Section 01
What it's used for
Fast antidepressant effect in mice
A 2010 study found 4 days of spadin worked like an antidepressant in mice across 5 tests, while 4-day fluoxetine did nothing and needed about 15 days. No human has been treated with spadin. Nearly all research comes from one French lab.
▸Clinical wording
Spadin is a 17-amino-acid fragment of the propeptide released during maturation of sortilin/NTSR3, and the founding 2010 study reported that four days of intravenous spadin produced antidepressant-like effects in mice across five paradigms — forced swim, tail suspension, conditioned suppression of motility, learned helplessness and novelty-suppressed feeding — whereas a four-day fluoxetine regimen had no effect and chronic fluoxetine required about 15 days. The same four-day treatment roughly doubled the number of BrdU-positive cells and of pCREB-labelled neurons in the hippocampal dentate gyrus. All of this is rodent work; no human has been treated with spadin in a published study. Nearly all in vivo spadin research originates from a single laboratory, the Institut de Pharmacologie Moléculaire et Cellulaire (CNRS, Valbonne, France), which is a substantial limitation on how far the findings can be trusted.
A precise research tool in mice
Spadin binds TREK-1 tightly (~10 nM) and blocks it (IC50 40-60 nM), without affecting related channels, heart rhythm, blood pressure, pain, seizures or stroke damage in mice. A standard tool for TREK-1 research, tested only in rodents.
▸Clinical wording
Spadin binds TREK-1 with an affinity around 10 nM and inhibits the current with a reported IC50 of 40–60 nM in later work from the same group. A dedicated selectivity and safety study in mice found that spadin did not inhibit the related channels TREK-2, TRAAK, TASK or TRESK, did not block the cardiac IKr or IKs currents, did not alter systolic pressure or heart rate, and did not alter pain thresholds, kainate-induced seizures or infarct size after focal ischaemia. Because of that selectivity, spadin has become a standard pharmacological tool for TREK-1 in laboratories unrelated to its discoverers, for example in mouse decompression-sickness experiments. Note that this selectivity profile was established in rodents only.
A non-standard route to mood effects
Spadin acts on a potassium channel, not the serotonin system. In mice, it boosted markers of brain plasticity and BDNF. In stressed rats, it reduced depression-like behavior and calmed brain inflammation. Both findings are animal-only.
▸Clinical wording
Spadin's target is a two-pore-domain potassium channel rather than a monoamine transporter, and its reported downstream effects are on plasticity: in mice it increased the synaptic markers PSD-95 and synapsin, promoted mature dendritic spine formation, and rapidly raised hippocampal BDNF expression. An unrelated Chinese group later used spadin in rats exposed to six weeks of chronic unpredictable mild stress and reported reduced depressive-like behaviour together with suppression of A1-like reactive astrocytes through the NF-κB pathway — the closest thing to independent support for the antidepressant claim. Both studies are in rodents, and neither addresses whether the mechanism translates to human depression.
No human evidence yet
No study has tested spadin in treatment-resistant depression, and no trials are registered. The only human data: in 45 patients, levels of spadin's parent molecule rose about a month after ECT, only in responders — not proof spadin helps.
▸Clinical wording
No study was found in which spadin was tested in a model of treatment-resistant depression or given to patients, and a ClinicalTrials.gov query for spadin as an intervention returned no registered trials. The only human data touching this peptide family are observational: in 45 patients with treatment-resistant major depression, serum concentrations of the sortilin-derived propeptide — the parent molecule from which spadin is derived — rose significantly about one month after electroconvulsive therapy, and only in treatment responders. That is a biomarker association measured after an unrelated therapy, not evidence that spadin treats resistant depression.
One early mouse stroke study
In mice with stroke, mini-spadin (0.03 µg/kg, then 3 µg/kg 4x weekly) given 30 min later for 7 days prevented weight loss, nerve loss and post-stroke depression. One unreplicated study from its own lab, called first evidence.
▸Clinical wording
In a mouse model of focal cerebral ischaemia, the shortened analogue mini-spadin was given intraperitoneally at a low dose of 0.03 µg/kg starting 30 minutes after the onset of ischaemia, once daily for seven days, then at 3 µg/kg four days a week; electrophysiology showed the peptide activates TREK-1 at low doses and inhibits it at higher ones. The authors reported prevention of body-weight loss and of delayed dopaminergic degeneration in the substantia nigra, improved motor and cognitive deficits, and prevention of post-stroke depressive behaviour in the forced swim and novelty-suppressed feeding tests. This is a single mouse study from the originating laboratory, described by its own authors as first evidence, and it has not been replicated.
