Efficacy of Sublingual 5-MeO-DMT for Reducing Anxiety and Depression in MCI

This Phase I/II clinical trial is designed to rigorously evaluate the efficacy of a novel sublingual formulation of 5-MeO-DMT in reducing symptoms of anxiety, depression, and cognitive decline in individuals diagnosed with mild to moderate Alzheimer's disease. The trial will employ a randomized, double-blind, placebo-controlled design, considered the gold standard in clinical research, to ensure unbiased and reliable results. By blinding both participants and investigators to treatment allocations, the study aims to generate robust data on the therapeutic potential of 5-MeO-DMT in this specific patient population.

Participants will be randomly assigned to one the placebo group or to the groups receiving 6 mg 5-MeO-DMT. Each dose group will include 10 participants, with a total of 20 volunteers enrolled. The dosing regimen consists of one sublingual administration per week over four consecutive weeks, allowing the study to assess both immediate and cumulative effects of 5-MeO-DMT on cognitive, mood, and anxiety symptoms.

Outcome Measures and Assessments: The primary outcome measure will focus on evaluating changes in cognitive function, mood, and anxiety symptoms, using a comprehensive set of neuropsychological and psychiatric assessments at multiple time points throughout the trial. Key cognitive assessments will include the Clinical Dementia Rating (CDR), Activities of Daily Living Questionnaire (ADLQ), and the Addenbrooke's Cognitive Examination III (ACE-III). These scales will provide a detailed overview of cognitive decline and the ability of 5-MeO-DMT to potentially mitigate these effects. Additionally, the Ineco Frontal Screening (IFS) will be administered to assess frontal lobe functioning.

Key psychiatric assessments will include the State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), and Suicidal Ideation Scale (SSI), which are validated tools for measuring anxiety, depression, and suicidal thoughts. These assessments will help evaluate the emotional and psychological impact of 5-MeO-DMT on participants with Alzheimer's-related cognitive impairment.

Neurocognitive Assessments: To further evaluate the impact of 5-MeO-DMT on cognitive function, a battery of neurocognitive tests will be conducted. These will include the Rey Auditory Verbal Learning Test (RAVLT) to assess episodic memory, the Trail Making Test (TMT) for attention and cognitive flexibility, and the Digit Span Subtests (DSS) to measure working memory and attention. These tests will be administered at baseline, during dosing, and at the conclusion of the study (week 5) to monitor changes in cognitive function across time.

Study Design and Safety Measures: Safety will be closely monitored throughout the study. Regular assessments will be conducted to track vital signs, including heart rate, blood pressure, and temperature. Electrocardiograms (ECGs) will be taken to monitor any potential cardiovascular effects. Biochemical markers will be measured to assess any systemic effects, and psychological evaluations will be conducted to identify any changes in emotional or cognitive states that may signal adverse reactions or therapeutic benefits of the drug.

The findings from this study will offer valuable insights into the potential efficacy of sublingual 5-MeO-DMT in improving cognitive function and reducing symptoms of anxiety and depression in individuals with mild to moderate Alzheimer's disease. By focusing on participants with cognitive impairment and comorbid emotional symptoms, this trial aims to determine whether 5-MeO-DMT could be a beneficial treatment option for individuals suffering from both neurodegeneration and mental health disorders. The results will contribute to the growing body of evidence supporting the use of psychedelic compounds in treating cognitive decline, anxiety, and depression, providing new possibilities for managing Alzheimer's disease.

Inclusion criteria

• Adults aged 40 to 80 years
• Diagnosis of mild to moderate Alzheimer's disease
• Clinical Dementia Rating (CDR) score between 0.5 and 1
• ACE-III score ≤ 86 for individuals with high educational levels (≥12 years of schooling)
• ACE-III score < 62 for individuals with low educational levels (≤12 years of schooling)
• Moderate to high levels of anxiety, as defined by:
• State-Trait Anxiety Inventory (STAI-S) State score ≥20 for men, ≥23 for women
• STAI-Trait score ≥20 for men, ≥26 for women
• Mild to moderate depressive symptoms, as indicated by a Beck Depression Inventory (BDI) score ≥21
• Must provide written informed consent to participate in the study

Exclusion criteria

• Liver dysfunction
• Cardiovascular conditions (e.g., uncontrolled hypertension, angina, significant ECG abnormalities, recent transient ischemic attack or stroke, peripheral/pulmonary vascular disease without active claudication).
• Blood pressure >140 mmHg systolic or >90 mmHg diastolic
• Epilepsy or history of seizures
• Kidney failure
• Insulin-dependent diabetes
• Chronic obstructive pulmonary disease (COPD)
• Increased intracranial or cerebrospinal pressure
• Hyperthyroidism
• Psychotic symptoms or family history of psychotic disorders
• Prodromal symptoms of schizophrenia or dissociative identity disorder
• Severe depression or anxiety requiring immediate treatment with antidepressants or daily anxiolytics, particularly in cases with suicidal ideation
• Medications: Regular use of psychoactive medications, including benzodiazepines, serotonin-active medications (e.g., ondansetron), or monoamine oxidase inhibitors (MAOIs)
• Drug Interactions: Use of potent metabolic inducers or inhibitors, such as: Inducers: rifampicin, anticonvulsants (e.g., carbamazepine, phenytoin), nevirapine, efavirenz, taxol, dexamethasone. Inhibitors: HIV protease inhibitors, itraconazole, ketoconazole, erythromycin, clarithromycin, troleandomycin.