This Phase I/II clinical trial aims to test the effectiveness of a new sublingual formulation of 5-MeO-DMT in reducing symptoms of anxiety, depression, and cognitive decline in individuals with mild to moderate Alzheimer's disease. The study will include participants who have a Clinical Dementia Rating (CDR) score between 0.5 and 1, indicating mild to moderate cognitive impairment, and who meet specific educational and cognitive criteria. Participants must have an ACE-III score of ≤86 for individuals with a high level of education (≥12 years) or <62 for those with a low educational level (≤12 years). Additionally, participants must show moderate to high levels of anxiety, as indicated by the State-Trait Anxiety Inventory (STAI), with STAI-S (State) scores ≥20 for men and ≥23 for women, and STAI-T (Trait) scores ≥20 for men and ≥26 for women. Participants also need to exhibit moderate to severe depressive symptoms, as indicated by a Beck Depression Inventory (BDI) score of ≥21.

To ensure that participants are cognitively functional but showing signs of impairment, they are assessed with the CDR and ADLQ scales to confirm they can maintain independence in daily activities. All participants must have scores above the threshold on cognitive screening tests like the ACE III and IFS, ensuring no significant cognitive impairment at the baseline.

The study will measure the effects of 5-MeO-DMT through a range of cognitive and psychiatric assessments:

Cognitive Assessments: These include the Rey Auditory Verbal Learning Test (RAVLT) for episodic memory, the Trail Making Test (TMT) for attention and cognitive flexibility, the Semantic and Phonological Fluency Test (SFT-FAS) for verbal fluency, the Paced Auditory Serial Addition Test (PASAT) for processing speed, and the Digit Span Subtests (DSS) for attention and working memory. These tests will provide valuable insights into how 5-MeO-DMT affects cognitive functions.

Psychiatric Assessments: These will assess symptoms of suicidal ideation (SSI), mood (BDI II), anxiety (STAI), and mindfulness (FFMQ), as well as self-reported cognitive complaints (CQC). These evaluations will help determine the psychological and emotional impact of 5-MeO-DMT on participants.

In addition, the study will include biochemical assessments such as microalbuminuria, blood glucose levels, liver and kidney function, cholesterol, and several biomarkers of inflammation. Cardiovascular evaluations will also be conducted during the trial, ensuring comprehensive monitoring of potential side effects.

This structured approach will help researchers assess the cognitive and psychological effects of 5-MeO-DMT in individuals with mild to moderate Alzheimer's disease. By focusing on participants with elevated anxiety, depression, and early cognitive decline, this trial aims to provide insights into the therapeutic potential of 5-MeO-DMT for neurodegenerative conditions.

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.

The study is committed to advancing scientific research by planning to share individual participant data (IPD) to contribute valuable insights to the research community. We will provide a detailed data dictionary alongside the IPD, outlining the variables and types of data collected for each participant, facilitating comprehensive analysis by researchers.

Specifically, we plan to share all IPD collected throughout the trial, including data that underlie published results. Importantly, all personal information and identifying details of participants will remain strictly confidential and will not be disclosed. This commitment ensures the privacy of individuals involved while enabling meaningful contributions to scientific knowledge.

The individual participant data (IPD) and any supporting information will be made available starting 6 months after the publication of the study results. This will allow sufficient time for data analysis and the dissemination of primary findings. The data will remain available for at least 5 years following the publication, ensuring ample time for other researchers to access and utilize the data for further analysis or related studies. In case of any modifications to the availability period, these will be communicated clearly along with the reasons. This time frame is subject to ethical and regulatory requirements and may be adjusted if necessary.

Researchers seeking access to the individual participant data (IPD) and supporting information must submit a formal request outlining their proposed analyses. This proposal should detail the types of analyses, including the statistical methods to be used, which will be reviewed for scientific merit and methodological rigor. A signed data sharing agreement will be required, and the request must be submitted through the designated data sharing platform or by email to the study's data management team. Access to IPD will be granted based on ethical review and approval, ensuring that the proposed research aligns with the study's objectives and respects participant confidentiality. All requests will be reviewed by an independent committee responsible for overseeing data sharing, ensuring transparency, and safeguarding participant privacy.