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MIF-1 (Pro-Leu-Gly-NH2)3 residuesPLGEach bubble = one amino acid. Size = residue mass. Color = chemical class.Also known as: melanostatin, PLG, MIF-1
Eight of nine patients with treatment-resistant depression responded to MIF-1 in a 1994 double-blind trial. That's an 89% Hamilton Scale responder rate, from a peptide the body already makes. MIF-1 (Pro-Leu-Gly-NH2, also called melanostatin or PLG) is an endogenous tripeptide cleaved from oxytocin. It works as a positive allosteric modulator of dopamine D2 and D4 receptors, a mechanism no approved antidepressant uses. The catch: only one small RCT exists (n=20), and nobody has replicated it in over 30 years. Sourcing is difficult, with just one or two verified US vendors. Biohackers targeting anhedonia and treatment-resistant depression run 5 to 7 day courses at 10 mg subcutaneous daily, following the exact protocol from that single trial.
An 89% responder rate in treatment-resistant depression from a peptide your hypothalamus already produces. That's what Ehrensing and colleagues reported in 1994 [1], and nobody has tried to replicate it since. MIF-1 (Pro-Leu-Gly-NH2, CAS 2002-44-0) goes by melanostatin and PLG. It's a tripeptide derived from enzymatic cleavage of oxytocin, first isolated from hypothalamic extracts in the 1970s. The original research interest was MSH inhibition, but the pharmacology turned out to be far more interesting than pituitary regulation. The mechanism is unusual. MIF-1 binds to an allosteric site on dopamine D2 and D4 receptors, distinct from where dopamine itself docks. This potentiates dopaminergic signaling without directly activating the receptor. Think of it as adjusting the gain on a microphone rather than speaking into it. In parallel, MIF-1 antagonizes mu-opioid receptors, which adds a separate antidepressant pathway. In practice, the community uses MIF-1 almost exclusively for anhedonia and treatment-resistant depression. The standard protocol mirrors the Ehrensing trial: 10 mg subcutaneous daily for 5 to 7 days, then a 3-week washout. Sourcing is the biggest practical barrier; only one or two verified domestic vendors carry it. Benefits typically emerge around day 4 and persist for 1 to 3 weeks post-course. The peptide exhibits an inverted-U dose-response curve, so exceeding 10 mg per day actually reduces effectiveness. A 2007 marmoset study [2] found no motor benefit in Parkinson's models, narrowing the realistic use case to mood and cognition.
MIF-1 operates through two receptor systems simultaneously. The primary action is positive allosteric modulation of dopamine D2 and D4 receptors. Photoaffinity labeling studies confirmed that PLG binds at a site distinct from the orthosteric dopamine pocket on D2 receptors [3]. This means it doesn't compete with dopamine. Instead, it amplifies the signal when dopamine is already present. The allosteric mechanism explains why side effects are mild compared to direct dopamine agonists. MIF-1 tunes existing dopaminergic tone rather than flooding receptors. c-Fos mapping studies [4] showed dose-dependent and time-dependent neuronal activation in the cingulate cortex, hypothalamus, amygdala, and nucleus accumbens after peripheral administration. These are the brain regions most involved in mood regulation, reward processing, and anxiety. The second pathway is anti-opioid activity. MIF-1 antagonizes mu-opioid receptor activation, which contributes to its antidepressant properties through a different mechanism than standard antidepressants. At the intracellular level, the peptide activates pERK signaling and modulates phosphorylated STAT3. MIF-1 also suppresses alpha-MSH release from the pituitary and potentiates melatonin, tying its effects into neuroendocrine circadian regulation. The functional CNS half-life is roughly 2 hours based on brain activation kinetics, but plasma stability runs around 5 days at 37 degrees. That disconnect between brain activity and plasma persistence partly explains the inverted-U dose-response: plasma accumulation across a multi-day course eventually saturates the therapeutic window.
Single 1994 pilot RCT (Ehrensing)[1] showed 89% Hamilton responder rate (8/9 patients) with 10mg SC daily × 5 days vs 18% placebo in treatment-resistant depression. Inverted-U dose-response well-established in animal literature [6]. No replication trials in 30+ years. 2025-2026 research active only on synthetic analogs, not parent PLG.
Ehrensing et al. 1994 (PMID 7989637): double-blind RCT, n=20 (9 MIF-1, 11 placebo), TRD population, 10mg SC × 5 days
Single small RCT (n=20) from 1994; never replicated; no Phase 3 data; no long-term safety follow-up; optimal cycle duration not formally tested beyond 5–10 days; only TRD population studied clinically
Community protocols closely mirror Ehrensing 1994 design. 10mg SC daily for 5–7 days is the consensus dose. Primary concern is inverted-U effect: users consistently warn against exceeding 7-day runs or dose-escalating. Anhedonia is the most commonly targeted symptom. Small experiencer base due to extreme sourcing difficulty.
