The goal of this clinical trial is to learn if propranolol can help reduce challenging behaviors associated with Autism Spectrum Disorder, including aggression, self-injury, and severe disruptive behaviors. Participants will be randomly assigned to receive either propranolol or a placebo (a look-alike substance that contains no drug) daily for 12 weeks. After the 12 weeks, all participants will have the opportunity to receive propranolol for an additional 12 weeks.

The study will evaluate the efficacy and safety of high dose propranolol in 60 male and female participants between the ages of 12 and 40 years who have a diagnosis of Autism Spectrum Disorder (ASD) and experience serious challenging behaviors. Participants must meet severity criteria, defined as a Clinical Global Impression Severity (CGI-S) score of 4 or higher and an Aberrant Behavior Checklist-2 Irritability/Agitation (ABC-I/A) score greater than 18. Participants will be randomly assigned to receive either propranolol or a placebo. Over the first 8 weeks, participants will gradually increase their study medication following a set schedule to find the highest dose they can tolerate (up to a maximum of 200 mg three times daily). This will be followed by 4 weeks at a steady dose. After completing the 12-week randomized phase, participants will be offered the option to learn their group assignment (propranolol or placebo) and continue into a 12-week open-label extension, where all participants will receive propranolol.

Inclusion Criteria:

• Age between 12-40 years.
• Clinical best-estimate diagnosis of autism spectrum disorder
• Occurrence of severe challenging behaviors, such as aggression, self-injury, and/or severely disruptive or destructive behavior, leading to safety concerns or serious impact of the quality of life, at least weekly over the past 2 months before screening.
• Score in the ASD range on the Autism Diagnostic Observation Schedule conducted at the time of study entry or in the past 5 years
• Clinical Global Impression Severity scale (CGI-S) score of 4 or above at Baseline
• Aberrant Behavior Checklist-2 Irritability/Agitation Subscale Score of 18 or above at Screening.
• A resting pulse of greater than 60 and a resting blood pressure of greater than 100/60.
• Participant must have a designated study partner who spends a minimum of 5 hours/week with the participant, and can, in the opinion of the investigator, provide a reliable report on the participant's behaviors, symptoms, and complete or supervise at-home safety monitoring and other assessments required during the study
• Participants of childbearing potential who are sexually active must agree to practice effective contraception from time of screening through 30 days after their last dose of study drug. Effective contraception is the use of two methods of contraception: hormonal contraceptives or intrauterine device and barrier (i.e., condoms, diaphragm, or cervical cap).
• Participant must be able to fully swallow study medication capsule.
• English must be primary language for participant. Study partner must be able to consent in English and complete study related form in English.

Exclusion Criteria:

• Those who are unable to provide informed consent and have no parent/guardian/legally authorized representative to provide informed consent for study enrollment
• Change in psychotropic medication or behavioral intervention (except when caused by vocational, habilitation, or school schedule) within two months before randomization.
• Asthma or history of any disorder involving bronchoconstriction in the past 5 years.
• Cardiovascular history in which the use of propranolol at high doses would be contraindicated, as determined by consulting cardiologist (such as AV block, sick sinus syndrome, valvular pathologies, cardiomyopathies, or vascular disease).
• Uncontrolled seizure disorder (a seizure within the past year and/or changes in seizure medication in the previous six months).
• Diabetes mellitus
• History of lactose intolerance that requires the potential participant to abstain from all dairy products or to take lactase supplements.
• Medical history of renal or hepatic impairment.
• Medical history of hypoglycemia
• Inability to provide blood testing when there is a medical indication for blood testing to allow clinical safety determination by the study safety physician
• Depressive episode currently or within the previous six months
• History of allergy or adverse reaction to propranolol or another beta-blocker
• Current use of any of the following: propafenone, quinidine, amiodarone, lidocaine, digitalis glycosides, calcium channel blockers, ACE inhibitors, clonidine, alpha blockers, reserpine, inotropic agents (epinephrine), isoproterenol and dobutamine, nonsteroidal anti-inflammatory drugs (indomethacin), antidepressants (MAO inhibitors, tricyclics), anesthetic agents (methoxyflurane, trichloroethylene), warfarin, neuroleptics (haloperidol), thyroxine, alcohol
• Any other medical disorder or medication which would contraindicate the use of propranolol.
• Is judged to be inappropriate for the study for any reason by the Investigator
• Has recently participated in another investigational medication study or device study within last 3 months
• Participant is unable to complete blood pressure or ECG safety assessments
• If female, is pregnant or breastfeeding.

Data from this study may be submitted to the NIMH Data Archive (NDA). NDA is a computer system run by the National Institute of Mental Health (NIMH) that allows researchers to collect and share information with each other. During and after the study, the researchers will send health and behavioral information about the subject, in some cases, the subject's genetic information, to NDA. However, before they send it to NDA, names, addresses, phone numbers, and other identifiable information will be removed, and replaced that information with a code number called a Global Unique Identifier (GUID). Other researchers nationwide can then file an application with the National Institutes of Health to obtain access to this study data for research purposes.

Only approved researchers with NDA access will be able to use the data