Short-lived, so labs made analogs
Spadin's effect fades within about 7 hours in animals. Newer versions PE 22-28 and G/A-PE 22-28 are more potent, lasting 14-23 hours, with antidepressant effects in mice after 4 days. Animal-only; spadin was never tested in clinics.
▸Clinical wording
Spadin's practical drawback is stability: its effect in vivo does not persist beyond about seven hours, with a reported half-time of roughly six hours at 100 µg/kg, which is why the same group has pursued shorter derivatives. The analogues PE 22-28 and G/A-PE 22-28 inhibit TREK-1 with IC50 values of 0.12 nM and 0.10 nM against 40–60 nM for spadin, act for 14–23 hours, and produced antidepressant-like effects in mice in the forced swim, novelty-suppressed feeding and learned helplessness tests after four days. These analogues remain preclinical, and the pharmacokinetic limitation is one reason spadin itself has never entered clinical development.
Section 02
Mechanism of Action
A leftover fragment blocks a brain channel
- Spadin is a 17-amino-acid fragment cut from a longer piece discarded when a receptor protein matures.
- It sticks tightly to a potassium channel called TREK-1, at roughly 10 nanomolar affinity.
- In monkey kidney cells it blocked about 63% of the channel's current; in brain slices about 91%.
- That block was entirely absent in mice engineered without the gene for the channel.
▸Clinical wording
TREK-1 blockade by a fragment of the sortilin propeptide
Spadin is a 17-residue peptide (PE 12-28) carved from the 44-amino-acid propeptide that furin releases when it matures prosortilin, also known as neurotensin receptor-3, in the trans-Golgi. It binds TREK-1 with an affinity of about 10 nM. In COS-7 cells, 100 nM spadin blocked 63 ± 12% of the arachidonic-acid-stimulated TREK-1 current, with an IC50 of 70.7 nM at 0 mV. In CA3 neurons of hippocampal brain slices it blocked 90.8 ± 6.0% of the arachidonic-acid-induced current, and that effect was entirely absent in kcnk2-deficient mice. Cultured hippocampal pyramidal neurons showed 49.7% inhibition at 1 µM. Sortilin is itself a TREK-1 partner and raises the channel's surface expression.
The target was proven by mouse genetics
- The rationale rests on mice bred without the channel, studied before spadin existed.
- Those mice resisted depression-like behaviour in five separate models and showed stronger serotonin signalling.
- Their stress hormone rise was much blunted, and they behaved like animals given fluoxetine.
- The channel normally holds neurons below firing threshold, so removing it makes them more excitable.
▸Clinical wording
Genetic validation of the target in TREK-1 knockout mice
The pharmacology rests on a mouse genetic phenotype described before spadin existed. Mice lacking kcnk2 resisted depression-like behaviour in five separate models, showed increased efficacy of serotonergic neurotransmission, and had substantially blunted corticosterone elevation under stress; their behaviour resembled that of naive animals treated with fluoxetine. TREK-1 is a background potassium channel that holds the resting membrane potential below the depolarisation threshold, so removing it — genetically or pharmacologically — raises excitability in the neurons that carry it. Sortilin and TREK-1 are markedly co-expressed in the dorsal raphe nucleus.
Freeing serotonin neurons to fire faster
- In live mice, injected spadin raised serotonin neuron firing from 1.26 to 3.1 times per second.
- That roughly 146% increase matched the rate measured in mice bred without the channel.
- After four days of treatment mice behaved like antidepressant-treated animals across five predictive tests.
- Only about one thousandth of the injected dose reached the brain, near its binding affinity.
▸Clinical wording
Serotonergic disinhibition in the dorsal raphe nucleus
Recording from dorsal raphe 5-HT neurons in vivo, intraperitoneal spadin raised the mean firing rate from 1.26 ± 0.27 Hz to 3.1 ± 0.7 Hz, an increase of roughly 146%, matching the rate measured in TREK-1 knockout mice. Mice treated for four days behaved like antidepressant-treated animals across five predictive paradigms: forced swim, tail suspension, conditioned suppression of motility, learned helplessness and novelty-suppressed feeding. Roughly one thousandth of injected spadin crossed the blood-brain barrier, giving brain concentrations near 10 nM, the same order as both its binding affinity and its electrophysiological IC50.
New neurons and synapses within days
- Four days of spadin doubled the new progenitor cells in a memory-forming region of mouse brain.
- Most of those new cells, 85.2%, became neurons; fluoxetine needed 15 days for a comparable change.
- Two synapse proteins rose in cultured neurons, and a growth protein (BDNF) rose in mice within seven days.
- It left one growth-signalling pathway (mTOR) untouched, which separates it from ketamine.
