Summary Fifty-four per cent of the patients had no psychic disturbance. Most of those with reactions showed the euphorigenic effect, but did not manifest alarming psychic reactions. Only 15 per cent showed distinctly aberrant reactions. Most of them were transient, self-limited, and mild in character. Nosologically, they were classified as depressions, paranoid reactions, and schizophrenic and toxic syndromes. A complete discrepancy existed between the dosage, the pretreatment state, and the psychic outcome. Actually, in general, those instances with psychic change were associated with a smaller exposure to the drugs. The intensity of psychic change did not increase with the passage of time under treatment. Despite an impression that ACTH was more likely to be associated with psychic phenomena, our material did not allow a definitive evaluation on this score. The psychic reaction to these drugs is usually not only benign, but also unpredictable. Metabolic alterations due to the drug were not per se associated with corresponding mental changes. In contrast to prevailing expressed opinion, our studies indicate that the pretreatment psychic structure bears no important relationship to the effect of the drugs. Both those with a precariously balanced psyche or with distinct psychotic manifestations before treatment neither suffered nor failed to improve. Fears regarding disastrous consequences following the removal of chronic affect-laden symptoms were not borne out. The primary mental change with ACTH or cortisone is the production of a state of cerebral excitability characterized as the "ready state." This state may occur during the first 4-6 hours, and merge with a formed psychic reaction within a mean period of 3.6 days after the beginning of treatment. Affect perturbation is the central clinical event; the lability is a very important characteristic. Ideational stimuli assumes much greater temporary importance than before in determining the direction of affect change. The locale of the psychic disturbance produced by the drugs was found to be primarily in that functional area of the ego dealing with the reception of stimuli. Evidence was present of a disturbance in repression, selective in character. Well fixed modes of defenses may undergo alteration as a drug effect. The changes noted were mainly in a favorable direction.