Exploring the other psychoactive constituents of coffee While caffeine is considered to be the major psychoactive constituent of coffee, other constituents play a role in the mood and cognitive benefits of coffee, including polyphenols like chlorogenic acids (CGAs) and the metabolite caffeic acid, alkaloids including trigonelline and β-carbolines and other constituents such as diterpenes such as cafestol and kahweol also likely play a role [1] The hydroxycinnamic acid polyphenols like chlorogenic acid and it's metabolite caffeic acid are CNS active and reach the brain exerting neuroprotective effects [2]. Chlorogenic acid, which is particularly found in the green unroasted beans seemingly has some mood and cognitive effects "including increased alertness and reduced mental fatigue" even in decaffeinated coffee [3]. In humans, continuous intake of chlorogenic acids improved cognitive functions in patients with mild cognitive impairment, especially attention and executive function. In animal models, the chlorogenic acids exert weak caffeine-like psychostimulant effects, 1 which is attributed to the metabolites m-coumaric acid and caffeic acid [4]. Considering the comparatively large percentage of hydroxycinnamic acids vs caffeine, it may play an underestimated role. Caffeic acids also show antidepressant [5] [also via epigenetic [6]] and neurotrophic activity [7]. Chlorogenic and caffeic acid in the brain, from [8] Caffeic acid seems to have beneficial effects on insulin sensitivity and memory in diet- induced models of Alzheimer's, decreasing serum glucose, insulin and leptin levels [9]. Via their effect on nitric oxide and cerebral blood flow, acute cognitive benefits may be noted from chlorogenic acids and it's metabolites. Chronic coffee consumption appears to slow cognitive decline in humans [10] and intake of chlorogenic acids seems to improve attentional, executive, and memory functions after 6 months of consumption [11], or more mildly, short-term intake of CGAs [12] has also been shown to improve cognitive function and reduce fatigue. After tobacco consumption, coffee becomes the predominate dietary source of beta- 2 carbolines. It is estimated that persistent coffee intake, through the neuroactive norharman and harman, can measurably reduce human MAO activity (30% for coffee, vs 60% for tobacco) [13] Trigonelline shows neuroprotective and neurotrophic effects and stimulates dopamine release, displays competitive inhibition of GABAA receptors and weak inhibition of AChE [14] The diterpenes kahweol and cafestol seem to display neuroprotective effects but little is known about their pharmacology [1] although cafestol and kahweol have been show to induce Nrf2 activation. [1] https://doi.org/10.3390%2Fijms22010107 [2] https://doi.org/10.3390%2Fnu12051531 [3] https://doi.org/10.1371%2Fjournal.pone.0082897 [4] https://doi.org/10.1271/bbb.60243 [5] https://doi.org/10.1097/01.wnr.0000073427.02536.b0 [6] https://doi.org/10.3892/mmr.2020.11609 [7] https://doi.org/10.1016/j.ejphar.2006.01.026 [8] https://doi.org/10.1016/j.foodres.2015.04.010 [9] https://doi.org/10.3389/fnagi.2021.744872 [10] https://doi.org/10.3390/nu14204309 [11] https://doi.org/10.3390/brainsci12030370 [12] https://doi.org/10.1155/2018/8608497 [13] https://doi.org/10.1016/B978-0-12-409517-5.00082-6 [14] https://doi.org/10.1016%2Fj.bmc.2020.115820 3