Neuropeptides and brain injury: what the research actually shows

Concussion is a mild traumatic brain injury: a blow or jolt that disturbs brain function, often without any visible damage on a scan. The 2022 international consensus on concussion in sport — first-authored from Wits Sport and Health in Johannesburg — sets the standard: recognise it, remove the player, assess, and return through a graded protocol[1].

Moderate-to-severe TBI is a hospital condition, typically defined by a reduced Glasgow Coma Scale score, and it is where almost all of the neuropeptide trial evidence sits. That matters: a result in hospitalised TBI patients receiving intravenous treatment tells you very little about a rugby concussion.

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy linked to repetitive head impacts. In McKee’s 2013 series, 68 of 85 post-mortem brains from people with histories of repetitive mild TBI showed CTE, staged I–IV, with symptoms from headache and attention loss in early stages to dementia in stage IV[2]. In a 2017 series of 202 donated brains of American-football players, CTE was diagnosed in 177, including 110 of 111 former NFL players[3] — a donated sample, so not a prevalence figure, but a striking one. CTE cannot yet be confirmed in life; in 2021 an NINDS panel agreed research criteria for "traumatic encephalopathy syndrome", its clinical counterpart[4]. Contact-sport cohorts point the same way: former Scottish international rugby players had roughly double the rate of neurodegenerative diagnoses of matched controls[16], former Scottish professional footballers died with neurodegenerative disease as the primary cause at 1.7% against 0.5%[17], and active fighters with more fight exposure had smaller thalamic volumes and slower processing[15].

Cerebrolysin is a porcine-brain-derived mixture of peptides and amino acids with neurotrophic activity in laboratory and animal models[9]. It is the only neuropeptide preparation with randomised trials in TBI.

CAPTAIN I randomised 46 patients with moderate-to-severe TBI to Cerebrolysin (50 mL daily for 10 days, then two cycles of 10 mL daily) or saline, on top of standard care. Three individual cognitive tests favoured Cerebrolysin, but the primary multivariate endpoint just missed significance in the intention-to-treat population; the per-protocol analysis was significant[5]. That is a small trial with a borderline primary result.

A prospective meta-analysis of the CAPTAIN series pooled 185 patients (mean admission GCS 10.3) and reported a "small-to-medium" effect in favour of Cerebrolysin on a combined functional and neuropsychological endpoint at days 30 and 90, with comparable safety to placebo[6].

Broader meta-analyses are more mixed. One pooled five studies (5,685 participants) and found better Glasgow Outcome Scale and modified Rankin scores — but most of the data were cohort studies, heterogeneity was very high (I² around 88–90%), and the authors called the lack of trials a limitation[7]. A 2023 review of ten mostly retrospective studies (8,749 patients) found improved GCS and GOS but no effect on mortality or length of stay[8].

Read together: a plausible, modest signal in hospital-treated moderate-to-severe TBI, from a small randomised base and a larger non-randomised one. Nothing here was tested in concussion, in athletes, or in CTE.

Semax has human data in ischaemic stroke — a 2018 Russian study of 110 post-stroke patients linked it to higher plasma BDNF and better functional recovery[10] — and animal work showing BDNF/TrkB regulation[11]and neurotrophin gene activation after experimental ischaemia[12]. We found no controlled human trial in traumatic brain injury or concussion.

Selank’s brain-relevant evidence is rat BDNF expression[13]; its human trials are in anxiety. Pinealon has cell-culture and review-level mechanism[14]. Neither has a brain-injury trial.

Mechanistic plausibility is where many failed brain-injury drugs started. Dozens of neuroprotective agents that worked in animals have failed in human TBI trials. A rat BDNF result is a reason to run a trial, not a reason to expect one to succeed.

There is no proven treatment for CTE — not a peptide, not a drug, not a supplement. No neuropeptide has been tested in people with CTE or traumatic encephalopathy syndrome, and because CTE is confirmed only after death, designing such a trial is itself an unsolved problem[4].

What does have evidence is prevention: fewer head impacts. That is why rugby has changed tackle laws and head-injury assessment, why youth football limits heading, and why combat-sport medicine increasingly focuses on sparring volume. Anyone worried about cognitive, mood or behavioural change after years of contact sport should see a neurologist; memory clinics can assess and treat symptoms even where the underlying process cannot yet be reversed.