Many patients with Postural Orthostatic Tachycardia Syndrome (POTS) experience debilitating fatigue and this significantly impacts their daily lives. Unfortunately, there are no treatments to help POTS patients with their fatigue. One medication, called low dose naltrexone (LDN), has been tested as a treatment for fatigue in other medical conditions. In this other research, LDN helped patients feel less fatigue. Other research studies have shown that LDN can help reduce markers of inflammation called cytokines. Reducing these cytokines could help reduce symptoms as well. There have been no research studies testing LDN in POTS to date. We are planning to do a research study to test LDN as a treatment to see if it helps POTS patients feel less fatigue.

Research Objectives: To evaluate LDN as a treatment for fatigue in patients diagnosed with POTS. The primary hypothesis is that LDN will reduce fatigue in patients with POTS when compared to placebo using a 0-100 Fatigue Visual Analogue Scale. The secondary hypotheses are that LDN will improve quality of life in patients with POTS when compared to placebo using the RAND36 Health Related Quality of Life Survey, and that LDN will reduce inflammatory cytokine concentrations in patients with POTS compared to placebo. Tertiary outcomes will compare autonomic symptoms and orthostatic vital signs between LDN and placebo and also evaluate feasibility of a larger scale clinical trial.

Study Design and Methodology: We will recruit 80 patients with POTS across three sites.Participants will be randomized to the LDN group or the placebo group, for a 16 week study. Before beginning the study drug, POTS patients will complete a baseline assessment including fatigue evaluation, cytokine levels, orthostatic vital signs, orthostatic symptoms, and quality of life. After the baseline assessment, POTS patients will begin the study drug titration (LDN or placebo) as follows: 1.5mg for 2 weeks, 3.0mg for 2 weeks, 4.5 mg for 12 weeks. If participants do not tolerate the target dose (4.5mg), then will reduce to the highest tolerable dose. Participants will complete virtual assessments at 1, 2 and 3 months (surveys). Participants will also be provided with a diary to record symptoms. After 4 months, participants will again attend the research clinic/lab for a final assessment (same procedure as the baseline assessment).

Anticipated Outcomes: These data will allow us to evaluate the efficacy of LDN as a treatment in POTS. The results of this study could be used to inform the feasibility and design of larger clinical trials evaluating LDN use in POTS with funding from a national granting agency.

Inclusion Criteria:

• Physician diagnosis of POTS as defined by the American Autonomic Society consensus statement
• Ability to attend research lab in Calgary, Vancouver or Hamilton, Canada
• Not pregnant and not planning to become pregnant for the duration of the study
• Maintain current other medications at regular doses for the duration of the study

Exclusion Criteria:

• Overt cause for postural tachycardia (e.g. acute dehydration, hyperthyroidism)
• Positive pregnancy test
• Breastfeeding
• Other factors which in the investigator's opinion would prevent participant from completing the protocol, including poor compliance during previous studies
• Current use of Low Dose Naltrexone
• Use of opioid containing medications or positive urine opioid test
• History of alcohol, opioid or other substance use disorder

Study drug and placebo will be masked by the pharmacy.