This study is designed to test if megestrol acetate induces changes in declarative memory in healthy controls and if pre-administration of phenytoin can ameliorate any induced cognitive impairments.

Healthy adults (n=20) will be recruited and informed consent will be obtained. Participants will agree to a number of visits, a Baseline Visit, 6 Study Visits, and a follow-up Safety Visit. Each course of study drug will be followed by a washout, but allowed preexisting medications will not be stopped for study participation. A small subset (n=4) of participants will also undergo MRI scanning as a component of their visits following drug administration.

Baseline Visit: Cognition will be assessed by a variety of measures, which will determine baseline declarative memory and working memory. Mood will be assessed by a psychiatric interview, self-assessments, and a review of any standing physical symptoms will be completed for comparison to any side effects which develop after medication administration. Vital signs will be recorded and women will be screened for pregnancy. Blood will be collected for complete blood count (CBC) and comprehensive metabolic panel (CMP).

Visit 1: Participants will be randomized to one of three treatment possibilities: 1) phenytoin with megestrol, 2) placebo with megestrol, 3) placebo with placebo. Participants will receive phenytoin (200 mg BID) or placebo and will be instructed to take this medication for one full day (two doses) before starting their megestrol. They will take this medication for a total of 3.5 days.

Visit 2: After the participants have completed their medication course on the morning of this visit day, they will return to have cognition and mood reassessed. Vital signs will be taken and blood will be drawn to assess CMP, CBC, cortisol and phenytoin levels. Participants will now enter a "washout" period of this medicine combination (approximately 3 weeks) before returning for their next visit. For those participants offered the MRI scans, their visit will extend to approximately 3 hours.

Visit 3: Participants will return and be randomized to one of remaining two treatment possibilities as detailed above. Participants will again be instructed to start the first medication and take for one full day before taking the second medication, and will be instructed to take their second medication at starting the following day after starting the first medication at 0900 hours and continue taking the drugs for 3 consecutive days.

Visit 4: After the participants have completed their medication course on the morning of this visit day, they will return to have cognition and mood reassessed; completing all previously administered assessments excepting the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID). Vital signs will be taken and blood will be drawn to assess CMP, CBC, cortisol and phenytoin levels. Participants will now enter a "washout" period of this medicine combination (approximately 3 weeks) before returning for their next visit. For those participants offered the MRI scans, their visit will extend to approximately 3 hours.

Visit 5: Participants will return and receive the remaining treatment possibility, detailed above. Participants will again be instructed to start the first medication and take for one full day before taking the second medication and will be instructed to take their second medication at starting the following day after starting the first medication at 0900 hours and continue taking the drugs for 3 consecutive days.

Visit 6: After the participants have completed their medication course on the morning of this visit day, they will return to have cognition and mood reassessed. Vital signs will be taken and blood will be drawn to assess CMP, CBC, cortisol and phenytoin levels. Participants will now enter a "washout" period of this medicine combination (approximately 3 weeks) before returning for their final visit. For those participants offered the MRI scans, their visit will extend to approximately 3 hours.

Safety Visit: Participants will return for a final "safety" visit which will evaluate any remaining side effects, take vital signs, and include a final urinary pregnancy test (for women).

Inclusion Criteria:

• Healthy men and women age 18-50 years
• Education of ≥ 12 years and baseline Rey Auditory Verbal Learning Test (RAVLT) total words recalled score ≥ 40 (normal baseline memory)
• Body mass index (BMI) between 18.5-35
• The ability to read and speak English as not all neurocognitive assessments have been translated and validated in other languages.

Exclusion Criteria:

• History (lifetime) of Bipolar Disorder, Major Depressive Disorder, psychotic depressive, schizophrenic, schizoaffective, or other Axis I psychotic disorders
• Has an unstable general medical condition (GMC) or significant medical condition, including but not limited to myocardial infarction, cancer, diabetes (hypertension is allowed if condition is being treated and is stable)
• Vulnerable populations including pregnant or nursing women, the incarcerated, or those with severe cognitive disorders
• Education history that includes Special Education or history of mental disability
• History of psychotropic medication therapy in the past 30 days
• Baseline Quick Inventory of Depressive Symptoms-Clinician Rated (QIDS-C) > 5
• Initiation of new medications within 14 days of the baseline visit, with the exception of over-the-counter (OTC) as needed medications (e.g. Tylenol, Advil, Motrin, etc.)
• Significant hypertensive blood pressure at baseline, defined as either systolic pressure > 150 or diastolic pressure > 95
• Febrile at baseline, defined as body temperature ≥ 100.5°F (38°C)
• Baseline heart rate > 100 bpm or < 50 bpm
• Medical history of diseases with central nervous system (CNS)-involvement, including but not limited to stroke, traumatic brain injury, and loss of consciousness > 1 minute
• History of allergic reaction or medical contraindication to megestrol or phenytoin
• Clinically significant abnormalities on baseline labs (e.g. hypokalemia, hypernatremia, anemia)
• Lifetime history of an immunosuppressive disorder or immunosuppressive therapy with within the past 6 months
• History of blood clots such as myocardial infarction (MI), stroke, deep vein thromboses (DVTs), pulmonary embolism (PE) or blood clotting disorder
• Currently actively suicidal or considered a high suicide risk (e.g. more than one lifetime suicide attempt or any attempt in the past 12 months)
• Any reason not listed which, as determined by the principle investigator (PI), would affect participant safety in the study

4 days for each intervention.

The safety population included all participants who received at least one dose of intervention.