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1432-207223732020MarPsychopharmacology (Berl)Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers.841853841-85310.1007/s00213-019-05417-7Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT_2A receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease.This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 μg, 10 μg, and 20 μg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response.This was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 μg, 10 μg, 20 μg LSD, and placebo), and received their assigned dose on six occasions (i.e., every 4 days).Forty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 μg (n = 12), 10 μg (n = 12), or 20 μg (n = 12) LSD. LSD plasma levels were undetectable for the 5 μg group and peak blood plasma levels for the 10 μg and 20 μg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment.Our results suggest safety and tolerability of orally administered 5 μg, 10 μg, and 20 μg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer's disease (AD).FamilyNeiloufarN0000-0002-0201-7119Eleusis Benefit Corporation, New York, NY, USA. neiloufar.family@eleusisltd.com.MailletEmeline LELEleusis Benefit Corporation, New York, NY, USA.WilliamsLuke T JLTJEleusis Benefit Corporation, New York, NY, USA.KredietErwinEEleusis Benefit Corporation, New York, NY, USA.Carhart-HarrisRobin LRLImperial College London, London, UK.WilliamsTim MTMBristol University, Bristol, UK.NicholsCharles DCDDepartment of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA, USA.GobleDaniel JDJSan Diego State University, San Diego, CA, USA.RazShlomiSEleusis Benefit Corporation, New York, NY, USA.engClinical Trial, Phase IJournal ArticleRandomized Controlled Trial20191218

GermanyPsychopharmacology (Berl)76080250033-31580Hallucinogens8NA5SWF92OLysergic Acid DiethylamideIMAdministration, OralAgedCognitiondrug effectsphysiologyCross-Over StudiesDose-Response Relationship, DrugDouble-Blind MethodFemaleHallucinogensadministration & dosagepharmacologyHealthy VolunteersHumansLysergic Acid Diethylamideadministration & dosagepharmacokineticsMaleMiddle AgedProprioceptiondrug effectsphysiologyReaction Timedrug effectsphysiology5-HT2AAlzheimer’sCNSClinical trialImmune systemInflammationNeurodegenerative diseasePsychedelicsSerotoninAll authors were paid consultants of Eleusis Benefit Corporation.2019312201911272019122060202081260201912206020191218ppublish31853557PMC703606510.1007/s00213-019-05417-710.1007/s00213-019-05417-7Bershad Anya, Schepers Scott, Bremmer Michael, de Wit Harriet. S125. Subjective and Behavioral Effects of Microdoses of LSD in Healthy Human Volunteers. Biological Psychiatry. 2019;85(10):S345. doi: 10.1016/j.biopsych.2019.03.876.10.1016/j.biopsych.2019.03.876PMC681452731331617Bidwell LC, Joseph McClernon F, Kollins SH. Cognitive enhancers for the treatment of ADHD. Pharmacol Biochem Behav. 2011;99(2):262–274. doi: 10.1016/j.pbb.2011.05.002.10.1016/j.pbb.2011.05.002PMC335315021596055Butchart J, Brook L, Hopkins V, Teeling J, Püntener U, Culliford D, Sharples R, Sharif S, McFarlane B, Raybould R, Thomas R, Passmore P, Perry VH, Holmes C. Etanercept in Alzheimer disease: a randomized, placebo-controlled, double-blind, phase 2 trial. Neurology. 2015;84(21):2161–2168. doi: 10.1212/WNL.0000000000001617.10.1212/WNL.0000000000001617PMC445104525934853Cambridge Cognition. 2016. CANTAB® [cognitive assessment software]. All rights reserved. www.cantab.comCarhart-Harris RL, Kaelen M, Whalley MG, Bolstridge M, Feilding A, Nutt DJ. LSD enhances suggestibility in healthy volunteers. Psychopharmacology. 2015;232(4):785–794. doi: 10.1007/s00213-014-3714-z.10.1007/s00213-014-3714-z25242255Carhart-Harris RL, Bolstridge M, Rucker J, Day CMJ, Erritzoe D, Kaelen M, Bloomfield M, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3(7):619–627. doi: 10.1016/S2215-0366(16)30065-7.10.1016/S2215-0366(16)30065-727210031Coleman P, Federoff H, Kurlan R. A focus on the synapse for neuroprotection in Alzheimer disease and other dementias. Neurology. 2004;63(7):1155–1162. doi: 10.1212/01.WNL.0000140626.48118.0A.10.1212/01.WNL.0000140626.48118.0A15477531Dittrich A. The standardized psychometric assessment of altered states of consciousness (ASCs) in humans. Pharmacopsychiatry. 1998;31(S2):80–84. doi: 10.1055/s-2007-979351.10.1055/s-2007-9793519754838Dolder Patrick C., Schmid Yasmin, Haschke Manuel, Rentsch Katharina M., Liechti Matthias E. Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans. International Journal of Neuropsychopharmacology. 2015;19(1):pyv072. doi: 10.1093/ijnp/pyv072.10.1093/ijnp/pyv072PMC477226726108222Donovan NJ, Hsu DC, Dagley AS, Schultz AP, Amariglio RE, Mormino EC, Okereke OI, et al. Depressive symptoms and biomarkers of Alzheimer’s disease in cognitively normal older adults. Journal of Alzheimer’s Disease : JAD. 2015;46(1):63–73. doi: 10.3233/JAD-142940.10.3233/JAD-142940PMC454463825697700Elangbam Chandikumar S. Drug-induced Valvulopathy: An Update. Toxicologic Pathology. 2010;38(6):837–848. doi: 10.1177/0192623310378027.10.1177/019262331037802720716786Fadiman J (2011) The psychedelic explorer’s guide: safe, therapeutic, and sacred journeys. http://ftp5.futbooks.com/the-psychedelic-explorers-guide-safe-therapeutic-and-sacred-journeys-P-49245.pdf25188706Farré Magí, Abanades Sergio, Roset Pere N., Peiró Ana M., Torrens Marta, O'Mathúna Bryan, Segura Mireia, de la Torre Rafael. Pharmacological Interaction between 3,4-Methylenedioxymethamphetamine (Ecstasy) and Paroxetine: Pharmacological Effects and Pharmacokinetics. Journal of Pharmacology and Experimental Therapeutics. 2007;323(3):954–962. doi: 10.1124/jpet.107.129056.10.1124/jpet.107.12905617890444Ferreira ST, Klein WL. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem. 2011;96(4):529–543. doi: 10.1016/j.nlm.2011.08.003.10.1016/j.nlm.2011.08.003PMC439039521914486First MB, Spitzer RL, Gibbon M, Williams JBW (2007) SCID-I/PFriedman RA (2017) LSD to cure depression? New York Times, February 13, 2017. https://www.nytimes.com/2017/02/13/opinion/lsd-to-cure-depression-not-so-fast.htmlGarcia-Romeu A, Griffiths RR, Johnson MW. Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Current Drug Abuse Reviews. 2014;7(3):157–164. doi: 10.2174/1874473708666150107121331.10.2174/1874473708666150107121331PMC434229325563443Gasser Peter, Holstein Dominique, Michel Yvonne, Doblin Rick, Yazar-Klosinski Berra, Passie Torsten, Brenneisen Rudolf. Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases. The Journal of Nervous and Mental Disease. 2014;202(7):513–520. doi: 10.1097/NMD.0000000000000113.10.1097/NMD.0000000000000113PMC408677724594678Geerlings MI, Den Heijer T, Koudstaal PJ, Hofman A, Breteler MMB. History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology. 2008;70(15):1258–1264. doi: 10.1212/01.wnl.0000308937.30473.d1.10.1212/01.wnl.0000308937.30473.d118391157Geldenhuys WJ, Van der Schyf CJ. Role of serotonin in Alzheimer’s disease. CNS Drugs. 2011;25(9):765–781. doi: 10.2165/11590190-000000000-00000.10.2165/11590190-000000000-0000021870888Glebov K, Löchner M, Jabs R, Lau T, Merkel O, Schloss P, Steinhäuser C, Walter J. Serotonin stimulates secretion of Exosomes from microglia cells. Glia. 2015;63(4):626–634. doi: 10.1002/glia.22772.10.1002/glia.2277225451814Goble Daniel J. Proprioceptive Acuity Assessment Via Joint Position Matching: From Basic Science to General Practice. Physical Therapy. 