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Ethnopharmacological relevance Melissa officinalis L., commonly known as lemon balm, is one of the most well known edible and medicinal plants of the Lamiaceae family. It is quoted in almost all known medical treatises, from Antiquity up to modern era, such as Corpus Hippocraticum, Dioscorides’ De Materia Medica and later on in medieval medical manuscripts and Pharmacopoeias. Actually, it is widely used as herbal medicine for the relief of mild symptoms of mental stress, to aid sleep and for symptomatic treatment of mild gastrointestinal complaints including bloating and flatulence. In Greece, the empirical physicians “vikoyiatroi” recommended the decoction of dry flowers and leaves to treat tracheobronchitis, hysteria, epilepsy, heart arrhythmias, as hypnotic and against skin disorders. Aim of the study The present study was conducted to investigate the potential beneficial effects in psoriasis in mice of M. officinalis ssp. altissima and to carry out the chemical analysis in order to reveal its main bioactive secondary metabolites. Materials and methods Non polar and polar extracts of M. officinalis ssp. altissima aerial parts were prepared by using dichloromethane and methanol, successively; in addition a decoction was made upon oral information by local users in Crete, where the plant was collected. All three preparations were chemically analyzed in order to isolate their main constituents. Chemical structures of all isolated compounds were determined by 1D, 2D-NMR and UV–Vis spectroscopy. Furthermore, the antioxidant potential of extracts and decoction was evaluated through DPPH radical scavenging capability. The in vivo in mice anti-psoriatic efficacy of all preparations was estimated through clinical and histopathological assessment and measurements of TEWL and hydration. Results The dichloromethane extract yielded ursolic acid, 2α-hydroxy-ursolic acid, pomolic acid, 3β-stearyloxy-urs-12-ene, oleanolic acid, noropacursane and campesterol; the methanol extract afforded rosmarinic acid and methyl rosmarinate, while from the decoction caffeic acid, 3-(3,4-dihydroxyphenyl)lactic acid and rosmarinic acid were isolated. The psoriasis evaluation, based on PASI score, photodocumentation and histopathological estimation showed that the decoction primarily and the dichloromethane extract secondly could significantly contribute to psoriasis treatment. The decoction seems able to reestablish skin physiology by decreasing dryness and enhancing skin barrier function. Moreover, the decoction showed the best antioxidant activity, while the dichloromethane extract the weakest. Conclusions The triterpene derivatives of the dichloromethane extract are likely to be responsible for its anti-psoriatic activity. The abundant polyphenolic load of the decoction contributes to its high antioxidant activity and the most effective results against psoriasis. The anti-psoriatic activity of the decoction confirmed the traditional use of this plant as antioxidant, wound healing and skin barrier repair agent.