WHITE PAPER Lysergic Acid Diethylamide as a Multi-Target Therapeutic for Alzheimer’s Disease By Shlomi Raz, Eleusis Therapeutics Ltd September 2020 Additional contributors: Nichols C.D. , Maillet E. L. , Grantham C. , Family N. new approachesnew to diseaseapproaches modification to disease 7, 8modification. Multi-targeted 7, 8. Multidrugs- targeted(MTDs) with drugs established (MTDs) with safety established profiles safety profiles could empiricallycould engag empiricallye identified engag therapeutice identified targets therapeutic 9. targets 9. We propose theW hypothesise propose thatthe hypothesis low-dose l ysergicthat low acid-dose diethylamide lysergic acid (LSD diethylamide) represents (LSD a promising) represents a promising INTRODUCTIONdisease modifyingdisease therapeutic modifying for therapeuticAD. LSD is a forclassic AD. psychedelic LSD is a classic drug psychedelic and is one drugof the and most is one well of-studied the most well-studied 10, 11 10, 11 Alzheimer’s Disease psychoactive(AD) is adrugs psychoactiveheterogenous in the history drugs pharmacology ofin modernthe history pharmacology10,11 of and modern shares pharmacology structural. It shares similarity structural. It sharesto similarity structural to 5- HTsimilarity to 5-HT neurodegenerative disease expected to afflict nearly 5-HT (FIGURE 1). 15 million people over 65(FIGURE in the US 1). by 2050(FIGURE (Alzheimer’s 1). Association, 2020). Mild cognitive impairment (MCI) is a prodromal state of AD, associated with amnesic cognitive dysfunction distinct from normal aging. The progression of MCI to AD features multiple dysregulated physiological cascades that characteristically feature the accumulation of abnormally folded amyloid-β (Aβ) and tau proteins in amyloid plaques and neurofibrillary tangle deposits1. The multifactorial nature of early-stage AD suggests multiple pathophysiological processes, including neuroinfammmation2, synaptic degeneration3, neuropsychiatric/neurendocrine dysfunction4,5 and brain insulin resistance6, all of which are potential targets for therapeutic intervention. Targeted immunotherapies capable of disease modification by reducing βA and tau burden have failed to influence AD progression in late-stage clinical trials, and the only FDA-approved drug therapies are symptomatic in natureFIGURE with marginal1. illustrationsFIGURE and transient of1. 5illustrations-HT and LSD, of highlighting5-HT and LSD, their highlighting similarities their in structure similarities in colorin structure (Adapted in colorfrom (Adapted from clinical efficacy, highlighting the urgent need for new FIGURE 1. illustrations of 5-HT and LSD, highlighting their approaches to disease modification7,8. Multi-targeted similarities in structure in color (Adapted from Nichols DE. Nichols DE. Serotonin,Nichols DE. and Serotonin, theSerotonin, Past and and and Future the Past Past ofand andLSD Future Future. MAPS of LSD. of MAPSBulletin LSD Bulletin. MAPS Spring Bulletin 2013). Spring 2013). drugs (MTDs) with established safety profiles could Spring 2013). empirically engage identified therapeutic targets9. This article sets out the evidence and arguments for We propose the hypothesis that low-dose lysergic why the pharmacology of LSD, when administered acid diethylamide (LSD) represents a promising This article setsThis out article the atevidence setssub-psychoactive out andthe argumentsevidence doses, and for makes argumentswhy itthe an pharmacology forappealing why the pharmacologyof LSD, when of LSD, when disease modifying therapeutic for AD. LSD is a disease-modifying therapeutic candidate for AD, and classic psychedelic drug and is one of the most well- provides background for the design and conduct of studied psychoactive drugsadministered in the history atadministered sub -ofpsychoactive modern at subfurther doses,-psychoactive studiesmakes it todoses, an evaluate appealing makes its efficacy.itdisease an appealing-modifying disease therapeutic-modifying candidate therapeutic candidate for AD, and providesfor AD, background and provides for background the design and for theconduct design of andfurther conduct studies of furtherto evaluate studies its efficacy.to evaluate its efficacy. SEROTONINERGIC SYSTEM IN AGEING AND AD 5-HT is a monoamine neurotransmitterSEROTONINERGICSEROTONINERGIC and hormone SYSTEM CNS IN by AGEINGSYSTEM 5-HT could ANDIN result AGEING AD in opposing AND effects.AD Instead, that exerts a direct modulatory influence on nearly selective activation of only relevant 5-HT receptors all the pathological, physiological and behavioral may maximize therapeutic value of 5-HT receptor changes observed in AD12,13. Preclinical5-HT is a monoamine and 5clinical-HT is neurotransmittera monoaminetargeted therapeutics. neurotransmitter and