▸Clinical wording
Neurogenesis, synaptic proteins and BDNF on a four-day timescale
Four days of spadin doubled the number of BrdU-positive progenitors in the subgranular zone of the dentate gyrus and doubled phosphorylated CREB in hippocampal tissue, with 85.2% of the new cells becoming DCX-positive neurons; fluoxetine required 15 days to produce a comparable change. In cultured cortical neurons, spadin raised PSD-95 immunoreactivity by 5 hours and synapsin protein by 36 hours, with mRNA peaking near 8 hours, and it activated ERK1/2 and PI3K/Akt with an optimum around 100 nM. It did not phosphorylate mTOR, which separates it from ketamine. In mouse hippocampus, BDNF rose within 7 days and persisted to day 21.
Hitting one channel and not its relatives
- Spadin blocks its target channel at low concentrations, with no significant action on five related channels.
- Mice lacking the channel entirely are more seizure-prone, more pain-sensitive and fare worse after stroke.
- In rodents spadin did not reproduce those liabilities in pain, seizures, heart function or glucose handling.
- Separately, in pancreatic beta cells and mouse islets it raised calcium and glucose-stimulated insulin.
▸Clinical wording
Channel selectivity and the consequences of blocking TREK-1
Spadin inhibits TREK-1 with an IC50 of 40-60 nM and showed no significant action on TREK-2, TRAAK, TRESK, TASK-1 or cardiac hERG; the shortened analogue PE 22-28 reached 0.12 nM. Selectivity matters because TREK-1 is protective elsewhere: knockout mice are more prone to kainate seizures, more sensitive to thermal and mechanical pain, and fare worse after global ischaemia. In rodents, spadin did not reproduce those liabilities — no change in pain sensitivity, seizure threshold, ischaemic outcome, cardiac function or glucose metabolism. Separately, TREK-1 is expressed in MIN6-B1 beta cells and mouse islets, where spadin raised intracellular calcium and glucose-stimulated insulin.
Section 03
Biological Pathways
No data for this section yet.
Section 04
Dosage Information
ALGSLHSE...(17 aa, sortilin propeptide fragment)| Route / system | Context | Range studied | Limitation |
|---|---|---|---|
| Into the belly — depression models | Mice, standard antidepressant screening tests | 100 µg/kg a day for 4–5 days, a 100 µL saline shot 30 minutes before testing. Four days was equated to 21–28 days of an antidepressant | A shot into a mouse's belly that was never scaled to a person: no human-dose conversion was calculated, and the effect fades after about 7 hours in a rodent. |
| Intravenous / into brain fluid | The 2010 paper that first described spadin | Strengths, not weights: 1 µM in a 100 µL vein shot daily for 4 or 15 days; 100 µM to 10 nM into brain fluid, 30 minutes before testing | A strength in a bolus does not convert into milligrams for a person, and the brain arm skipped the blood–brain barrier — never measured in a human. |
| Into the belly / oral — PE 22-28 | Seven-amino-acid analogue, mice | 3.2–4.0 µg/kg into the belly — about 25 times less than spadin — or 1.0 mg/kg by stomach tube, with an effect lasting up to 23 hours | Numbers for a different peptide: it half-blocks the channel at 0.12 nM against 40–60 nM for spadin. That gap is how far a spadin dose would miss. |
| Intranasal / subcutaneous — self-use | Practice around PE 22-28, sold as mini-spadin | 100–300 µg once a day by nose or under the skin, with reports up to 500 µg — roughly 1–7 µg/kg for a 70–90 kg adult | Circulating practice, and for the analogue, not spadin. Spadin itself has never been given to a person: as of 2026 there is no registered trial. |
Results
Syringe Fill Level (100u syringe)
Set positive values for: Recommended dose per kg.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Section 05
Protocols
No protocols featuring this peptide yet. Browse All Protocols
Section 06
Stability & Storage
Lyophilised powder
The lyophilised powder is stored at −20 °C. It dissolves in water — the supplier states 1 mg/ml. The study that first described spadin prepared the stock in distilled water and diluted it to working concentrations with 0.9% sodium chloride.
After reconstitution
Solutions are best prepared on the day they are used. If a solution has to be kept, it is held at −20 °C for no longer than a month — a published study stored commercial spadin as stock solutions at the same temperature.
Section 07
Side Effects & Precautions
Spadin and its shorter analog PE-22-28 were never tested in humans: no trial is registered, and every publication is rodent or cell-culture work from one research group, with no independent replication. A targeted mouse screen found spadin did not affect pain, seizures, ischemic injury, or cardiac function, but it checked specific known risks, not general toxicology — no dose-ranging toxicity or genotoxicity study exists. For PE-22-28, a similar screen ruled out effects on the hERG channel, but beyond that the source paper only states an absence of side effects is 'expected,' not measured.