2010;90(8):1176–1184. doi: 10.2522/ptj.20090399.10.2522/ptj.2009039920522675Goble DJ, Hearn MC, Baweja HS. Combination of BTrackS and Geri-Fit as a targeted approach for assessing and reducing the postural sway of older adults with high fall risk. Clin Interv Aging. 2017;12:351–357. doi: 10.2147/CIA.S131047.10.2147/CIA.S131047PMC531269128228655Greiner T, Burch NR, Edelberg R. Psychopathology and psychophysiology of minimal LSD-25 dosage; a preliminary dosage-response spectrum. Arch Neurol Psychiatr. 1958;79(2):208–210. doi: 10.1001/archneurpsyc.1958.02340020088016.10.1001/archneurpsyc.1958.0234002008801613497365Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181–1197. doi: 10.1177/0269881116675513.10.1177/0269881116675513PMC536755727909165Grinberg LT, Rüb U, Ferretti REL, Nitrini R, Farfel JM, Polichiso L, Gierga K, Jacob-Filho W, Heinsen H, Brazilian Brain Bank Study Group The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer’s disease. A precocious onset? Neuropathol Appl Neurobiol. 2009;35(4):406–416. doi: 10.1111/j.1365-2990.2009.00997.x.10.1111/j.1365-2990.2009.00997.x19508444Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, Greer GR. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68(1):71–78. doi: 10.1001/archgenpsychiatry.2010.116.10.1001/archgenpsychiatry.2010.11620819978Group, The Alzheimer’s Disease Anti-inflammatory Prevention Trial Research Results of a follow-up study to the randomized Alzheimer’s disease anti-inflammatory prevention trial (ADAPT) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2013;9(6):714–723. doi: 10.1016/j.jalz.2012.11.012.10.1016/j.jalz.2012.11.012PMC382375623562431Haertzen Charles A., Hill Harris E., Belleville Richard E. Development of the Addiction Research Center Inventory (ARCI): Selection of items that are sensitive to the effects of various drugs. Psychopharmacologia. 1963;4(3):155–166. doi: 10.1007/BF02584088.10.1007/BF0258408814054658Haijen ECHM, Kaelen M, Roseman L, Timmermann C, Kettner H, Russ S, Nutt D, Daws RE, Hampshire ADG, Lorenz R, Carhart-Harris RL. Predicting responses to psychedelics: a prospective study. Front Pharmacol. 2018;9(November):897. doi: 10.3389/fphar.2018.00897.10.3389/fphar.2018.00897PMC622573430450045Hartogsohn I. Set and setting, psychedelics and the placebo response: an extra-pharmacological perspective on psychopharmacology. J Psychopharmacol. 2016;30(12):1259–1267. doi: 10.1177/0269881116677852.10.1177/026988111667785227852960Harvey JA. Role of the Serotonin 5-HT(2A) receptor in learning. Learning & Memory (Cold Spring Harbor, N.Y.) 2003;10(5):355–362. doi: 10.1101/lm.60803.10.1101/lm.60803PMC21800114557608Hasselbalch SG, Madsen K, Svarer C, Pinborg LH, Holm S, Paulson OB, Waldemar G, Knudsen GM. Reduced 5-HT2A receptor binding in patients with mild cognitive impairment. Neurobiol Aging. 2008;29(12):1830–1838. doi: 10.1016/j.neurobiolaging.2007.04.011.10.1016/j.neurobiolaging.2007.04.01117544547Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer’s disease. Nat Immunol. 2015;16(3):229–236. doi: 10.1038/ni.3102.10.1038/ni.310225689443Hibicke M, Landry AN, Talman ZK, Nichols C. Psychedelics improve the mental health of rats. The FASEB Journal. 2019;33(1_supplement):666.1. doi: 10.1096/fasebj.2019.33.1_supplement.666.1.10.1096/fasebj.2019.33.1_supplement.666.1Holmes C, McCulley M, Nicoll JAR, Alder JT, Chen CPLH, Francis PT. Genetic variation in the 5-HT2A receptor and altered neocortical [3H] ketanserin binding in Alzheimer’s disease. Neurosci Lett. 2007;420(1):58–60. doi: 10.1016/j.neulet.2007.04.009.10.1016/j.neulet.2007.04.00917481814Horstmann S, Lucae S, Menke A, Hennings JM, Ising M, Roeske D, Müller-Myhsok B, Holsboer F, Binder EB. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology. 2010;35(3):727–740. doi: 10.1038/npp.2009.180.10.1038/npp.2009.180PMC305562119924111Hutcheson Joshua D., Setola Vincent, Roth Bryan L., Merryman W. David. Serotonin receptors and heart valve disease—It was meant 2B. Pharmacology & Therapeutics. 2011;132(2):146–157. doi: 10.1016/j.pharmthera.2011.03.008.10.1016/j.pharmthera.2011.03.008PMC317985721440001Johnson MW, Richards WA, Griffiths RR. Human hallucinogen research: guidelines for safety. Journal of Psychopharmacology (Oxford, England) 2008;22(6):603–620. doi: 10.1177/0269881108093587.10.1177/0269881108093587PMC305640718593734Johnson MW, Andrew Sewell R, Griffiths RR. Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers. Drug Alcohol Depend. 2012;123(1–3):132–140. doi: 10.1016/j.drugalcdep.2011.10.029.10.1016/j.drugalcdep.2011.10.029PMC334529622129843Krabbe G, Matyash V, Pannasch U, Mamer L, Boddeke HWGM, Kettenmann H. Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behav Immun. 2012;26(3):419–428. doi: 10.1016/j.bbi.2011.12.002.10.1016/j.bbi.2011.12.00222198120Kuypers Kim PC, Ng Livia, Erritzoe David, Knudsen Gitte M, Nichols Charles D, Nichols David E, Pani Luca, Soula Anaïs, Nutt David. Microdosing psychedelics: More questions than answers? An overview and suggestions for future research. Journal of Psychopharmacology. 2019;33(9):1039–1057. doi: 10.1177/0269881119857204.10.1177/0269881119857204PMC673282331303095Ledo JH, Azevedo EP, Beckman D, Ribeiro FC, Santos LE, Razolli DS, Kincheski GC, Melo HM, Bellio M, Teixeira AL, Velloso LA, Foguel D, de Felice FG, Ferreira ST. Cross talk between brain innate immunity and serotonin signaling underlies depressive-like behavior induced by Alzheimer’s amyloid- oligomers in mice. J Neurosci. 2016;36(48):12106–12116. doi: 10.1523/JNEUROSCI.1269-16.2016.10.1523/JNEUROSCI.1269-16.2016PMC660197827903721Liechti ME, Dolder PC, Schmid Y. Alterations of consciousness and mystical-type experiences after acute LSD in humans. Psychopharmacology. 2017;234:1499–1510. doi: 10.1007/s00213-016-4453-0.10.1007/s00213-016-4453-0PMC542038627714429Lyketsos CG, Olin J. Depression in Alzheimer’s disease: overview and treatment. In Biological Psychiatry. 2002;52:243–252. doi: 10.1016/S0006-3223(02)01348-3.10.1016/S0006-3223(02)01348-312182930Marinova Z, Walitza S, Grünblatt E. Progress in neuro-psychopharmacology & biological psychiatry 5-HT 2A serotonin receptor agonist DOI alleviates cytotoxicity in neuroblastoma cells : role of the ERK pathway. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;44:64–72. doi: 10.1016/j.pnpbp.2013.01.017.10.1016/j.pnpbp.2013.01.01723380172Marinova Z, Walitza S, Grünblatt E. The hallucinogen 2,5-dimethoxy-4-Iodoamphetamine hydrochloride activates neurotrophin receptors in a neuronal cell line and promotes Neurites extension. Journal of Neural Transmission (Vienna, Austria : 1996) 2017;124:749–759. doi: 10.1007/s00702-017-1706-y.10.1007/s00702-017-1706-y28315978Marner L, Frokjaer VG, Kalbitzer J, Lehel S, Madsen K, Baaré WFC, Knudsen GM, Hasselbalch SG. Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer’s disease: a combined [11C]DASB and [18F]altanserin-PET study. Neurobiol Aging. 2012;33(3):479–487. doi: 10.1016/j.neurobiolaging.2010.03.023.10.1016/j.neurobiolaging.2010.03.02320510480Nagatomo T, Rashid M, Muntasir HA, Komiyama T. Functions of 5-HT2A receptor and its antagonists in the cardiovascular system. Pharmacol Ther. 2004;104(1):59–81. doi: 10.1016/j.pharmthera.2004.08.005.10.1016/j.pharmthera.2004.08.00515500909Nau F, Yu B, Martin D, Nichols CD. Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo. PLoS One. 2013;8(10):e75426. doi: 10.1371/journal.pone.0075426.10.1371/journal.pone.0075426PMC378879524098382Nau F, Miller J, Saravia J, Ahlert T, Yu B, Happel KI, Cormier SA, Nichols CD. Serotonin 5-HT 2 receptor activation prevents allergic asthma in a mouse model. Am J Physiol Lung Cell Mol Physiol. 2015;308(2):L191–L198. doi: 10.1152/ajplung.00138.2013.10.1152/ajplung.00138.2013PMC433893925416380Nichols CD (2016) 5-HT2A receptor agonist R-DOI suppresses atherosclerotic inflammation and restores glucose homeostasis in APOE -/- mouse model (UNPUBLISHED)Nitsch RM, Deng M, Growdon JH, Wurtman RJ. Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. Wurtman. 1996. Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. J Biol Chem. 1996;271(8):4188–4194. doi: 10.1074/jbc.271.8.4188.10.1074/jbc.271.8.41888626761O’Connor SM, Baweja HS, Goble DJ. Validating the BTrackS balance plate as a low cost alternative for the measurement of sway-induced center of pressure. J Biomech. 2017;49(16):4142–4145. doi: 10.1016/j.jbiomech.2016.10.020.10.1016/j.jbiomech.2016.10.02027789036Polito Vince, Stevenson Richard J. A systematic study of microdosing psychedelics. PLOS ONE. 2019;14(2):e0211023. doi: 10.1371/journal.pone.0211023.10.1371/journal.pone.0211023PMC636496130726251Preller Katrin H., Herdener Marcus, Pokorny Thomas, Planzer Amanda, Kraehenmann Rainer, Stämpfli Philipp, Liechti Matthias E., Seifritz Erich, Vollenweider Franz X. The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation. Current Biology. 2017;27(3):451–457. doi: 10.1016/j.cub.2016.12.030.10.1016/j.cub.2016.12.03028132813Preller KH, Razi A, Zeidman P, Stämpfli P, Friston KJ, Vollenweider FX. Effective connectivity changes in LSD-induced altered states of consciousness in humans. Proc Natl Acad Sci. 2019;116(7):2743–2748. doi: 10.1073/PNAS.1815129116.10.1073/PNAS.1815129116PMC637747130692255Ramirez J, McNeely AA, Scott CJM, Stuss DT, Black SE. Subcortical hyperintensity volumetrics in Alzheimer’s disease and normal elderly in the Sunnybrook Dementia Study: correlations with atrophy, executive function, mental processing speed, and verbal memory. Alzheimers Res Ther. 2014;6(4):49. doi: 10.1186/alzrt279.10.1186/alzrt279PMC425541625478020Repantis D, Laisney O, Heuser I. Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res. 2010;61(6):473–481. doi: 10.1016/j.phrs.2010.02.009.10.1016/j.phrs.2010.02.00920193764Romano AG, Quinn JL, Li L, Dave KD, Schindler EA, Aloyo VJ, Harvey JA. Intrahippocampal LSD accelerates learning and desensitizes the 5-HT(2A) receptor in the rabbit, Romano et Al. Psychopharmacology. 2010;212(3):441–448. doi: 10.1007/s00213-010-2004-7.10.1007/s00213-010-2004-720827462Roseman L, Nutt DJ, Carhart-Harris RL (2018) Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol. 10.3389/fphar.2017.00974PMC577650429387009Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12):1165–1180. doi: 10.1177/0269881116675512.10.1177/0269881116675512PMC536755127909164Russ Suzanne L., Carhart-Harris Robin L., Maruyama Geoffrey, Elliott Melody S. States and traits related to the quality and consequences of psychedelic experiences. Psychology of Consciousness: Theory, Research, and Practice. 2019;6(1):1–21.Schmid Y, Enzler F, Gasser P, Grouzmann E, Preller KH, Franz XFX, Vollenweider FX, Brenneisen R, et al. Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry. 2014;78(8):544–553. doi: 10.1016/j.biopsych.2014.11.015.10.1016/j.biopsych.2014.11.01525575620Schmid Yasmin, Enzler Florian, Gasser Peter, Grouzmann Eric, Preller Katrin H., Vollenweider Franz X., Brenneisen Rudolf, Müller Felix, Borgwardt Stefan, Liechti Matthias E. Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects. Biological Psychiatry. 2015;78(8):544–553. doi: 10.1016/j.biopsych.2014.11.015.10.1016/j.biopsych.2014.11.01525575620Sheline YI, Mintun MA, Barch DM, Wilkins C, Snyder AZ, Moerlein SM. Decreased hippocampal 5-HT2A receptor binding in older depressed patients using [18F]altanserin positron emission tomography. Neuropsychopharmacology. 2004;29(12):2235–2241. doi: 10.1038/sj.npp.1300555.10.1038/sj.npp.130055515367923Shram MJ, Schoedel KA, Bartlett C, Shazer RL, Anderson CM, Sellers EM. Evaluation of the abuse potential of lorcaserin, a serotonin 2C (5-HT2C) receptor agonist, in recreational polydrug users. Clin Pharmacol Ther. 2011;89(5):683–692. doi: 10.1038/clpt.2011.20.10.1038/clpt.2011.2021412231Šimić Goran, Babić Leko Mirjana, Wray Selina, Harrington Charles R., Delalle Ivana, Jovanov-Milošević Nataša, Bažadona Danira, Buée Luc, de Silva Rohan, Di Giovanni Giuseppe, Wischik Claude M., Hof Patrick R. Monoaminergic neuropathology in Alzheimer’s disease. Progress in Neurobiology. 2017;151:101–138. doi: 10.1016/j.pneurobio.2016.04.001.10.1016/j.pneurobio.2016.04.001PMC506160527084356Studerus E, Gamma A, Vollenweider FX. Psychometric evaluation of the altered states of consciousness rating scale (OAV) PLoS One. 2010;5(8):e12412. doi: 10.1371/journal.pone.0012412.10.1371/journal.pone.0012412PMC293085120824211Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, Lansu K, et al. Crystal structure of an LSD-bound human serotonin receptor. Cell. 2017;168(3):377–389.e12. doi: 10.1016/j.cell.2016.12.033.10.1016/j.cell.2016.12.033PMC528931128129538Wu C, Singh SK, Dias P, Kumar S, Mann DMA. Activated astrocytes display increased 5-HT2a receptor expression in pathological states. Exp Neurol. 1999;158(2):529–533. doi: 10.1006/exnr.1999.7105.10.1006/exnr.1999.710510415157Yanakieva S, Polychroni N, Family N, Williams LTJ, Luke DP, Terhune DB. The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial. Psychopharmacology. 2018;236:1159–1170. doi: 10.1007/s00213-018-5119-x.10.1007/s00213-018-5119-xPMC659119930478716Yu B, Becnel J, Zerfaoui M, Rasika R, Hamid Boulares A, Nichols CD. Serotonin 5-hydroxytryptamine 2A receptor activation suppresses tumor necrosis factor-α-induced inflammation with extraordinary potency. J Pharmacol Exp Ther. 2008;327(2):316–323. doi: 10.1124/jpet.108.143461.diated.10.1124/jpet.108.143461.diated18708586Zhang G, Stackman RW. The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol. 2015;6:225. doi: 10.3389/fphar.2015.00225.10.3389/fphar.2015.00225PMC4594018265005533297348220240329

1663-3563122020Front Synaptic NeurosciPsychedelics as a Treatment for Alzheimer's Disease Dementia.34343410.3389/fnsyn.2020.00034Currently, there are no disease-modifying treatments for Alzheimer's disease (AD) or any other dementia subtype. The renaissance in psychedelic research in recent years, in particular studies involving psilocybin and lysergic acid diethylamide (LSD), coupled with anecdotal reports of cognitive benefits from micro-dosing, suggests that they may have a therapeutic role in a range of psychiatric and neurological conditions due to their potential to stimulate neurogenesis, provoke neuroplastic changes and reduce neuroinflammation. This inevitably makes them interesting candidates for therapeutics in dementia. This mini-review will look at the basic science and current clinical evidence for the role of psychedelics in treating dementia, especially early AD, with a particular focus on micro-dosing of the classical psychedelics LSD and psilocybin.Copyright © 2020 Vann Jones and O’Kelly.Vann JonesSimon AndrewSACornwall Partnership NHS Foundation Trust, Liskeard, United Kingdom.O'KellyAllisonACornwall Partnership NHS Foundation Trust, Liskeard, United Kingdom.engJournal ArticleReview20200821

