red flag.

* **Formulation:** It is most commonly offered as oral capsules or tablets; some suppliers sell bulk powder. Capsule products with verified per-unit dosing are preferable to unmeasured powder.

* **Reputable sourcing:** No brand can be endorsed as reliably high quality on the basis of independent evidence. Where a clinician is involved, a compounding pharmacy that performs its own analytical verification is preferable to an online research-chemical vendor.

## Practical Considerations

* **Time to effect:** Not established in humans. In animal studies, metabolic changes accrued over about 4 weeks of daily dosing, so any real-world effect would likely require weeks, not days.

* **Common pitfalls:** Treating a compound with zero human data as if it were a proven supplement; stacking it immediately with multiple other agents so nothing can be attributed; trusting vendor purity claims without a certificate of analysis; and expecting fat-loss effects in a lean person for whom the animal rationale may not apply.

* **Regulatory status:** In major markets it is neither approved for human use nor sanctioned as a supplement; sale is typically labeled "for research use only," and human use is off-label and unmonitored.

* **Cost and accessibility:** It is readily available online at moderate cost, but accessibility should not be mistaken for validation; the low barrier to purchase outpaces the evidence base.

## Interaction with Foundational Habits

* **Sleep:** Indirect and unstudied. NAD⁺ metabolism intersects with circadian biology, so a theoretical influence on sleep timing exists, but no data show that 5-Amino-1MQ improves or disrupts sleep. No specific timing guidance can be given.

* **Nutrition:** Indirect and potentially additive. The compound's targets overlap with dietary vitamin B3 and methyl-donor nutrients (folate, B12, betaine), so nutritional status may modulate its effects. A nutrient-adequate diet is the sensible backdrop; there is no evidence for pairing it with any specific diet, though its animal benefits were demonstrated against a high-fat-diet background.

* **Exercise:** Potentially potentiating for muscle endpoints, by mechanism. The aged-muscle findings involved regeneration and strength, and exercise independently raises NAD⁺ and stimulates muscle repair, so the two could be complementary. No study has tested the combination, and there is no evidence it blunts or enhances training adaptations.

* **Stress management:** Direction unknown. Through NAD⁺/SIRT1 and methylation pathways there is a plausible indirect link to stress-response biology, but no data address cortisol, resilience, or stress outcomes with this compound.

## Monitoring Protocol & Defining Success

Because 5-Amino-1MQ acts on liver, metabolic, and methylation pathways, baseline testing before starting and periodic follow-up are prudent to detect benefit or harm. Baseline labs should be drawn before the first dose to establish each individual's starting point.

Ongoing monitoring is reasonable at roughly 8–12 weeks after starting, then every 3–6 months if use continues, with body composition tracked over the same intervals.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
|-----------|--------------------------|-----------------|---------------|
| Fasting glucose | 75–90 mg/dL | Tracks the glucose-control benefit seen in animals | Fasting sample; conventional "normal" extends to 99 mg/dL, higher than the functional target |
| Fasting insulin | 2–5 µIU/mL | Detects insulin-sensitivity change | Pair with glucose to compute HOMA-IR (a calculated index of insulin resistance) |
| HbA1c | < 5.4% | Longer-term (≈3-month) glucose average | Not affected by short-term fasting; reflects prior weeks |
| ALT / AST | < 25 U/L (both) | Screens for the liver-fat benefit and for liver stress/harm | Conventional upper limits (~40 U/L) are higher than the functional target |
| Lipid panel (total, LDL, HDL, triglycerides) | Triglycerides < 80 mg/dL; HDL > 50 mg/dL | Animal data show cholesterol and triglyceride reductions | Fasting sample preferred for triglycerides |
| Homocysteine | 5–7 µmol/L | Watches the methylation (SAM/SAH) pathway the drug alters | Fasting; interpret alongside folate and B12 status |
| hs-CRP | < 1.0 mg/L | General marker of systemic inflammation | High-sensitivity assay; avoid testing during acute illness |

Qualitative markers to track alongside labs:

* Energy levels and daytime fatigue
* Body composition and waist measurement (visual and tape-measure changes)
* Exercise recovery and strength
* Cognitive clarity and focus (claimed but unproven)

Success would be defined as favorable movement in metabolic markers and body composition without any rise in liver enzymes or homocysteine and without new symptoms; a lack of measurable change, or any adverse shift, argues for discontinuation given the unproven benefit.

## Emerging Research

* **No registered human trials:** As of 07/15/2026, a search of ClinicalTrials.gov returned no registered clinical trials of 5-Amino-1MQ (or 5-amino-1-methylquinolinium) in any indication. The entire human evidence base remains at zero.

* **Preclinical metabolic program:** The most recent primary study advancing the compound is [Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction](https://pubmed.ncbi.nlm.nih.gov/39161060/) (Babula et al., 2024), from Ridgeline Therapeutics, which characterized 5A1MQ's pharmacokinetics and confirmed metabolic and liver benefits in obese mice — a step toward the safety and dosing data a human trial would require.

* **Clinical translation outlook:** A 2026 review, [Emerging opportunities for nicotinamide N-methyltransferase (NNMT) inhibitor clinical translation](https://pubmed.ncbi.nlm.nih.gov/42067476/) (Puleo et al., 2026), argues NNMT inhibitors are approaching human readiness while candidly identifying bioavailability, durable target engagement, and unknown safety as the remaining barriers — evidence that could strengthen the case if resolved.

* **Directions that could weaken the case:** The same literature notes that the NAD⁺ rise from NNMT inhibition is modest and tissue-specific, and that NNMT's product 1-MNA has its own protective roles; studies clarifying whether chronic inhibition removes beneficial signaling could weaken the rationale. Future work on off-target methylation effects (per [Roberti et al., 2021](https://pubmed.ncbi.nlm.nih.gov/33453420/)) could similarly temper enthusiasm.

* **Cardiometabolic breadth:** Recent mechanistic work extending NNMT inhibition to [heart failure with preserved ejection fraction in a mouse model](https://pubmed.ncbi.nlm.nih.gov/40484359/) (Li et al., 2025) suggests the target may matter beyond obesity, a research area to watch that could either broaden or complicate the risk-benefit picture.

## Conclusion

5-Amino-1MQ is a purpose-built small molecule that blocks an enzyme, NNMT, which becomes overactive in fat tissue and aging muscle. By doing so, it helps cells hold onto more of the fuel-and-repair molecule NAD⁺ and the body's main methyl donor, nudging cells to burn fat rather than store it. In obese mice it reduced fat, improved blood-sugar handling, and lessened fatty liver, and in old mice it appeared to help injured muscle recover and regain strength.

The decisive point is how thin the human evidence is: there is none. Every benefit rests on animal and cell studies, much of it produced by the compound's own developers and the company commercializing it — a financial interest worth keeping in view. No clinical trial has ever been run, and the compound is sold outside any quality-control system, so what is in a given capsule is uncertain. The known risks are mostly unknowns — long-term effects, methylation shifts, reproductive safety, and product contamination have not been studied.

For a reader focused on health and longevity, the mechanism is genuinely interesting and the direction of the animal findings is consistent, but the gap between a promising target and a validated human intervention is wide and unbridged. The most honest reading is that 5-Amino-1MQ is an early-stage experimental compound whose real-world benefits and risks in people remain undefined, and whose current use runs well ahead of its evidence.

**[Top](#top) - [Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol)**