Community protocols are direct adaptations of the Ehrensing 1994 RCT design (10mg SC × 5–7 days, 3-week washout). The inverted-U pharmacology warning prominent in preclinical literature is consistently echoed by experienced community users. No community protocol escalates beyond 10mg/day.
| Level | Dose / Injection | Frequency |
|---|---|---|
| Beginner | 5mg | Daily |
| Moderate | 10mg | Daily |
| Aggressive | 10mg | Daily |
Reconstitution math matters here because the vial sizes and standard dose create specific syringe calculations. For a 10 mg vial, add 1 mL bacteriostatic water to get 10 mg/mL. Your full 10 mg dose is the entire 1 mL syringe (100 units on an insulin syringe). A 5 mg starter dose is 50 units. Don't use the calculator default of 2 mL; that gives you 5 mg/mL and you'll underdose if you're not recalculating. For a 50 mg vial, add 2 mL bacteriostatic water for 25 mg/mL. Each 10 mg dose is 0.4 mL (40 units). That gets you five 10 mg doses per vial, which covers one full course. The non-obvious thing most beginners miss: MIF-1 is NOT the same molecule as MIF (macrophage migration inhibitory factor). When reading forums or ordering, confirm CAS 2002-44-0 and the sequence Pro-Leu-Gly-NH2. The naming collision causes real confusion in search results and vendor listings. Sourcing is the biggest practical problem. Only 1 to 2 verified US vendors carry it. Order enough for 2 to 3 cycles before starting; supply disruptions have left users stranded mid-protocol.
Clinical trials used 5-10 consecutive daily injections per course. The inverted U-shaped dose-response curve means it's best not to escalate dose if effects plateau: instead, take a break and repeat the course. Some protocols suggest repeating 5-day courses with 3-4 week breaks.
MIF-1 has an unusually long plasma half-life (~5 days at 37°C), causing progressive accumulation across a multi-day course. This accumulation eventually pushes plasma exposure into the descending arm of the inverted-U dose-response curve, reducing efficacy or producing paradoxical worsening. The 3-week washout (>5 plasma half-lives) allows complete clearance and restoration of D2/D4 receptor sensitivity before the next course.
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Expected: Subtle baseline mood improvement by days 3–5; hedonic tone normalization; non-stimulant effect profile. Lower response rate expected vs 10mg clinical dose.
Monitor: Log mood and anhedonia daily. If no response by day 5, do not escalate to 5mg 2x daily: restart next cycle at 10mg after full washout.
Reconstitute one vial of lyophilized MIF-1 with bacteriostatic water. For a 10 mg vial, add 1 mL (gives 10 mg/mL). For a 50 mg vial, add 2 mL (gives 25 mg/mL).
Don't shake it.
For the standard 10 mg dose: pull to 100 units from a 10 mg/mL solution, or 40 units from a 25 mg/mL solution. For a 5 mg starter dose: pull to 50 units from a 10 mg/mL solution.
Pinch a fold of skin, insert the needle at a 45 degree angle, and inject slowly.
Rotate injection sites each day across the 5 to 7 day course.
MIF-1 is not a stimulant, but morning dosing aligns with the clinical trial protocol.
Do not exceed 10 mg per injection or add a second daily injection.
After the course, take a full 3-week washout before repeating. The 5-day plasma half-life means 3 weeks clears approximately 5 to 6 half-lives.
Store reconstituted vials at 2 to 8 degrees Celsius and use within 14 days. Don't freeze reconstituted solution.
Historical oral trials required 60–150 mg/day to achieve CNS effects vs 10 mg SC; >6–15× higher dose required to compensate for poor oral bioavailability (<1% systemic absorption reaching CNS)
Early 1980s depression trials used oral MIF-1 (60mg/day > 150mg/day per inverted-U). Not practical for self-administration given dose volumes required and the inverted-U ceiling. SC is the only viable route for the community dosing range.
Complementary cognitive mechanisms: Semax is BDNF-driven / ACTH-derived with dopaminergic and serotonergic effects; MIF-1 is a D2/D4 PAM with anti-opioid activity. Combined dopaminergic and neuroplastic action without direct overlap.
Most frequently cited community stack. L-DOPA provides dopamine substrate; MIF-1 PAM at D2R amplifies sensitivity to that substrate. Combined dopamine system restoration approach rather than pure symptom suppression.
