Coluracetam

No other human study of coluracetam is registered on ClinicalTrials.gov, and a search of the registry by sponsor returned five BrainCells Inc. records, of which only this one involves BCI-540.

Animal studies of learning and memory

• Rats, water maze, 1996 (PMID: 8740080). Oral coluracetam at 1 to 10 mg/kg improved learning deficits in the Morris water maze in rats treated with the cholinergic toxin AF64A, while tacrine at 0.1 to 3 mg/kg failed to do so. In hippocampal synaptosomes, coluracetam raised high-affinity choline uptake in AF64A-treated rats but not in normal rats, and it did not inhibit acetylcholinesterase or bind muscarinic receptors.
• Mice, T-maze, 1994 (PMID: 7710736). In AF64A-treated mice tested on delayed non-matching to sample, single doses of coluracetam at 0.3, 1.0 and 3.0 mg/kg had no effect, while 11 days of daily dosing improved the memory deficit at all three doses. Repeated dosing at 0.3 and 1.0 mg/kg also reversed the fall in hippocampal acetylcholine content, which neither linopirdine nor tacrine did.
• Rats, repeated dosing and persistence, 2008 (PMID: 18461272). Eight days of coluracetam at 1 and 3 mg/kg by mouth improved water maze learning in AF64A-treated rats, and the improvement was still present 24 hours after the last dose, when the compound could not be detected in brain. The rise in high-affinity choline uptake followed the same time course.
• Rats, phencyclidine model, 2007 (PMID: 17467960). After repeated phencyclidine exposure, subchronic coluracetam reversed the deficit in novel object recognition and the reduction in choline acetyltransferase-positive cells in the medial septum, and corrected the altered locomotor responses to cocaine and carbachol, but not the response to a phencyclidine challenge.

Cell and tissue studies

• Rat hippocampal synaptosomes and slices (PMID: 18446264). Coluracetam at 10 and 100 nanomolar reversed the AF64A-induced fall in high-affinity choline uptake and in potassium-stimulated acetylcholine release, and 10 mg/kg by mouth restored basal acetylcholine concentrations measured by microdialysis.
• Transporter mechanism (PMID: 18461273). Coluracetam raised the maximum velocity of choline uptake 1.6-fold and the maximum binding of hemicholinium-3 1.7-fold, and bound the cloned high-affinity choline transporter CHT1, which the authors interpreted as an effect on transporter trafficking.
• Cultured rat cortical neurons (PMID: 9541286). Exposure to coluracetam for 12 to 24 hours reduced glutamate cytotoxicity and ionomycin cytotoxicity, but not cytotoxicity from a nitric oxide donor.

Studies using coluracetam as a tool rather than a candidate treatment

Three rat studies of chronic water avoidance stress used coluracetam to raise choline transporter activity. Enhancing CHT1 with coluracetam raised colonic motility in control rats (PMID: 30347940), relieved visceral pain responses in stressed rats by raising acetylcholine production (PMID: 30288092), and relieved stress-induced hyperalgesia in the spinal cord while suppressing microglial activation (PMID: 36808325). A 2015 review of glutamate-targeting antidepressants lists coluracetam among the compounds it discusses alongside ketamine (PMID: 25467702).

The exclusion criteria of that trial record show what its sponsor treated as a risk. They excluded people with a known hypersensitivity to any cholinesterase inhibitor or cholinergic agonist, people with a history of seizures, people with a history or current evidence of low red cell, haemoglobin, white cell, platelet or reticulocyte counts, and people who would use drugs known to be related to agranulocytosis or aplastic anaemia during the study (ClinicalTrials.gov NCT00621270). Those are study design choices, not findings about coluracetam.

Animal observations

In the 1996 comparison with tacrine, oral coluracetam at 1 to 10 mg/kg improved learning in AF64A-treated rats "without any significant side effects, like tremor, salivation or hypothermia, which were observed in rats treated with high doses of tacrine" (PMID: 8740080).

When injected into the ventricles of rats, coluracetam raised plasma glucose much less than neostigmine, and the authors judged its potency for producing peripheral hyperglycaemia to be pharmacologically negligible (PMID: 10082325).

In rats, coluracetam given into the spinal canal or by gavage changed gut function: it raised colonic motility in control animals and relieved stress-induced visceral pain, both through the choline transporter CHT1 (PMID: 30347940, PMID: 30288092, PMID: 36808325). Gut effects of this kind have not been looked for in people.

Gaps

No published study reports the pharmacokinetics, tolerated dose range, long-term safety, pregnancy safety or drug interactions of coluracetam in humans.