Clinical research into Choline glycerophosphate

Introduction

Choline glycerophosphate (GPC) is a deacylated phosphatidylcholine derivative and is widely used as a dietary supplement. In addition, Choline glycerophosphate is a precursor of acetylcholine and can enhance cholinergic transmission in the brain . [1]Pre-clinical studies have shown that Choline glycerophosphate has an anti-amnesic effect against scopolamine-induced amnesia and a neuroprotective effect in animal models of cerebrovascular disease. Moreover, GPC ameliorates seizure-induced cognitive impairment by reducing neuronal cell death and blood–brain barrier disruption [4]. Clinical trials have been performed to evaluate the efficacy of Choline glycerophosphate for treating cognitive decline in patients with Alzheimer's disease and vascular dementia. [2]

Choline glycerophosphate Increases Motivation in Healthy Volunteers

Choline glycerophosphate is a water-soluble deacylated metabolite of phosphatidylcholine and a precursor of acetylcholine. In clinical trials, Choline glycerophosphate improved cognitive impairment in patients with Alzheimer’s disease and vascular dementia. Furthermore, Choline glycerophosphate ameliorated cognitive decline in several experimental animal models and enhanced acetylcholine levels in the brains of rodents. These reports suggest that Choline glycerophosphate might show ameliorating effects on cognitive function via increased cholinergic transmission. In addition, GPC increases the level of DA and 5-HT and the expression of DAT in rat brains. The report indicates that GPC functions as a modulator of DA and 5-HT systems as well as cholinergic transmission. DA transmission is closely linked to motivation and reward processing, whereas the 5-HT system is associated with anxiety and depression. These findings provoked the hypothesis that Choline glycerophosphate affects human feelings and emotions, including motivation, anxiety, and depression. In this study, this hypothesis was investigated with healthy volunteers. The administration of Choline glycerophosphate showed a tendency to increase self-reported motivation levels during the intervention period, and in particular, significantly improved those at night. In a previous study with rats, Choline glycerophosphate improved cognitive decline following seizure, and such effects were observed from 3 weeks, but were not found at 1 week of Choline glycerophosphate administration. These data suggest that long-term administration (>1 week) is necessary for the onset of action of Choline glycerophosphate. Moreover, Choline glycerophosphate shows blood–brain barrier permeability and can enter neuronal cell bodies of rodent brains when orally administered. Therefore, Choline glycerophosphate may affect feelings of increased motivation in human subjects, potentially through interaction with dopamine circuits in the brain. However, their mechanism of action remains unclear at present. Choline glycerophosphate did not show specific effects on anxiety However, the placebo group showed an increased feeling of relief compared with the Choline glycerophosphate treatment group, which may be the result of placebo. Indeed, it has been reported that placebo can have anti-anxiety effects in humans.[3]

In this clinical trial, healthy subjects self-administered a total Choline glycerophosphate dosage of 400 mg per day for 2 weeks. This dose of Choline glycerophosphate was determined based on previous studies in animals and humans. In dogs, chronic administration of GPC (≥300 mg/kg/day) did not show serious adverse effects for 26 weeks. In addition, clinical trials showed that there are no severe side effects or toxicities following oral administration of Choline glycerophosphate (1200 mg/day) for 6 months. These findings suggested that the risk of toxicity in administering 400 mg/day of Choline glycerophosphate for 2 weeks was extremely low. Indeed, we confirmed that Choline glycerophosphate (400 mg/day) administration did not exhibit any side effects or addictions during the 2 weeks of intervention and at least 12 months after taking the medication. Nevertheless, we showed that Choline glycerophosphate exhibited a tendency to increase motivation during the intervention period.

However, the present study has some limitations. In this study, we could not address whether Choline glycerophosphate acted directly or indirectly on human motivation and neural circuits, especially the dopamine system in the human brain. Further research with experimental animals may resolve this limitation. Next, this study was conducted on a relatively small scale, using a short-term (2 weeks) intervention and a single-blind test as a pilot clinical trial. Thus, our results can be validated by performing further studies on a large scale and with long-term intervention. In this study, the investigation and the data analysis were performed by different researchers to minimize experimental biases. Finally, the changes of human feelings and emotions might be affected by several factors and events in daily life. Thus, the participants were instructed to input the matters with their feelings if they experienced extraordinary events and sensations. These data were excluded from the data analysis.

References

[1] Sigala S., Imperato A., Rizzonelli P., Casolini P., Missale C., Spano P. L-α-glycerylphorylcholine antagonizes scopolamine-induced amnesia and enhances hippocampal cholinergic transmission in the rat. Eur. J. Pharmacol. 1992;211:351–358.

[2] Amenta F., Tayebati S.K., Vitali D., Di Tullio M.A. Association with the cholinergic precursor choline alphoscerate and the cholinesterase inhibitor rivastigmine: An approach for enhancing cholinergic neurotransmission. Mech. Ageing Dev. 2006;127:173–179.

[3] Tamura Y, Takata K, Matsubara K, Kataoka Y. Alpha-Glycerylphosphorylcholine Increases Motivation in Healthy Volunteers: A Single-Blind, Randomized, Placebo-Controlled Human Study. Nutrients. 2021 Jun 18;13(6):2091.

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