Mucuna Pruriens taken 30–60 min before MIF-1 injection during active course days
BDNF priming hypothesis: ketamine-induced rapid neuroplasticity may amplify the antidepressant effect of the subsequent MIF-1 course. Community protocol only; no clinical data.
Complete ketamine session(s) first; begin MIF-1 course 24–72 hours after last ketamine
Opioid receptor conflict: MIF-1 antagonizes mu-opioid receptor activation as part of its antidepressant mechanism; LDN intermittently blocks these same receptors. Concurrent use is theorized to cancel or attenuate both mechanisms.
Do not combineAdditive D2/D4 stimulation risk. MIF-1 PAM at D2/D4 plus direct dopamine agonism may produce hyperdopaminergic adverse effects (nausea, orthostatic hypotension, impulse control issues). Requires medical supervision if combined.
MIF-1 antagonizes opioid receptor activation: may reduce analgesic efficacy of opioid medications. Clinically significant if opioids are being used for pain management.
Pricing updated 2026-04-09
The most important safety concern with MIF-1 isn't a side effect in the traditional sense. It's the inverted-U dose-response curve. Exceeding the optimal dose or running courses too long can paradoxically worsen the symptoms you're trying to treat. Animal models [6] showed that 10 mg/kg worsened depressive behavior, and human oral trials found 60 mg/day outperformed 150 mg/day. This isn't theoretical; community users who extend courses beyond 7 days consistently report benefit reversal. MIF-1 modulates dopamine D2 and D4 receptors allosterically. In individuals with active psychosis or bipolar disorder, this dopaminergic modulation could alter symptom presentation unpredictably. No clinical trials have been conducted in these populations. Active psychotic episodes remain a hard contraindication. Because MIF-1 antagonizes mu-opioid receptors, anyone using opioid analgesics for pain management faces a real clinical conflict. The peptide may reduce the analgesic effectiveness of morphine, codeine, or oxycodone. Don't start MIF-1 while depending on opioids for pain control without medical supervision. Published side effects from the clinical trials are genuinely mild. The Ehrensing 1994 trial (n=20)[1] reported no serious adverse events at 10 mg subcutaneous daily for 5 days. Common effects include mild injection site discomfort, occasional dizziness shortly after the injection, and transient headache. Rare reports mention brief restlessness or mild agitation. MIF-1 suppresses alpha-MSH release from the pituitary. The long-term consequences of sustained MSH suppression across repeated cycles are not characterized in the literature. This gap deserves attention for anyone planning extended use. Pregnancy and breastfeeding data do not exist. Insufficient safety information makes this a clear contraindication. The same applies to anyone with known hypersensitivity to MIF-1 or related peptides. Concurrent use with dopamine agonists like pramipexole or ropinirole risks additive D2 stimulation, which could produce nausea, orthostatic hypotension, or impulse control problems. MAO inhibitors present a theoretical interaction risk through dopaminergic pathway overlap. The peptide also potentiates melatonin, so combining it with melatonin supplements may produce excessive sedation. When to stop: if your mood worsens during an active course (especially after day 5), that is pharmacological saturation. End the course immediately and begin the 3-week washout. If you experience unusual agitation or restlessness, stop and consult a physician.
Verify MIF-1 (Pro-Leu-Gly-NH2) dosing and safety with a second opinion
Extreme sourcing difficulty with only 1–2 verified domestic US vendors as of April 2026; no compounding option (not on FDA 503A Bulks List); significant naming confusion risk with macrophage MIF immune cytokine (entirely different molecule); community reports of supply disruptions
| Test | When | Target |
|---|---|---|
| Hamilton Depression Rating Scale (HAM-D) or PHQ-9 (self-administered) | Baseline before first course, then day 7 of each course | Clinical response = ≥50% reduction from baseline HAM-D score |
| Subjective anhedonia/mood daily log (1–10 scale) | Daily throughout active course | — |
Quantifies antidepressant response and matches Ehrensing 1994 RCT endpoints; provides objective data for cycle-to-cycle comparison
Early detection of inverted-U saturation effect (plateau or reversal of benefit mid-course) before completing unnecessary injection days
Subtle mood improvements may begin. Clinical trials noted some patients responding within the first few days. Mild activation or alertness is common.
Measurable antidepressant effects typically emerge. In the Ehrensing 1994 trial, MIF-1 produced significant Hamilton Scale improvements by the end of the first week.
Peak therapeutic response for a single treatment course. The van der Velde 1983 study noted rapid and often dramatic antidepressant effects within this window.
