The goal of this study is to investigate the effects of cannabis on brain function among adolescents with depression.

Inclusion criteria at baseline.

• Cannabis users: To capture a wide range of cannabis use frequency, meeting DSM-5 criteria for cannabis use disorder will not be required. However, in order to ensure sufficient exposure, we will require majority of adolescents with cannabis use to have a significant cannabis use (self-reported use on more or equal to 10 of the prior 30 days and positive THC urine toxicology).
• Depression: Similarly, to capture a wide range of depression illness severity, we will allow participants with subthreshold depression, defined as a raw severity score of >=30 on the Children's Depression Rating Scale-Revised (CDRS-R, for ages 14-17) and as a raw severity score of >=12 on the Montgomery Asberg Depression Rating Scale (MADRS, for ages 18-20). However, we plan for at least 50% of participants with depressive symptoms to have a raw severity score of >=40 on the CDRS-R and of >=20 MADRS, which are considered reliable for depression. Additionally, we will allow participants with a research diagnosis of Major Depressive Disorder as defined by the MINI, even with a CDRS-R score below 30 or a MADRS score below 12. Moreover, because there could be individuals without MDD who have current depressive symptoms, individuals who lack a diagnosis of a depressive disorder but have a CDRS-R score of 30 (or higher) or a MADRS score of 12 (or higher) will be allowed. Through careful recruitment, we will ensure distributions of depression severity. Based on our prior studies employing similar criteria, we anticipate that anhedonia, anxiety and depression severity scores will be normally distributed in our samples.

Exclusion criteria.

All participants:

• Psychotropic medication free for more than 1 month (or more than three months for medications with a long half-life such as fluoxetine) prior to study enrollment. We have successfully enrolled hundreds of psychotropic medication-free depressed adolescents and young adults to date. Psychotherapy will be allowed.
• MRI contraindications such as claustrophobia, metallic ink tattoos, orthodontic braces, or pacemakers
• Positive pregnancy tests
• Neurological illnesses and medical conditions such as unique pain syndromes (e.g. multiple sclerosis, rheumatoid arthritis)
• Estimated full-scale IQ <=80 to ensure that participants have the ability to understand the study
• Current SUD other than cannabis or nicotine. Excluding nicotine use will limit generalization of our findings and impact feasibility. Similarly, alcohol use will be allowed as long as it is not hazardous and does not meet criteria of a DSM-5 disorder (AUDIT-C >5). Therefore, nicotine and alcohol use will be allowed and controlled for. Alcohol and cannabis use (assessed based on breathalyzer from alcohol and self-report for cannabis/THC) on the day of the scan will result in rescheduling the scan as it can affect MRI data.
• Certified for or self-reported medical cannabis use, or intent to become certified, current stimulant use (methamphetamine or cocaine) by self-report or urine toxicology. Adderall and Vyvanse for ADHD will be allowed as long as use is temporarily paused medication usage at least 3 days before neuroimaging visit. If medication is not discontinued on scan day, scanning at that time will be up to PI discretion.
• Oral contraceptives will be allowed and controlled for in order to maximize recruitment of older adolescents.

Depressed THC non-users:

• DSM-5 diagnoses of bipolar disorder, psychotic disorders, autism spectrum disorders, and all non-cannabis substance-related disorders will be exclusionary. However, anxiety disorders, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) are not uncommon among depressed individuals and will be allowed as long as depressive symptoms are primary. Our focus on behavioral constructs aims to address comorbidity and mechanistic overlap among psychiatric disorders. Were these diagnoses exclusionary, the sample would be highly atypical of depression.
• Self-injurious acts (e.g. cutting) and suicidal ideations (SI) without a specific plan (defined as passive SI) are common in adolescent depression and will be allowed. However, if SI constitutes an imminent risk to self or others (defined as active SI), the adolescent will be withdrawn from the study and emergency procedures will be initiated immediately, including ER admission (see Protection of Human Subjects).

Healthy controls will have no lifetime history of any major psychiatric diagnoses and no use of any THC.