SwitzerlandFront Synaptic Neurosci1015489721663-3563Front Synaptic Neurosci. 2020 Oct 26;12:607194. doi: 10.3389/fnsyn.2020.607194.33192445Alzheimer’s diseasedementiamicrodosingplasticicitypsychedelic2020572020728202092560202092660202092661202011epublish32973482PMC747266410.3389/fnsyn.2020.00034Aday J. S., Bloesch E. K., Davoli C. C. (2020). Can psychedelic drugs attenuate age-related changes in cognition and affect? J. Cogn. Enhan. 4, 219–227. 10.1007/s41465-019-00151-610.1007/s41465-019-00151-6Agin-Liebes G. I., Malone T., Yalch M. M., Mennenga S. E., Ponté K. L., Guss J., et al. (2020). Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. J. Psychopharmacol. 34, 155–166. 10.1177/026988111989761510.1177/026988111989761531916890Alzheimer’s Society (2019). Demography. Available online at: http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=412. Accessed May 20, 2019.Anderson T., Petranker R., Christopher A., Rosenbaum D., Weissman C., Dinh-Williams L. A., et al. (2019). Psychedelic microdosing benefits and challenges: an empirical codebook. Harm Reduct. J. 16:43. 10.1186/s12954-019-0308-410.1186/s12954-019-0308-4PMC661788331288862Athilingam J. C., Ben-Shalom R., Keeshen C. M., Sohal V. S., Bender K. J. (2017). Serotonin enhances excitability and γ frequency temporal integration in mouse prefrontal fast-spiking interneurons. eLife 6:e31991. 10.7554/elife.31991.02210.7554/elife.31991.022PMC574634229206101Basar E., Emek-Savas D. D., Güntekin B., Yener G. G. (2016). Delay of cognitive γ responses in Alzheimer’s disease. Neuroimage Clin. 11, 106–115. 10.1016/j.nicl.2016.01.01510.1016/j.nicl.2016.01.015PMC475381326937378Basar E., Femir B., Emek-Savas D. D., Güntekin B., Yener G. G. (2017). Increased long distance event-related γ band connectivity in Alzheimer’s disease. Neuroimage Clin. 14, 580–590. 10.1016/j.nicl.2017.02.02110.1016/j.nicl.2017.02.021PMC536187128367402Bershad A. K., Preller K. H., Lee R., Keedy S., Wren-Jarvis J., Bremmer M. P., et al. (2020). Preliminary report on the effects of a low dose of LSD on resting state amygdalar functional connectivity. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 5, 461–467. 10.1016/j.bpsc.2019.12.00710.1016/j.bpsc.2019.12.007PMC715063032033922Bershad A. K., Schepers S. T., Bremmer M. P., Lee R., de Wit H. (2019). Acute subjective and behavioral effects of microdoses of LSD in healthy human volunteers. Biol. Psychiatry 86, 792–800. 10.1016/j.biopsych.2019.05.01910.1016/j.biopsych.2019.05.019PMC681452731331617Bravermanová A., Viktorinová M., Tylš F., Novák T., Androvičová R., Korčák J., et al. (2018). Psilocybin disrupts sensory and higher order cognitive processing but not pre-attentive cognitive processing—study on P300 and mismatch negativity in healthy volunteers. Psychopharmacology 235, 491–503. 10.1007/s00213-017-4807-210.1007/s00213-017-4807-229302713Bryson A., Carter O., Norman T., Kanaan R. (2017). 5-HT2A agonists: a novel therapy for functional neurological disorders? Int. J. Neuropsychopharmacol. 20, 422–427. 10.1093/ijnp/pyx01110.1093/ijnp/pyx011PMC541705328177082Buchborn T., Grecksch G., Dieterich D. C., Höllt V. (2016). “Tolerance to lysergic acid diethylamide: overview, correlates, and clinical implications,” in Neuropathology of Drug Addictions and Substance Misuse, ed. Preedy V. R. (San Diego, CA: Academic Press; ), 846–858.Buchborn T., Schröder H., Höllt V., Grecksch G. (2014). Repeated lysergic acid diethylamide in an animal model of depression: normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling. J. Psychopharmacol. 28, 545–552. 10.1177/026988111453166610.1177/026988111453166624785760Cameron L. P., Benson C. J., DeFelice B. C., Fiehn O., Olson D. E. (2019). Chronic, intermittent microdoses of the psychedelic N, N-Dimethyltryptamine (DMT) produce positive effects on mood and anxiety in rodents. ACS Chem. Neurosci. 10, 3261–3270. 10.1021/acschemneuro.8b0069210.1021/acschemneuro.8b00692PMC663977530829033Carhart-Harris R. L., Bolstridge M., Day C. M., Rucker J., Watts R., Erritzoe D. E., et al. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology 235, 399–408. 10.1007/s00213-017-4771-x10.1007/s00213-017-4771-xPMC581308629119217Carhart-Harris R. L., Erritzoe D., Williams T., Stone J. M., Reed L. J., Colasanti A., et al. (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc. Natl. Acad. Sci. U S A 109, 2138–2143. 10.1073/pnas.111959810910.1073/pnas.1119598109PMC327756622308440Carhart-Harris R. L., Goodwin G. M. (2017a). The therapeutic potential of psychedelic drugs: past present and future. Neuropsychopharmacology 42, 2105–2113. 10.1038/npp.2017.8410.1038/npp.2017.84PMC560381828443617Carhart-Harris R. L., Roseman L., Bolstridge M., Demetriou L., Pannekoek J. N., Wall M. B., et al. (2017b). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci. Rep. 7:13187. 10.1038/s41598-017-13282-710.1038/s41598-017-13282-7PMC564060129030624Carhart-Harris R. L., Nutt D. J. (2017). Serotonin and brain function: a tale of two receptors. J. Psychopharmacol. 31, 1091–1120. 10.1177/026988111772591510.1177/0269881117725915PMC560629728858536Carter O. L., Burr D. C., Pettigrew J. D., Wallis G. M., Hasler F., Vollenweider F. X. (2005). Using psilocybin to investigate the relationship between attention, working memory and the serotonin 1A and 2A receptors. J. Cogn. Neurosci. 17, 1497–1508. 10.1162/08989290577459719110.1162/08989290577459719116269092Catlow B. J., Song S., Paredes D. A., Kirstein C. L., Sanchez-Ramos J. (2013). Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Exp. Brain Res. 228, 481–491. 10.1007/s00221-013-3579-010.1007/s00221-013-3579-023727882Cini F. A., Ornelas I., Marcos E., Goto-Silva L., Nascimento J., Ruschi S., et al. (2019). d-Lysergic acid diethylamide has major potential as a cognitive enhancer. bioRxiv [Preprint]. 10.1101/86681410.1101/866814Clinicaltrials.gov (2020). Psilocybin for Depression in People With Mild Cognitive Impairment or Early Alzheimer’s Disease. Available online at: https://clinicaltrials.gov/ct2/show/NCT04123314?term=psilocybinandcond=Alzheimer+Disease&draw=2&rank=1. Accessed June 24, 2020.Deco G., Cruzat J., Cabral J., Knudsen G. M., Carhart-Harris R. L., Whybrow P. C., et al. (2018). Whole-brain multimodal neuroimaging model using serotonin receptor maps explains non-linear functional effects of LSD. Curr. Biol. 28, 3065.e6–3074.e6. 10.1016/j.cub.2018.07.08310.1016/j.cub.2018.07.08330270185Draper B. (2013). Understanding Alzheimer’s Disease and Other Dementias. London: Jessica Kingsley.Fadiman J., Korb S. (2019). Might microdosing psychedelics be safe and beneficial? An initial exploration. J. Psychoactive Drugs 51, 118–122. 10.1080/02791072.2019.159356110.1080/02791072.2019.159356130925850Family N., Maillet E. L., Williams L. T., Krediet E., Carhart-Harris R. L., Williams T. M., et al. (2020). Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers. Psychopharmacology 237, 841–853. 10.1007/s00213-019-05417-710.1007/s00213-019-05417-7PMC703606531853557Fanibunda S. E., Deb S., Maniyadath B., Tiwari P., Ghai U., Gupta S., et al. (2019). Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1α axis. Proc. Natl. Acad. Sci. U S A 116, 11028–11037. 10.1073/pnas.182133211610.1073/pnas.1821332116PMC656119731072928Flanagan T. W., Nichols C. D. (2018). Psychedelics as anti-inflammatory agents. Int. Rev. Psychiatry 30, 363–375. 10.1080/09540261.2018.148182710.1080/09540261.2018.148182730102081Garibotto V., Herholz K., Boccardi M., Picco A., Varrone A., Nordberg A., et al. (2017). Clinical validity of brain fluorodeoxyglucose positron emission tomography as a biomarker for Alzheimer’s disease in the context of a structured 5-phase development framework. Neurobiol. Aging 52, 183–195. 10.1016/j.neurobiolaging.2016.03.03310.1016/j.neurobiolaging.2016.03.03328317648Gasser P., Kirchner K., Passie T. (2015). LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. J. Psychopharmacol. 29, 57–68. 10.1177/026988111455524910.1177/026988111455524925389218Griffiths R. R., Johnson M. W., Carducci M. A., Umbricht A., Richards W. A., Richards B. D., et al. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J. Psychopharmacol. 30, 1181–1197. 10.1177/026988111667551310.1177/0269881116675513PMC536755727909165Halberstadt A. L. (2015). Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav. Brain Res. 277, 99–120. 10.1016/j.bbr.2014.07.01610.1016/j.bbr.2014.07.016PMC464289525036425Hutten N. R., Mason N. L., Dolder P. C., Kuypers K. P. (2019). Motives and side-effects of microdosing with psychedelics among users. Int. J. Neuropsychopharmacol. 22, 426–434. 10.1093/ijnp/pyz02910.1093/ijnp/pyz029PMC660046431152167Hutten N., Mason N., Dolder P., Theunissen E., Liechti M., Feilding A., et al. (2020). Cognitive and subjective effects of different low ‘micro’ doses of LSD in a placebo-controlled study. Eur. Neuropsychopharmacol. 31, S63–S64. 10.1016/j.euroneuro.2019.12.08610.1016/j.euroneuro.2019.12.08633082016Jensen O., Kaiser J., Lachaux J.-P. (2007). Human γ-frequency oscillations associated with attention and memory. Trends Neurosci. 30, 317–324. 10.1016/j.tins.2007.05.00110.1016/j.tins.2007.05.00117499860Johnstad P. G. (2018). Powerful substances in tiny amounts: an interview study of psychedelic microdosing. Nordic Stud. Alcohol Drugs 35, 39–51. 10.1177/145507251775333910.1177/1455072517753339PMC743411532934512Jones S. V., Kounatidis I. (2017). Nuclear factor-κ B and Alzheimer disease, unifying genetic and environmental risk factors from cell to humans. Front. Immunol. 8:1805. 10.3389/fimmu.2017.0180510.3389/fimmu.2017.01805PMC573223429312321Jones K. A., Srivastava D. P., Allen J. A., Strachan R. T., Roth B. L., Penzes P. (2009). Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc. Natl. Acad. Sci. U S A 106, 19575–19580. 10.1073/pnas.090588410610.1073/pnas.0905884106PMC278075019889983König T., Prichep L., Dierks T., Hubl D., Wahlund L. O., John E. R., et al. (2005). Decreased EEG synchronization in Alzheimer’s disease and mild cognitive impairment. Neurobiol. Aging 26, 165–171. 10.1016/j.neurobiolaging.2004.03.00810.1016/j.neurobiolaging.2004.03.00815582746Kapogiannis D., Mattson M. P. (2011). Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurol. 10, 187–198. 10.1016/S1474-4422(10)70277-510.1016/S1474-4422(10)70277-5PMC302609221147038Kraehenmann R., Preller K. H., Scheidegger M., Pokorny T., Bosch O. G., Seifritz E., et al. (2015). Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Biol. Psychiatry 78, 572–581. 10.1016/j.biopsych.2014.04.01010.1016/j.biopsych.2014.04.01024882567Kuypers K. P., Ng L., Erritzoe D., Knudsen G. M., Nichols C. D., Nichols D. E., et al. (2019). Microdosing psychedelics: more questions than answers? An overview and suggestions for future research. J. Psychopharmacol. 33, 1039–1057. 10.1177/026988111985720410.1177/0269881119857204PMC673282331303095Laccarino H. F., Singer A. C., Martorell A. J., Rudenko A., Gao F., Gillingham T. Z., et al. (2016). γ frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235. 10.1038/nature2058710.1038/nature20587PMC565638927929004Lea T., Amada N., Jungaberle H. (2020a). Psychedelic microdosing: a subreddit analysis. J. Psychoactive Drugs 52, 101–112. 10.1080/02791072.2019.168326010.1080/02791072.2019.168326031648596Lea T., Amada N., Jungaberle H., Schecke H., Klein M. (2020b). Microdosing psychedelics: motivations, subjective effects and harm reduction. Int. J. Drug Policy 75:102600. 10.1016/j.drugpo.2019.11.00810.1016/j.drugpo.2019.11.00831778967Ly C., Greb A. C., Cameron L. P., Wong J. M., Barragan E. V., Wilson P. C., et al. (2018). Psychedelics promote structural and functional neural plasticity. Cell Rep. 23, 3170–3182. 10.1016/j.celrep.2018.05.02210.1016/j.celrep.2018.05.022PMC608237629898390Mably A. J., Colgin L. L. (2018). γ oscillations in cognitive disorders. Curr. Opin. Neurobiol. 52, 182–187. 10.1016/j.conb.2018.07.00910.1016/j.conb.2018.07.009PMC613906730121451Martin D. A., Marona-Lewicka D., Nichols D. E., Nichols C. D. (2014). Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia. Neuropharmacology 83, 1–8. 10.1016/j.neuropharm.2014.03.01310.1016/j.neuropharm.2014.03.013PMC409864524704148Martorell A. J., Paulson A. L., Suk H. J., Abdurrob F., Drummond G. T., Guan W., et al. (2019). Multi-sensory γ stimulation ameliorates Alzheimer’s-associated pathology and improves cognition. Cell 177, 256–271. 10.1016/j.cell.2019.02.01410.1016/j.cell.2019.02.014PMC677426230879788Mertens L. J., Wall M. B., Roseman L., Demetriou L., Nutt D. J., Carhart-Harris R. L. (2020). Therapeutic mechanisms of psilocybin: changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. J. Psychopharmacol. 34, 167–180. 10.1177/026988111989552010.1177/026988111989552031941394Mu Y., Gage F. H. (2011). Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol. Neurodegener. 6:85. 10.1186/1750-1326-6-8510.1186/1750-1326-6-85PMC326181522192775Muthukumaraswamy S. D., Carhart-Harris R. L., Moran R. J., Brookes M. J., Williams T. M., Errtizoe D., et al. (2013). Broadband cortical desynchronization underlies the human psychedelic state. J. Neurosci. 33, 15171–15183. 10.1523/JNEUROSCI.2063-13.201310.1523/JNEUROSCI.2063-13.2013PMC661840924048847Nichols D. E. (2004). Hallucinogens. Pharmacol. Ther. 101, 131–181. 10.1016/j.pharmthera.2003.11.00210.1016/j.pharmthera.2003.11.00214761703Palop J. J., Mucke L. (2016). Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17, 777–792. 10.1038/nrn.2016.14110.1038/nrn.2016.141PMC816210627829687Pilly P. K., Grossberg S. (2012). How do spatial learning and memory occur in the brain? Coordinated learning of entorhinal grid cells and hippocampal place cells. J. Cogn. Neurosci. 24, 1031–1054. 10.1162/jocn_a_0020010.1162/jocn_a_0020022288394Polito V., Stevenson R. J. (2019). A systematic study of microdosing psychedelics. PLoS One 14:e0211023. 10.1371/journal.pone.021102310.1371/journal.pone.0211023PMC636496130726251Prochazkova L., Lippelt D. P., Colzato L. S., Kuchar M., Sjoerds Z., Hommel B. (2018). Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting. Psychopharmacology 235, 3401–3413. 10.1007/s00213-018-5049-710.1007/s00213-018-5049-7PMC626714030357434Puig M. V., Watakabe A., Ushimaru M., Yamamori T., Kawaguchi Y. (2010). Serotonin modulates fast-spiking interneuron and synchronous activity in the rat prefrontal cortex through 5-HT1A and 5-HT2A receptors. J. Neurosci. 30, 2211–2222. 