Section 08
Regulatory Status
Clinical development
No human trials have ever been run
Spadin and its shorter analogue PE-22-28 were validated as TREK-1 potassium-channel blockers in five behavioural models of depression in mice, not in people (Mazella et al., 2010). As of 2026 a PubMed search for spadin or PE-22-28 in humans returns no completed study, and neither compound is registered on ClinicalTrials.gov.
FDA / United States
No approval pathway is open yet
No Investigational New Drug application or New Drug Application for spadin or PE-22-28 appears on the public FDA record, and neither peptide sits on any FDA bulk drug substance list that would allow compounding. The same absence of review applies to the EMA in the European Union.
WADA
Falls under category S0 by definition
WADA's S0 — Non-Approved Substances covers any pharmacological substance without current approval by a governmental health authority for human therapeutic use, including compounds still under preclinical development like spadin; the category applies even to substances not named individually on the Prohibited List, and the ban runs at all times.
A peptide with promising animal data is not the same as a proven treatment, and the regulatory picture can change quickly once human trials begin — check the current status with your own medicines regulator before drawing conclusions from this summary.
Section 09
Research Studies
- [1]Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug designMazella J, Petrault O, Lucas G, Deval E, Beraud-Dufour S, Gandin C, El-Yacoubi M, Widmann C, Guyon A, Chevet E, Taouji S, Conductier G, Corinus A, Coppola T, Gobbi G, Nahon JL, Heurteaux C, Borsotto M · PLoS Biology · 2010
- [2]Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotypeHeurteaux C, Lucas G, Guy N, El Yacoubi M, Thummler S, Peng XD, Noble F, Blondeau N, Widmann C, Borsotto M, Gobbi G, Vaugeois JM, Debonnel G, Lazdunski M · Nature Neuroscience · 2006
- [3]In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadinDevader C, Khayachi A, Veyssiere J, Moha Ou Maati H, Roulot M, Moreno S, Borsotto M, Martin S, Heurteaux C, Mazella J · British Journal of Pharmacology · 2015
- [4]Shortened spadin analogs display better TREK-1 inhibition, in vivo stability and antidepressant activityDjillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M · Frontiers in Pharmacology · 2017
- [5]Spadin as a new antidepressant: absence of TREK-1-related side effectsMoha Ou Maati H, Veyssiere J, Labbal F, Coppola T, Gandin C, Widmann C, Mazella J, Heurteaux C, Borsotto M · Neuropharmacology · 2012
- [6]Role of TREK-1 in health and disease, focus on the central nervous systemDjillani A, Mazella J, Heurteaux C, Borsotto M · Frontiers in Pharmacology · 2019
- [7]Potentiation of calcium influx and insulin secretion in pancreatic beta cell by the specific TREK-1 blocker spadinHivelin C, Beraud-Dufour S, Devader C, Abderrahmani A, Moreno S, Moha Ou Maati H, Djillani A, Heurteaux C, Borsotto M, Mazella J, Coppola T · Journal of Diabetes Research · 2016
Section 10
Frequently Asked Questions
Spadin is a 17-amino-acid fragment cut from the propeptide released when the neuronal sorting protein sortilin matures, and it works by blocking the TREK-1 potassium channel. In mice, four days of spadin produced antidepressant-like effects across five standard behavioural tests, faster than the two to four weeks a comparison antidepressant needed in the same tests — but it remains an experimental compound never given to a person.
The evidence is entirely from mice, and mostly from a single French laboratory that discovered it. In its founding study, four days of spadin outperformed both short-course and chronic fluoxetine across five depression-model tests and roughly doubled markers of new neuron growth in the hippocampus; a separate, independent group later reported similar antidepressant-like effects in stressed rats. No human trial has ever tested it.
No — a search of ClinicalTrials.gov for spadin returns no registered trials, and no published study has dosed a person with it. The only human data touching this molecule are indirect: blood levels of the parent propeptide from which spadin is cut rose in depression patients about a month after electroconvulsive therapy, but that measured the natural propeptide after an unrelated treatment, not spadin given as a drug.
The only established dose is a mouse one — 100 µg/kg injected into the abdomen daily for four to five days — and it has never been converted to or tested at a human dose. Its effect in a rodent fades after about seven hours, which is why researchers developed shorter, much more potent fragments; those later molecules are chemically distinct from spadin and their doses do not transfer to it.
A dedicated rodent study found that spadin did not affect related potassium channels, cardiac electrical currents, blood pressure, heart rate, pain thresholds, seizure activity or stroke-injury size — a favourable selectivity profile. That work, like all spadin research, was done exclusively in rodents; no human safety data exist.
The lyophilised powder is kept at −20°C and dissolves readily in water. Prepared solutions are best used the same day; where a study needed to hold a solution longer, it was kept at −20°C for no more than a month.