Vasoactive intestinal peptide — VIP, or aviptadil as the synthetic drug — is unusual among the peptides sold as research chemicals: it has been given to several hundred people in placebo-controlled trials, and the trials posted their adverse-event tables. It is also one of a handful of substances neuroscientists infuse on purpose to give volunteers a headache. So VIP's side effects can be counted rather than guessed, with one large qualification set out below: every count comes from a vein, an inhaler or a licensed penile injection, not from a vial injected under the skin. What doses those trials used, and what they convert to in micrograms, is on our VIP dosage page.
The two placebo-controlled infusion trials
Both trials infused aviptadil intravenously for 12 hours a day over three days into hospitalised adults with severe COVID-19, against saline. The NIH trial's registered schedule rises from 50 to 100 to 150 pmol/kg/h; the earlier sponsor trial describes its arm as "escalating doses". Here are the events that separate drug from placebo, from the tables posted on ClinicalTrials.gov:
| Event | NCT04311697 — aviptadil (n = 131) | Placebo (n = 65) | NCT06729606 — aviptadil (n = 231) | Placebo (n = 230) |
|---|---|---|---|---|
| Diarrhoea | 43 (32.8%) | 1 (1.5%) | 13 (5.6%) | 5 (2.2%) |
| Flushing | 13 (9.9%) | 2 (3.1%) | 34 (14.7%) | 14 (6.1%) |
| Hypotension | 34 (26.0%) | 14 (21.5%) | 159 (68.8%) | 140 (60.9%) |
| Headache | — | — | 14 (6.1%) | 7 (3.0%) |
| Tachycardia | — | — | 25 (10.8%) | 15 (6.5%) |
| Atrial fibrillation | 15 (11.5%) | 3 (4.6%) | 5 (2.2%) | 12 (5.2%) |
Counts are the trials' own; the percentages are our arithmetic. A dash means the event was not listed for that trial at the reporting threshold. The first trial was sponsored by APR Applied Pharma Research and completed in 2021; the second is the NIH's ACTIV-3b/TESICO aviptadil trial, primary completion August 2022.
Three things follow from the table. Diarrhoea is the clearest drug effect in the first trial — about one in three against one in sixty-five — and VIP's name describes why: it is the gut hormone that drives intestinal secretion, and tumours that over-produce it cause a profuse watery diarrhoea. Flushing runs at roughly double or triple placebo in both. Low blood pressure is common on both arms, because these patients were critically ill, but higher on the drug in both. And the trials disagree on atrial fibrillation, which was more frequent on aviptadil in the first and less frequent in the second; with numbers this small, neither direction is established.
Serious events and deaths in both trials were dominated by COVID-19 itself. In the NIH trial, deaths through day 180 were 90 of 231 on aviptadil and 86 of 230 on placebo, and serious adverse events 25 against 23 — no signal of benefit and no clear signal of harm. How the efficacy result was reported is on the dosage page.
The headache record, measured in healthy people
VIP widens the arteries of the scalp and the coverings of the brain, and three studies from the Danish Headache Center measured what that does:
| Study | Who | Infusion | Result |
|---|---|---|---|
| Hansen et al., Cephalalgia 2006 | 12 healthy volunteers, crossover | 8 pmol/kg/min for 25 min | Headache in 5 of 12 vs 1 of 12 on placebo; very mild (max 2/10); heart rate rose; blood pressure unchanged |
| Rahmann et al., Cephalalgia 2008 | 12 people with migraine, crossover | 8 pmol/kg/min | Mild immediate headache; no migraine attacks |
| Pellesi et al., Cephalalgia 2020 | 12 healthy volunteers, crossover | 2-hour infusion | Delayed mild headaches; scalp-artery dilation lasting more than 2 hours |
| Pellesi et al., JAMA Netw Open 2021 | 21 people with migraine, crossover | 2-hour infusion | Migraine attacks in 15 of 21 (71%) vs 1 of 21 (5%) on placebo |
The pattern is duration. A short infusion produced a mild headache and no migraine; the same peptide run for two hours produced migraine attacks in seven of ten people prone to them, resembling their usual attacks. The 2021 authors concluded that the length of the vascular response, not its presence, made the difference.
The amounts are small. Our arithmetic for the 25-minute infusion: 8 pmol/kg/min × 25 minutes × 70 kg = 14 nanomoles, which at VIP's molecular weight of about 3,326 is roughly 47 micrograms — enough to give five of twelve healthy people a headache.
The one product in clinical use: Invicorp
The one VIP-containing medicine in clinical use is Invicorp: 25 micrograms of VIP with 1 or 2 mg of phentolamine, injected into the penis for erectile dysfunction (Dinsmore and Wyllie, BJU International, 2008). It is in clinical use in the UK — the 2025 series below comes from a London hospital — and it has never been approved in the US. Its characteristic side effect is facial flushing — the same vasodilation reaching the face. In a 2025 series from University College London Hospital, 308 men used it; 69 (22.5%) reported facial flushing, and one (0.3%) had ischaemic priapism (Al-Mitwalli et al., J Sex Med 2025). The series was retrospective and had no placebo arm, and phentolamine contributes to the effect.
What the record does not contain
- Any adverse-event data for VIP injected under the skin, the way research vials are generally used.
- Any exposure longer than three days of infusion in the trials above.
- Any controlled study in healthy people beyond a few hours.
- Anything about research-labelled vials, whose contents and sterility are not tested against any standard — see what research-use-only labelling means.
Anyone with migraine, low blood pressure, a heart-rhythm condition or a bowel disorder who is connecting a symptom to VIP should take it to a clinician. Peptide Lexicon's VIP entry covers what the peptide is, and our peptide side-effects overview covers the wider record.
Sources and dates
- ClinicalTrials.gov, NCT04311697, Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure (APR Applied Pharma Research), posted adverse-event tables. Read via API v2, 2026-10-11.
- ClinicalTrials.gov, NCT06729606, Aviptadil for Severely Ill Inpatients With COVID-19 (ACTIV-3b/TESICO), intervention schedule and posted adverse-event tables. Read via API v2, 2026-10-11.
- Hansen JM et al. Vasoactive intestinal polypeptide evokes only a minimal headache in healthy volunteers. Cephalalgia. 2006;26(8):992-1003. PMID 16886936.
- Rahmann A et al. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia. 2008;28(3):226-36. PMID 18254893.
- Pellesi L et al. Two-hour infusion of vasoactive intestinal polypeptide induces delayed headache and extracranial vasodilation in healthy volunteers. Cephalalgia. 2020;40(11):1212-1223. PMID 32594760 (NCT03989817).
- Pellesi L et al. Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial. JAMA Netw Open. 2021;4(8):e2118543. PMID 34357396.
- Dinsmore WW, Wyllie MG. Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction. BJU Int. 2008;102(8):933-7. PMID 18485029.
- Al-Mitwalli A et al. Intracavernosal injection of aviptadil and phentolamine for refractory erectile dysfunction. J Sex Med. 2025;22(5):726-730. PMID 40192471.