Background: Psychotherapy and pharmacotherapy are first-line treatments for mental disorders. Despite recent improvements, only approximately 50% of the patients reach sustained remission, indicating a need for novel developments. The main concept put forward in this systematic review and hypothesis article is the targeted co-administration of defined neurobiological interventions and specific psychotherapeutic techniques.Methods: We conducted a systematic literature search for randomized controlled trials comparing the efficacy of augmented psychotherapy to psychotherapy alone.Results: Thirty-five trials fulfilled the inclusion criteria. The majority (29 trials) used augmentation strategies such as D-cycloserine, yohimbine, or sleep to enhance the effects of exposure therapy for anxiety disorders. Fewer studies investigated noninvasive brain stimulation with the aim of improving cognitive control, psychedelic compounds with the aim of enhancing existentially oriented psychotherapy, and oxytocin to improve social communication during psychotherapy. Results demonstrate small augmentation effects for the enhancement of exposure therapy - however, some of the studies found negative results. Other methods are less thoroughly researched, and results are mixed.Conclusions: This approach provides an open matrix for further research and has the potential to systematically guide future studies.