10.1523/JNEUROSCI.3335-09.201010.1523/JNEUROSCI.3335-09.2010PMC663405220147548Rice L., Bisdas S. (2017). The diagnostic value of FDG and amyloid PET in Alzheimer’s disease—A systematic review. Eur. J. Radiol. 94, 16–24. 10.1016/j.ejrad.2017.07.01410.1016/j.ejrad.2017.07.01428941755Romano A. G., Quinn J. L., Li L., Dave K. D., Schindler E. A., Aloyo V. J., et al. (2010). Intrahippocampal LSD accelerates learning and desensitizes the 5-HT 2A receptor in the rabbit. Psychopharmacology 212, 441–448. 10.1007/s00213-010-2004-710.1007/s00213-010-2004-720827462Ross S., Bossis A., Guss J., Agin-Liebes G., Malone T., Cohen B., et al. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J. Psychopharmacol. 30, 1165–1180. 10.1177/026988111667551210.1177/0269881116675512PMC536755127909164Schmid Y., Liechti M. E. (2018). Long-lasting subjective effects of LSD in normal subjects. Psychopharmacology 235, 535–545. 10.1007/s00213-017-4733-310.1007/s00213-017-4733-3PMC581306228918441Schott B. H., Seidenbecher C. I., Richter S., Wüstenberg T., Debska-Vielhaber G., Schubert H., et al. (2011). Genetic variation of the serotonin 2a receptor affects hippocampal novelty processing in humans. PLoS One 6:e15984. 10.1371/journal.pone.001598410.1371/journal.pone.0015984PMC302273121267461Setti S. E., Hunsberger H. C., Reed M. N. (2017). Alterations in hippocampal activity and Alzheimer’s disease. Transl. Issues Psychol. Sci. 3, 348–356. 10.1037/tps000012410.1037/tps0000124PMC597283729862310Shahidi S., Hashemi-Firouzi N., Afshar S., Asl S. S., Komaki A. (2019). Protective effects of 5-ht1a receptor inhibition and 5-ht2a receptor stimulation against streptozotocin-induced apoptosis in the hippocampus. Malays. J. Med. Sci. 26, 40–51. 10.21315/mjms2019.26.2.510.21315/mjms2019.26.2.5PMC668721731447607Smigielski L., Scheidegger M., Kometer M., Vollenweider F. X. (2019). Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. NeuroImage 196, 207–215. 10.1016/j.neuroimage.2019.04.00910.1016/j.neuroimage.2019.04.00930965131Tagliazucchi E., Roseman L., Kaelen M., Orban C., Muthukumaraswamy S. D., Murphy K., et al. (2016). Increased global functional connectivity correlates with LSD-induced ego dissolution. Curr. Biol. 26, 1043–1050. 10.1016/j.cub.2016.02.01010.1016/j.cub.2016.02.01027085214UK Government Web Archive (2020). The National Archives. Life Tables. Available online at: http://www.ons.gov.uk/ons/rel/lifetables/historic-and-projected-data-from-the-period-and-cohort-life-tables/2012-based/stb-2012-based.html. Accessed January 2, 2020.Vaidya V. A., Marek G. J., Aghajanian G. K., Duman R. S. (1997). 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 17, 2785–2795. 10.1523/JNEUROSCI.17-08-02785.199710.1523/JNEUROSCI.17-08-02785.1997PMC65731099092600Van Deursen J. A., Vuurman E. F., Verhey F. R., van Kranen-Mastenbroek V. H., Riedel W. J. (2008). Increased EEG γ band activity in Alzheimer’s disease and mild cognitive impairment. J. Neural Transm. 115, 1301–1311. 10.1007/s00702-008-0083-y10.1007/s00702-008-0083-yPMC252584918607528Verret L., Mann E. O., Hang G. B., Barth A. M., Cobos I., Ho K., et al. (2012). Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149, 708–721. 10.1016/j.cell.2012.02.04610.1016/j.cell.2012.02.046PMC337590622541439Vollenweider F. X., Leenders K. L., Scharfetter C., Maguire P., Stadelmann O., Angst J. (1997). Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 16, 357–372. 10.1016/s0893-133x(96)00246-110.1016/s0893-133x(96)00246-19109107Wang J., Fang Y., Wang X., Yang H., Yu X., Wang H. (2017). Enhanced γ activity and cross-frequency interaction of resting-state electroencephalographic oscillations in patients with Alzheimer’s disease. Front. Aging Neurosci. 9:243. 10.3389/fnagi.2017.0024310.3389/fnagi.2017.00243PMC552699728798683Weber E. T., Andrade R. (2010). Htr2a gene and 5-HT^2A receptor expression in the cerebral cortex studied using genetically modified mice. Front. Neurosci. 4:36. 10.3389/fnins.2010.0003610.3389/fnins.2010.00036PMC292870720802802Wood J., Kim Y., Moghaddam B. (2012). Disruption of prefrontal cortex large scale neuronal activity by different classes of psychotomimetic drugs. J. Neurosci. 32, 3022–3031. 10.1523/JNEUROSCI.6377-11.201210.1523/JNEUROSCI.6377-11.2012PMC353199722378875Yoshida H., Kanamaru C., Ohtani A., Li F., Senzaki K., Shiga T. (2011). Subtype specific roles of serotonin receptors in the spine formation of cortical neurons in vitro. Neurosci. Res. 71, 311–314. 10.1016/j.neures.2011.07.182410.1016/j.neures.2011.07.182421802453Zhang G., Ásgeirsdóttir H. N., Cohen S. J., Munchow A. H., Barrera M. P., Stackman R. W., Jr. (2013). Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Neuropharmacology 64, 403–413. 10.1016/j.neuropharm.2012.06.00710.1016/j.neuropharm.2012.06.007PMC347761722722027Zhang G., Stackman R. W., Jr. (2015). The role of serotonin 5-HT2A receptors in memory and cognition. Front. Pharmacol. 6:225. 10.3389/fphar.2015.0022510.3389/fphar.2015.00225PMC459401826500553383074242024041520240701

1872-9649962024AprAgeing Res RevPsychedelics for alzheimer's disease-related dementia: Unveiling therapeutic possibilities and pathways.10221110221110.1016/j.arr.2024.102211S1568-1637(24)00029-1Psychedelics have traditionally been used for spiritual and recreational purposes, but recent developments in psychotherapy have highlighted their potential as therapeutic agents. These compounds, which act as potent 5-hydroxytryptamine (5HT) agonists, have been recognized for their ability to enhance neural plasticity through the activation of the serotoninergic and glutamatergic systems. However, the implications of these findings for the treatment of neurodegenerative disorders, particularly dementia, have not been fully explored. In recent years, studies have revealed the modulatory and beneficial effects of psychedelics in the context of dementia, specifically Alzheimer's disease (AD)-related dementia, which lacks a definitive cure. Psychedelics such as N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and Psilocybin have shown potential in mitigating the effects of this debilitating disease. These compounds not only target neurotransmitter imbalances but also act at the molecular level to modulate signalling pathways in AD, including the brain-derived neurotrophic factor signalling pathway and the subsequent activation of mammalian target of rapamycin and other autophagy regulators. Therefore, the controlled and dose-dependent administration of psychedelics represents a novel therapeutic intervention worth exploring and considering for the development of drugs for the treatment of AD-related dementia. In this article, we critically examined the literature that sheds light on the therapeutic possibilities and pathways of psychedelics for AD-related dementia. While this emerging field of research holds great promise, further studies are necessary to elucidate the long-term safety, efficacy, and optimal treatment protocols. Ultimately, the integration of psychedelics into the current treatment paradigm may provide a transformative approach for addressing the unmet needs of individuals living with AD-related dementia and their caregivers.Copyright © 2024 Elsevier B.V. All rights reserved.SinhaJitendra KumarJKGloNeuro, Sector 107, Vishwakarma Road, Noida 201301, India.TrisalAnchalADepartment of Biosciences, Jamia Millia Islamia, New Delhi 