hormone that and exertshormone a direct that exertsmodulatory a direct influence modulatory influence data suggest that modulating 5-HT receptors may be a useful therapeutic strategy for AD, eg. Selective LSD binds to a subset of serotonin (5-HT), dopamine 12, 13 12, 13 serotonin reuptake oninhibitors nearly all (SSRIs)theon pathological nearly preserve all the physiological pathologicaland other and biogenicphysiological behavior amineal andchanges receptors behavior observed alwith changes differentin AD observed . Preclinical in AD and. Preclinical and cognition, suppress microglial activation, and lower affinities. The biological effect of LSD is related to brain Aβ levels in AD clinicalanimal datamodels suggestclinical14-17, while that data long-modulating suggestits receptorthat 5-HT modulating receptors binding 5andmay-HT occupancy,receptorsbe a useful may which therapeutic be ina turnuseful strategy is therapeutic for AD, strategy eg. for AD, eg. term SSRI use (> 4 years) delays the conversion of governed by the concentration of LSD to which the MCI to AD in MCI patients18. Because SSRIs do not receptor is exposed. At low, sub-psychoactive doses, demonstrate a robust disease modifying effect LSD selectively occupies several of the 5-HT receptor in depressed MCI patients, it is possible that the subtypes (see heatmap in TABLE 1). indiscriminate activation of all 5-HT receptors in the LSD for Alzheimer's (Review) Copyright © 2020 Eleusis Therapeutics Ltd 1 SEROTONINERGIC SYSTEM IN exceptionAGEING of the 5-HT AND3 and 5-HT 4 ADreceptors, (CONT’D) and is quantitatively different in its activation profile, depending on dose 11. We have recently demonstrated the safety and tolerability of chronic low dose LSD NE NE DA DA DA DA Hist 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT (i.e. doses up to 20 μg) in healthy elderly volunteers19. In this study, no physiological or behavioral effects Receptor Target B1 B2 2 3 4 5 1 1A 1D 1E 2A 2B 2C 5A 6 7 Apparent significantly differed from placebo and pharmacokinetic evaluation suggest that plasma levels are in the 6.9 6.1 6.9 7.6 7.3 6.5 5.8 8.9 8.4 7.0 8.4 7.5 7.8 8.1 8.2 8.2 affinity (-pKi) low nanomolar concentration range consistent with moderate occupancy and a more subtle engagement LSD Poly-pharmacological Profile (receptor sites occupancy in %) concentration profile at 5-HT receptors in the brain devoid of excessive pharmacology hallmarks (FIGURE 2, Table 1 see 10 nM 7 1 8 27 15 3 1 90 72 10 69 25 38 53 60 61 1nM row of polypharmacological profile). We propose that the functional selectivity and potency of LSD 1 nM 1 0 1 4 2 0 0 47 20 1 18 3 6 10 13 13 20 at 5-HT2A receptors, which underlies its neuropsychological psychedelic properties at higher doses , 0.1 nM 0 0 0 0 0 0 0 8 3 0 2 0 1 1 1 2 together with its selective modulation of certain other 5-HT and dopamine receptors, represents a novel TABLE 1. Estimated polypharmacological profile of LSD shows the fraction of each receptor type that is saturated or bound by LSD Occupancy at different theoretical concentrations of LSD was estimatedpolypharmacological by the Hill-Langmuir-based strategy equation for the assumingdisease modification a Hill coefficient of AD. of 1 and using the average experimental Ki values for apparent affinity at human receptors in cellular models. Source of Ki information: CHEMBL (accessed April 2020) NE, norepinephrine; DA, dopamine; Hist, histamine, 5-HT, serotonin LSD is qualitatively distinct from 5-HT in that it differentially modulates 5-HT receptors, possessing 20 µg oral LSD partial agonist, agonist and antagonist properties at the various 5-HT receptor subtypes with the exception of the 5-HT3 and 5-HT4 receptors, and is quantitatively different in its activation profile, depending on dose11. We have recently demonstrated the safety and tolerability of chronic low dose LSD (i.e. doses up to 20 μg) in healthy elderly volunteers19. In this study, no physiological or behavioral effects significantly differed from placebo and pharmacokinetic evaluation suggest that plasma levels are in Plasmadrugconcentration a nanomolar concentration range consistent with moderate occupancy and a more subtle engagement profile at 5-HT receptors in the brain, devoid of excessive pharmacology hallmarks (FIGURE 2, Table 1 see 1 nM row of polypharmacological profile). We propose that the functional selectivity and FIGURE 2. Plasma drug levels of LSD in humans after potency of LSD at 5-HT2A receptors, which underlies administration of a non-psychedelic “microdose” of LSD. its neuropsychological psychedelic properties at The average CMax in plasma was 0.44 ng/ml, which is equivalent higher doses20, together with its selective modulation to 1.5 nanomolar (nM) concentrations. The dotted line represents