Escalating cannabis use may be linked to decreased motivation and anhedonia, which are symptoms of depression. Adolescent cannabis users with subthreshold depressive symptoms such as reduced motivation may be susceptible to the development of significant anhedonia in addition to impaired emotional development. The main issue regarding depression within the context of cannabis use is whether or not there is a neurobiological basis linking the two variables. A Medical Subject Headings (MeSH) function PubMed search using the keywords “cannabis, depression, adolescence, endocannabinoid, and temperament” returned 1,109 articles. Data were included from studies that satisfied the following criteria: (i) published within the last 10 years (older studies were included based on relevance), (ii) on adolescent subjects (animal or human), (iii) published in English, (iv) journal articles, systematic reviews, meta-analyses, clinical trials, observational studies (animal or human), (v) on subjects who had unipolar depression with no comorbidities, and (vi) on subjects who used cannabis [with no confounding variables such as the use of ethanol, nicotine, cocaine, lysergic acid diethylamide (LSD), and heroin; and no medical conditions such as comorbid psychosis, mania, or autism]. Depressive symptoms in cannabinoid users were a common co-occurrence partly explained by pleiotropic linkage of genetic locus identified on chromosome 11q23.1-q23.2 and comprises the gene sequence nuclear cell adhesion molecule 1-tetratricopeptide repeat domain 12-ankyrin repeat and kinase domain containing 1-dopamine receptor D2 (NCAM1-TTC12-ANKK1-DRD2). The relationship between the two is not invariant and is influenced by polymorphic DRD, endocannabinoid receptor (CNR), and 5-HT genes. Anhedonia seemed to be the most important symptom. Cannabinoid-induced long-term neuroplastic changes, particularly in the dorsal striatum, is a possible mechanism resulting in anhedonia and long-term effects on motivation.Copyright © 2020, Forrester et al.