110025, India.GhoshShampaSGloNeuro, Sector 107, Vishwakarma Road, Noida 201301, India.GuptaSaurabhSDepartment of Biotechnology, GLA University, Mathura, Uttar Pradesh, India.SinghKrishna KumarKKSymbiosis Centre for Information Technology (SCIT), Rajiv Gandhi InfoTech Park, Hinjawadi, Pune, Maharashtra 411057, India.HanSung SooSSSchool of Chemical Engineering, Yeungnam University, Gyeonsang 38541, the Republic of Korea; Research Institute of Cell Culture, Yeungnam University, 280 Daehak-Ro, Gyeongsan 38541, the Republic of Korea.MahapatraMadhumitaMDelhi Technical Campus, Knowledge Park III, Greater Noida 201306, India.AbomughaidMosleh MohammadMMDepartment of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia.AbomughayedhAli MAMPharmacy Department, Aseer Central Hospital, Ministry of Health, Saudi Arabia.AlmutaryAbdulmajeed GAGDepartment of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi P.O. Box 59911, United Arab Emirates.IqbalDanishDDepartment of Health Information Management, College of Applied Medical Sciences, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia.BhaskarRakeshRSchool of Chemical Engineering, Yeungnam University, Gyeonsang 38541, the Republic of Korea; Research Institute of Cell Culture, Yeungnam University, 280 Daehak-Ro, Gyeongsan 38541, the Republic of Korea. Electronic address: bhaskar88@yu.ac.kr.MishraPrabhu ChandraPCDepartment of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India.JhaSaurabh KumarSKDepartment of Zoology, Kalindi College, University of Delhi, 110008, India. Electronic address: jhasaurabh017@gmail.com.JhaNiraj KumarNKCentre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Centre of Research Impact and Outcome, Chitkara University, Rajpura 140401, Punjab, India; School of Bioengineering & Biosciences, Lovely Professional University, Phagwara 144411, India; Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India. Electronic address: nirajkumarjha2011@gmail.com.SinghAbhishek KumarAKManipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India. Electronic address: abhishek.singh@manipal.edu.engJournal ArticleReviewResearch Support, Non-U.S. Gov't20240201

EnglandAgeing Res Rev1011289631568-16370Hallucinogens8NA5SWF92OLysergic Acid Diethylamide2RV7212BP0PsilocybinWUB601BHAAN,N-DimethyltryptamineIMHumansHallucinogenspharmacologytherapeutic useAlzheimer Diseasedrug therapyLysergic Acid Diethylamidepharmacologytherapeutic usePsilocybinpharmacologytherapeutic useN,N-Dimethyltryptamine5-Hydroxytryptamine receptorsAlzheimer’s diseaseBrain-derived neurotrophic factorDementiaPsychedelicsTropomyosin receptor kinase BDeclaration of Competing Interest There is no conflict of interest to be declared.202310192024125202412620244156432024230422024221933ppublish3830742410.1016/j.arr.2024.102211S1568-1637(24)00029-1375698882023081420230815

1422-006724152023Aug07Int J Mol SciA Brief Review on the Potential of Psychedelics for Treating Alzheimer's Disease and Related Depression.1251310.3390/ijms241512513Alzheimer's disease (AD), the most common form of senile dementia, is poised to place an even greater societal and healthcare burden as the population ages. With few treatment options for the symptomatic relief of the disease and its unknown etiopathology, more research into AD is urgently needed. Psychedelic drugs target AD-related psychological pathology and symptoms such as depression. Using microdosing, psychedelic drugs may prove to help combat this devastating disease by eliciting psychiatric benefits via acting through various mechanisms of action such as serotonin and dopamine pathways. Herein, we review the studied benefits of a few psychedelic compounds that may show promise in treating AD and attenuating its related depressive symptoms. We used the listed keywords to search through PubMed for relevant preclinical, clinical research, and review articles. The putative mechanism of action (MOA) for psychedelics is that they act mainly as serotonin receptor agonists and induce potential beneficial effects for treating AD and related depression.PilozziAlexanderANeurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.FosterSimmieS0000-0002-1703-4181Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.Depression Clinical & Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.MischoulonDavidD0000-0001-7233-5860Depression Clinical & Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.FavaMaurizioMDepression Clinical & Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.HuangXudongX0000-0002-4811-1901Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.engK23 GM129630GMNIGMS NIH HHSUnited StatesR01 AG056614AGNIA NIH HHSUnited StatesR01AG056614NHNIH HHSUnited StatesJournal ArticleReview20230807

SwitzerlandInt J Mol Sci1010927911422-00670Hallucinogens333DO1RDJYSerotonin8NA5SWF92OLysergic Acid DiethylamideIMHumansHallucinogenspharmacologytherapeutic useAlzheimer Diseasedrug therapyDepressiondrug therapySerotoninLysergic Acid DiethylamidepharmacologyAlzheimer’s diseaseDMTLSDdementiadepressionketaminemescalinepsilocybinpsychedelicsMischoulon has received research support from Nordic Naturals and Heckel Medizintechnik GmbH. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, Peerpoint Medical Education Institute, LLC, and Harvard blog. He also works with the MGH Clinical Trials Network and Institute (CTNI), which has received research funding from multiple pharmaceutical companies and NIMH. The remaining authors declare no conflicts of interest. The funder had no role in the writing of the manuscript.2023162023832023852023814642202381210502023812112202387epublish37569888PMC1041962710.3390/ijms241512513ijms241512513Haaland K.Y., Price L., Larue A. What does the WMS-III tell us about memory changes with normal aging? J. Int. Neuropsychol. Soc. 2003;9:89–96. doi: 10.1017/S1355617703910101.10.1017/S135561770391010112570362Darowski E.S., Helder E., Zacks R.T., Hasher L., Hambrick D.Z. Age-related differences in cognition: The role of distraction control. Neuropsychology. 2008;22:638–644. doi: 10.1037/0894-4105.22.5.638.10.1037/0894-4105.22.5.63818763883Salthouse T.A., Mitchell D.R., Skovronek E., Babcock R.L. Effects of adult age and working memory on reasoning and spatial abilities. J. Exp. Psychol. Learn. Mem. Cogn. 1989;15:507–516. doi: 10.1037/0278-7393.15.3.507.10.1037/0278-7393.15.3.5072524548Larrieu S., Letenneur L., Orgogozo J.M., Fabrigoule C., Amieva H., Le Carret N., Barberger-Gateau P., Dartigues J.F. Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology. 2002;59:1594–1599. doi: 10.1212/01.WNL.0000034176.07159.F8.10.1212/01.WNL.0000034176.07159.F812451203Aerts L., Heffernan M., Kochan N.A., Crawford J.D., Draper B., Trollor J.N., Sachdev P.S., Brodaty H. Effects of MCI subtype and reversion on progression to dementia in a community sample. Neurology. 2017;88:2225–2232. doi: 10.1212/WNL.0000000000004015.10.1212/WNL.0000000000004015284906512022 Alzheimer’s disease facts and figures. Alzheimers Dement. 2022;18:700–789. doi: 10.1002/alz.12638.10.1002/alz.1263835289055Schneider L. A resurrection of aducanumab for Alzheimer’s disease. Lancet Neurol. 2020;19:111–112. doi: 10.1016/S1474-4422(19)30480-6.10.1016/S1474-4422(19)30480-631978357Casey D.A., Antimisiaris D., O’Brien J. Drugs for Alzheimer’s disease: Are they effective? Pharm. Ther. 2010;35:208.PMC287371620498822Carhart-Harris R.L., Goodwin G.M. The therapeutic potential of psychedelic drugs: Past, present, and future. Neuropsychopharmacology. 