Intranasal creatine prodrug shows early brain activity in phase 1 trial

In a first-in-human phase 1 trial, intranasal CBT101—a creatine prodrug designed to deliver creatine toward the brain—was well tolerated across tested single and repeated doses in healthy male volunteers and produced exploratory changes in brain electrical activity consistent with central engagement. The randomized, double-blind, placebo-controlled study enrolled 48 men at one clinical center in France. Volunteers received CBT101 or placebo in sequential single-dose and 14-day multiple-dose cohorts, while quantitative electroencephalography and event-related potentials were used to look for early pharmacodynamic effects. No serious or severe treatment-emergent adverse events, dose-limiting toxicity or clinically relevant safety findings were reported. Because the trial was small, exploratory and conducted in healthy people rather than patients with neurological disorders, it does not establish clinical benefit.

CBT101 is a formulation of dodecyl creatine ester, a chemically unstable prodrug developed to overcome limitations in getting creatine into brain cells. Creatine is part of the phosphocreatine-creatine system that helps regenerate ATP, particularly in tissues with limited endogenous synthesis such as the brain. Conventional creatine supplementation has shown limited utility for central nervous system applications because of poor neuronal distribution, while the creatine transporter is directly impaired in creatine transporter deficiency. After intranasal administration, part of a prodrug can travel along olfactory and trigeminal pathways, a mechanism commonly described as a nose-to-brain route. Previous non-human primate and mouse studies supplied the rationale, but the present trial was the first to examine safety and exploratory neurophysiological responses in humans.

The study comprised two sequential parts, each with 24 volunteers randomized 3:1 to active treatment or matching placebo. In the single ascending dose part, cohorts received one administration of 4.2, 8.4 or 12.6 mg. In the multiple ascending dose part, volunteers received 4.2, 8.4 or 12.6 mg per day for 14 days, with follow-up through Day 23. Each spray contained 2.1 mg of CBT101, and investigators administered it while participants were seated. The men were healthy, aged 21 to 54, and had a mean age of 36.7 years; their mean body mass index was 24.4 kg/m². Restricting enrollment to men was intended to reduce biological variability in this early safety study, not because the drug was expected to act through a sex-specific mechanism.

Safety was assessed through adverse-event reporting, physical examinations, vital signs, electrocardiograms, laboratory tests and detailed nasal evaluations, including rhinoscopy. In the single-dose part, three of 24 participants experienced treatment-emergent adverse events, with one of the three receiving placebo. In the repeated-dose part, seven of 24 had events, including two receiving placebo. Most were mild, although two were moderate, and all resolved without lasting consequences. Events judged possibly or probably related to treatment were dominated by local nasal effects, including congestion, inflammation, sneezing, mucosal erythema and tingling. Two congestion events in the highest-dose repeated-dose cohort lasted approximately 15 and 19 days, but they resolved without corrective treatment or functional consequences. One participant stopped treatment because of symptomatic orthostatic hypotension, which the investigator judged unlikely to be related to CBT101.

Both the highest tested single dose of 12.6 mg and highest daily dose of 12.6 mg for 14 days were tolerated. The nasal device produced no reported failures, clogging or leakage, and participants rated the spray as ergonomic and easy to handle. No clinically meaningful changes were identified on ECG, and no clear increase in adverse-event frequency was seen with CBT101 relative to placebo. The findings therefore support short-term local and systemic tolerability within the tested range. They do not establish longer-term safety, and the small, exclusively male population prevents firm conclusions about how the drug may behave in patients, women or people with more variable health status.

Conventional blood testing offered little information about delivery. Plasma CBT101 concentrations were below the assay’s 1 ng/mL lower limit of quantification in every analyzed sample, preventing calculation of formal pharmacokinetic parameters for the parent compound. That result was anticipated because CBT101 is an ester with an in vitro metabolic half-life of about three minutes and was intended to act through brain-directed delivery rather than persistent systemic exposure. Exploratory measurements in selected samples found no change in plasma creatine or creatinine. This absence of quantifiable parent compound was therefore consistent with the formulation’s properties, but it also means that the trial did not directly measure how much CBT101 or creatine reached the human brain.

Instead, researchers used quantitative EEG to examine drug-associated changes in cortical oscillations. EEG was recorded before dosing and at one and three hours afterward in the single-dose part, with additional recordings on Days 2 and 13 of repeated dosing. After one dose, the clearest statistically significant signal was an acute increase in relative beta power under eyes-closed resting conditions. The effect involved the total beta band at 12.5–30 Hz, beta-1 at 12.5–18.5 Hz and beta-3 at 21–30 Hz, with the most prominent fronto-parietal difference at one hour and a smaller effect at three hours. No significant absolute- or relative-power effect was detected with eyes open. Time-course analyses at central scalp sites showed similar directional differences from placebo, with broadly similar baseline values.

The repeated-dose EEG pattern was more sustained. A significant increase in relative beta-1 power under eyes-open conditions was detected mainly in parietal regions three hours after dosing on Day 2. On Day 13, differences from placebo remained visible at both post-dose measurements and shifted from a more frontotemporal distribution at one hour to a more parietal distribution at three hours. Relative power also differed in the total gamma band from 30 to 40 Hz and in two high-gamma ranges, from 41 to 49 Hz and 51 to 80 Hz, mainly in central and temporal regions early in repeated dosing. Because individual cohorts contained few participants and no consistent dose-response gradient emerged, the investigators pooled active-dose groups post hoc while keeping measurement times separate. This approach may improve sensitivity, but the analysis was exploratory and its p-values were not adjusted for multiplicity.

Event-related potentials provided a complementary but limited signal. During an auditory oddball task in the multiple-dose part, CBT101 was associated with a transient reduction in P300 latency one hour after dosing on Day 2, principally over fronto-central scalp areas. The difference was no longer present two hours later, and P300 amplitude did not change significantly. Thus, the trial did not demonstrate improved cognitive performance: separate neurocognitive testing found no detectable pharmacodynamic effect and no detrimental signal. The investigators interpreted the beta and gamma findings as early evidence consistent with central pharmacodynamic engagement, while emphasizing that pharmacodynamic engagement is not equivalent to clinical efficacy. Together, the results support continued study of CBT101 in patient populations affected by impaired neuronal energy homeostasis, including creatine transporter deficiency and amyotrophic lateral sclerosis, but those therapeutic uses remain unproven.

Subject of Research: First-in-human evaluation of intranasal creatine prodrug CBT101 for safety and central pharmacodynamic activity

Article Title: Intranasal CBT101 demonstrates favorable safety and neurophysiological evidence of central activity in healthy male volunteers

Article References: Benech, H., Krebs-Drouot, L., Viardot, G., Bertaina-Anglade, V., Lhotellier, C., Flament, V., Roucairol, C., Mabondzo, A., Pinquier, J.-L., & Joudinaud, T. (2026). Intranasal CBT101 demonstrates favorable safety and neurophysiological evidence of central activity in healthy male volunteers. Frontiers in Neurology, 17, Article 1940627. https://doi.org/10.3389/fneur.2026.1940627

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1940627

Keywords: CBT101, intranasal drug delivery, creatine prodrug, nose-to-brain delivery, phase 1 trial, quantitative EEG, P300, neuronal energy homeostasis, healthy volunteers, neurotherapeutics, Intranasal, demonstrates