Benefits may persist after the injection course ends due to sustained dopamine receptor modulation. Monitor for any return of symptoms to determine timing of the next course.
Days 1 to 3 (Onset window): D2 receptor allosteric potentiation begins with the first injection. Brain activation peaks about 2 hours post-dose in the cingulate cortex, hypothalamus, amygdala, and nucleus accumbens. Plasma levels build toward accumulation across these first days. Community users describe a subtle baseline mood shift; some report the numbness or hopelessness lifting within hours of the first 10 mg injection. Not everyone feels anything in this window. Mild injection site discomfort, occasional dizziness, or a brief headache are the most common side effects. No stimulant-type effects. Days 4 to 7 (Primary therapeutic window): This is where the clinical data gets interesting. Ehrensing's 1994 RCT [1] showed statistically significant Hamilton Scale improvements by the end of day 5 to 7 in responders. Van der Velde's 1983 trial [5] described the effects as "rapid and often dramatic." Users report restoration of hedonic tone and anticipatory positive emotion. The effect profile is non-stimulant: no increase in heart rate or blood pressure, no insomnia, no anxiety. Side effects remain mild, with rare reports of transient restlessness. Days 8 to 10 (Accumulation caution zone): Proceed carefully here if you've extended beyond 7 days. Plasma half-life of roughly 5 days means continued accumulation. The risk of crossing into the descending arm of the inverted-U dose-response is real. Animal data [6] showed worsening at accumulation-equivalent exposures. Community users who push past day 7 consistently report benefit plateau followed by reversal. If effects fade or mood worsens, stop the course and begin washout. Weeks 2 to 4 (Post-course persistence): Sustained D2 receptor allosteric modulation may outlast plasma clearance. Full plasma clearance takes approximately 3 weeks (five to six half-lives of a 5-day half-life compound). Benefits often persist 1 to 3 weeks after the last injection. When anhedonia or low mood returns, that signals timing for the next cycle. Some users repeat every 4 weeks; others cycle based on symptom return.
D2R allosteric potentiation begins; c-Fos activation in cingulate cortex, hypothalamus, amygdala, and nucleus accumbens peaks ~2 hours post-injection (functional CNS half-life ~2 hours). Plasma levels building toward accumulation.
Subtle baseline mood shift; some users report hopelessness or numbness resolving within hours of the first 10mg injection. Not all users feel anything in this window.
Ehrensing 1994: statistically significant Hamilton Scale improvements measurable by end of day 5–7 in responders. Van der Velde 1983 (PMID 6138756): "rapid and often dramatic" effects within this window.
Restoration of hedonic tone and anticipatory positive emotion; described as a non-stimulant antidepressant: no increase in HR/BP, no insomnia. Subtle but consistent baseline mood elevation.
Plasma half-life of ~5 days means continued accumulation. Risk of crossing into the descending arm of the inverted-U dose-response. PMID 2568001: 10mg/kg in animal model worsened symptoms at accumulation-equivalent exposures.
Users who extend beyond 7 days report plateau of benefits, then reversal. This is the most consistent community safety signal for MIF-1.
Sustained D2R allosteric modulation may persist after plasma clearance. Full plasma clearance expected by ~3 weeks (5-day half-life × 5–6 half-lives). Receptor sensitivity restoration during this window.
Benefits often persist 1–3 weeks post-course. Return of anhedonia or low mood signals timing for next cycle. Some users cycle every 4 weeks; others cycle PRN.
Source: Functional CNS half-life estimated at ~2 hours based on brain activation kinetics; plasma stability is exceptionally long (~5 days for 50% degradation at 37°C) but doesn't reflect functional duration (Kastin & Pan, 2007)
Loading the interactive decay curve.
MIF-1 (Pro-Leu-Gly-NH2) is classified as a research chemical. It does not have FDA approval for any therapeutic indication. The 1994 Ehrensing trial was conducted under IND protocols, but development did not advance beyond Phase 2. Current research activity focuses on synthetic analogs of PLG rather than the parent tripeptide. MIF-1 is not on the FDA 503A Category 1 Bulks List, which means licensed compounding pharmacies cannot legally compound it. All current sourcing is through research chemical vendors. As of April 2026, the primary community-verified vendor is Limitless Life Biotech. MIF-1 is not listed as a controlled substance in the United States. WADA status has not been formally addressed; athletes subject to anti-doping testing should verify with their governing body before use. This content is for educational and research purposes only. It is not medical advice, and MIF-1 is not approved for human therapeutic use. Consult a licensed healthcare provider before using any research peptide.
Peptide Schedule Research TeamReviewed Apr 20268 Citations
