Semaglutide and Cognition in Healthy Volunteers

Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1RA). It is a safe medication approved for use in type-2 diabetes mellitus (T2DM) and obesity. Primarily, it works by counteracting insulin-resistance and inducing weight loss. It also acts on several other interconnected neurobiological, immunological (esp. inflammatory), endocrine-metabolic, and gut-brain axis processes that play a role in depressive symptoms. Its effects on cognition and energy are currently unknown. In this study we are using semaglutide as an experimental tool to further investigate these relationships.

Semaglutide is a novel GLP-1RA licensed for T2DM and obesity, which mainly works by offsetting insulin-resistance and stimulating weight loss (1). It also acts on various neurobiological, immunological, endocrine-metabolic, and gut-brain axis processes that play a role in depressive symptoms (2). Preliminary evidence suggests these drugs are safe from a neuropsychiatric perspective (3) and could be beneficial in unipolar (4) and bipolar depression (5) - an outcome possibly mediated by inflammatory pathways (6).

The proposed study investigates the effects of semaglutide on cognition and energy, which are currently unknown. Work in our laboratory established that short-term use of conventional antidepressants in healthy volunteers shifts reward sensitivity and emotional cognition (7) - an important neuropsychological mechanism of antidepressant action (8). An experimental medicine trial that assesses the effects of semaglutide on reward sensitivity emotional cognition can validate its potential to be repurposed for treating depressive disorders (9). Moreover, brain insulin resistance, likely lessened by semaglutide, is associated with deficit in impulse-control as well as non-emotional cognitive and energy impairment in people with depression (10). Finally, defining the overall cognitive and energy profile of semaglutide is important for the many people already taking it for its licensed indications (i.e., T2DM, obesity).

Therefore, the primary objective of this study is to assess the effect of a single dose of semaglutide 0.5mg subcutaneous injection vs placebo on reward sensitivity tasks in healthy volunteers. Secondary objectives include the investigation of the effects of semaglutide on other cognitive domains (emotional processing, impulsivity, memory) and energy/activity levels. Psychological questionnaires are also measured as relevant covariates.

Eligibility Criteria:
Inclusion Criteria:

* Male or female
* Aged from 21 to 55 years
* Body Mass Index (BMI) from 18 to 30 (because our main outcomes involve cognitive and energy measures, this decision regarding the BMI range has been taken with the purpose of including a more homogeneous sample of healthy participants in terms of baseline cognitive and energy levels)
* Sufficiently fluent English to understand and complete the tasks
* Participant is willing and able to give informed consent for participation in the research
* Not currently taking any regular medications (except the contraceptive pill)

Exclusion Criteria:

* Currently on any regular prescribed medications (except the contraceptive pill), unless unlikely to compromise safety or affect data quality in the opinion of the medical supervisor according to clinical judgement
* History of, or current significant psychiatric illness in the opinion of the medical supervisor according to clinical judgement
* Current alcohol or substance misuse disorder (\<6 months)
* Current moderate or severe dyslexia
* History of, or current significant medical illness in the opinion of the medical supervisor according to clinical judgement
* History of, or current pancreatitis
* History of, or current severe congestive heart failure, end-stage renal disease, hepatic disease
* History of, or current significant neurological condition (e.g., epilepsy)
* History of, or current significant thyroid disorder
* History (including family history) of, or current multiple endocrine neoplasia syndrome type-2 (MEN 2) or medullary thyroid carcinoma (MTC)
* Known type-1 or type-2 diabetes mellitus
* Known hypersensitivity to the study drug (i.e., semaglutide)
* Pregnant, breast feeding, or person of child-bearing potential not using appropriate contraceptive measures including hormonal contraception, intrauterine device, bilateral tubal occlusion, vasectomised partner, condom, absolute sexual abstinence - periodic sexual abstinence, withdrawal, and spermicides-only are not acceptable methods of contraception
* Participation in a study that uses the same or similar computer tasks (O-ETB, see below) as those used in the present study
* Participation in a study that involves the use of a medication within the last 3 months