Psychedelic-assisted therapy has demonstrated substantial efficacy across a range of psychiatric and addictive disorders. However, heterogeneity between patients confers differential responsiveness. A systematic review and meta-analysis were conducted according to PRISMA guidelines to explore factors which may predict responses to psychedelic-assisted therapy. Forty-eight studies that investigated substance-use disorders, major depressive disorder, anxiety disorder, depression and anxiety in patients with life-threatening cancer, obsessive-compulsive disorder, post-traumatic stress disorder, bipolar disorder and symptoms of depression and anxiety were included. We found that the main variable predicting clinical outcomes was the intensity of the acute psychedelic experience. Albeit not always enduring, the intensity of the mystical-type experience, in particular, was the strongest predictor of therapeutic response. Further assessment of the studies showed that factors related to set, setting and dose influence phenomenological features of psychedelic experiences and in certain situations, potentiate mystical-type experiences. Whilst the neurobiological underpinnings of mystical-type experiences remain to be fully elucidated, 5-HT2A receptor agonism is believed to play an initiatory role. The modulation of the default mode network, however, may largely account for the occurrence of mystical-type experiences. In conclusion, our findings show that the intensity of the mystical-type experience during the dosing session is the most robust predictor of therapeutic response.