This study aims to study the feasibility of psilocybin therapy for patients with Amyotropic Lateral Sclerosis (ALS) with depressed mood. The secondary objective is to assess its impact on depression, quality of life, hopelessness, and functional status in this patient population.

The proposed research's primary objective is to study the feasibility of psilocybin therapy for patients with ALS with depressed mood. The secondary objective is to assess its impact on depression, quality of life, hopelessness, and functional status in this patient population. The proposed proof-of-concept interventional trial will use a single-arm design. The study will be an open-label trial in a sample of up to 24 treatment-seeking patients with a diagnosis of ALS and depressed mood. Participants will complete an 8-week course of study treatment including two psilocybin sessions (15 mg in week 4 and 15 or 25 mg in week 6), with follow-up assessments 1, 3, and 6 months after the final psilocybin session.

Inclusion Criteria:

1. Patients aged 18 years and older.
2. Patients must fulfill ALS El Escorial criteria for possible, probable, laboratory supported probable or definite ALS.
3. Patients with a pulmonary forced vital capacity (FVC) >60%. The investigators have chosen this measure of function to account for respiratory decompensation during the 6-month longitudinal portion of the study.
4. Patients with ability to swallow tablets by mouth. Participants may have a feeding tube, but must be able to swallow by mouth and cannot use the feeding tube to administer the psilocybin tablet.
5. Clinically significant depressive symptoms as evidenced by an Assessment of Depression Inventory (ADI)-12 score >22.

Exclusion Criteria:

1. Patients with severe speech impairments, including those who are nonverbal, require assisted speech devices, and those who can only communicate by writing or texting.
2. Patients who are unable to consent for themselves.
3. Patients with tracheostomy or continuous continuous positive airway pressure (CPAP) or BiPAP.
4. Known clinical evidence of frontotemporal dementia.
5. Cardiovascular conditions: corrected QT interval (QTc) >450 msec, uncontrolled hypertension (i.e., systolic blood pressure (SBP)> 139 mm Hg, diastolic blood pressure (DBP)> 89 mm Hg), resting heart rate (HR)> 90 beats per minute, angina, a clinically significant ECG abnormality (e.g., atrial fibrillation), transient ischemic attack (TIA) in the last 6 months, stroke, peripheral or pulmonary vascular disease (no active claudication).
6. Epilepsy with history of seizures
7. Renal disease (creatinine clearance <40 ml/min using the Cockraft and Gault equation)
8. Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia
9. Females who are pregnant (positive pregnancy test) or nursing, or are not practicing an effective means of birth control (i.e., intrauterine systems/devices, hormonal methods including implant, shot, patch, ring, or oral contraceptive, condom, diaphragm, sterilization, and abstinence).
10. Currently taking medications that interact with psilocybin on a regular (e.g., daily) basis: Atypical antidepressants, such as mirtazapine (Remeron), trazodone (Oleptro), vortioxetine (Brintellix), and vilazodone (Viibryd); Tricyclic antidepressants, such as amitriptyline, imipramine (Tofranil), nortriptyline (Pamelor), desipramine (Norpramin), doxepin, trimipramine (Surmontil), and protriptyline (Vivactil); and Monoamine oxidase inhibitors (MAOIs), such as Selegiline (Emsam), tranylcypromine (Parnate), phenelzine (Nardil) and isocarboxazid (Marplan).
11. Currently taking Nuedexta (dextromethorphan/quinidine combination), efavirenz, Acetaldehyde dehydrogenase inhibitors such as disulfiram (Antabuse), Alcohol dehydrogenase inhibitors, or UGT1A9 inhibitors or UGT1A10 inhibitors such as phenytoin, regorafenib, eltrombopag.
12. Current or history of meeting Diagnostic and Statistical Manual (DSM)-5 criteria for Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), or Bipolar I Disorder
13. Have a first degree relative with schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), or bipolar I disorder.