2017;42:2105–2113. doi: 10.1038/npp.2017.84.10.1038/npp.2017.84PMC560381828443617Kuypers K.P., Ng L., Erritzoe D., Knudsen G.M., Nichols C.D., Nichols D.E., Pani L., Soula A., Nutt D. Microdosing psychedelics: More questions than answers? An overview and suggestions for future research. J. Psychopharmacol. 2019;33:1039–1057. doi: 10.1177/0269881119857204.10.1177/0269881119857204PMC673282331303095Lyketsos C.G., Olin J. Depression in Alzheimer’s disease: Overview and treatment. Biol. Psychiatry. 2002;52:243–252. doi: 10.1016/S0006-3223(02)01348-3.10.1016/S0006-3223(02)01348-312182930Evans D.L., Charney D.S., Lewis L., Golden R.N., Gorman J.M., Krishnan K.R.R., Nemeroff C.B., Bremner J.D., Carney R.M., Coyne J.C. Mood disorders in the medically ill: Scientific review and recommendations. Biol. Psychiatry. 2005;58:175–189.16084838Enache D., Winblad B., Aarsland D. Depression in dementia: Epidemiology, mechanisms, and treatment. Curr. Opin. Psychiatry. 2011;24:461–472. doi: 10.1097/YCO.0b013e32834bb9d4.10.1097/YCO.0b013e32834bb9d421926624Ballard C., Bannister C., Solis M., Oyebode F., Wilcock G. The prevalence, associations and symptoms of depression amongst dementia sufferers. J. Affect. Disord. 1996;36:135–144. doi: 10.1016/0165-0327(95)00072-0.10.1016/0165-0327(95)00072-08821316Schmutte T., Olfson M., Maust D.T., Xie M., Marcus S.C. Suicide risk in first year after dementia diagnosis in older adults. Alzheimer’s Dement. 2021;18:262–271. doi: 10.1002/alz.12390.10.1002/alz.12390PMC861330734036738Baptista M.A.T., Santos R.L., Kimura N., Lacerda I.B., Dourado M.C.N. Disease awareness may increase risk of suicide in young onset dementia: A case report. Dement. Neuropsychol. 2017;11:308–311.PMC567467729213530Conejero I., Navucet S., Keller J., Olié E., Courtet P., Gabelle A. A complex relationship between suicide, dementia, and amyloid: A narrative review. Front. Neurosci. 2018;12:371.PMC599244129910709Caselli R.J., Langbaum J.B., Marchant G.E., Lindor R.A., Hunt K.S., Henslin B.R., Dueck A.C., Robert J.S. P2-356: Predictive Testing for alzheimer’s disease: Suicidal ideation among healthy participants. Alzheimer’s Dement. 2014;10:P610.PMC454338825984909Starkstein S.E., Ingram L., Garau M., Mizrahi R. On the overlap between apathy and depression in dementia. J. Neurol. Neurosurg. Psychiatry. 2005;76:1070–1074. doi: 10.1136/jnnp.2004.052795.10.1136/jnnp.2004.052795PMC173976616024880Starkstein S.E., Mizrahi R., Garau L. Specificity of symptoms of depression in Alzheimer disease: A longitudinal analysis. Am. J. Geriatr. Psychiatry. 2005;13:802–807. doi: 10.1097/00019442-200509000-00009.10.1097/00019442-200509000-0000916166410Lyketsos C.G., Steele C., Baker L., Galik E., Kopunek S., Steinberg M., Warren A. Major and minor depression in Alzheimer’s disease: Prevalence and impact. J. Neuropsychiatry Clin. Neurosci. 1997;9:556–561.9447496El Haj M., Altintas E., Chapelet G., Kapogiannis D., Gallouj K. High depression and anxiety in people with Alzheimer’s disease living in retirement homes during the covid-19 crisis. Psychiatry Res. 2020;291:113294. doi: 10.1016/j.psychres.2020.113294.10.1016/j.psychres.2020.113294PMC735750732763552Caraci F., Copani A., Nicoletti F., Drago F. Depression and Alzheimer’s disease: Neurobiological links and common pharmacological targets. Eur. J. Pharmacol. 2010;626:64–71.19837057Rovner B.W., Broadhead J., Spencer M., Carson K., Folstein M.F. Depression and Alzheimer’s disease. Am. J. Psychiatry. 1989;146:350–353.2919692Orgeta V., Tabet N., Nilforooshan R., Howard R. Efficacy of antidepressants for depression in Alzheimer’s disease: Systematic review and meta-analysis. J. Alzheimer’s Dis. 2017;58:725–733. doi: 10.3233/JAD-161247.10.3233/JAD-161247PMC546771828505970Vollenweider F.X., Vollenweider-Scherpenhuyzen M.F., Bäbler A., Vogel H., Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998;9:3897–3902.9875725Chen C.P., Eastwood S.L., Hope T., McDonald B., Francis P.T., Esiri M.M. Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer’s disease prospectively assessed for behavioural changes. Neuropathol. Appl. Neurobiol. 2000;26:347–355. doi: 10.1046/j.1365-2990.2000.00254.x.10.1046/j.1365-2990.2000.00254.x10931368Hendricksen M., Thomas A.J., Ferrier I.N., Ince P., O’Brien J.T. Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer’s disease with and without depression. Am. J. Psychiatry. 2004;161:1096–1102. doi: 10.1176/appi.ajp.161.6.1096.10.1176/appi.ajp.161.6.109615169699Metaxas A., Anzalone M., Vaitheeswaran R., Petersen S., Landau A.M., Finsen B. Neuroinflammation and amyloid-beta 40 are associated with reduced serotonin transporter (SERT) activity in a transgenic model of familial Alzheimer’s disease. Alzheimer’s Res. Ther. 2019;11:38. doi: 10.1186/s13195-019-0491-2.10.1186/s13195-019-0491-2PMC649559831043179Cirrito J.R., Disabato B.M., Restivo J.L., Verges D.K., Goebel W.D., Sathyan A., Hayreh D., D’Angelo G., Benzinger T., Yoon H. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc. Natl. Acad. Sci. USA. 2011;108:14968–14973. doi: 10.1073/pnas.1107411108.10.1073/pnas.1107411108PMC316915521873225Claeysen S., Bockaert J., Giannoni P. Serotonin: A new hope in Alzheimer’s disease? ACS Chem. Neurosci. 2015;6:940–943.26011650Kepe V., Barrio J.R., Huang S.-C., Ercoli L., Siddarth P., Shoghi-Jadid K., Cole G.M., Satyamurthy N., Cummings J.L., Small G.W. Serotonin 1A receptors in the living brain of Alzheimer’s disease patients. Proc. Natl. Acad. Sci. USA. 2006;103:702–707. doi: 10.1073/pnas.0510237103.10.1073/pnas.0510237103PMC133468116407119Lai M., Tsang S., Alder J., Keene J., Hope T., Esiri M., Francis P., Chen C. Loss of serotonin 5-HT 2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease. Psychopharmacology. 2005;179:673–677. doi: 10.1007/s00213-004-2077-2.10.1007/s00213-004-2077-215551121Rosier A., Dupont P., Peuskens J., Bormans G., Vandenberghe R., Maes M., de Groot T., Schiepers C., Verbruggen A., Mortelmans L. Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F] altanserin and positron emission tomographic imaging. Psychiatry Res. Neuroimaging. 1996;68:11–22. doi: 10.1016/S0925-4927(96)02806-5.10.1016/S0925-4927(96)02806-59027929Fox N., Warrington E., Freeborough P., Hartikainen P., Kennedy A., Stevens J., Rossor M.N. Presymptomatic hippocampal atrophy in Alzheimer’s disease: A longitudinal MRI study. Brain. 1996;119:2001–2007. doi: 10.1093/brain/119.6.2001.10.1093/brain/119.6.20019010004Bremner J.D., Narayan M., Anderson E.R., Staib L.H., Miller H.L., Charney D.S. Hippocampal volume reduction in major depression. Am. J. Psychiatry. 2000;157:115–118.10618023Videbech P., Ravnkilde B. Hippocampal volume and depression: A meta-analysis of MRI studies. Am. J. Psychiatry. 2004;161:1957–1966.15514393Artin H., Zisook S., Ramanathan D. How do serotonergic psychedelics treat depression: The potential role of neuroplasticity. World J. Psychiatry. 2021;11:201–214. doi: 10.5498/wjp.v11.i6.201.10.5498/wjp.v11.i6.201PMC820953834168967Vythilingam M., Vermetten E., Anderson G.M., Luckenbaugh D., Anderson E.R., Snow J., Staib L.H., Charney D.S., Bremner J.D. Hippocampal volume, memory, and cortisol status in major depressive disorder: Effects of treatment. Biol. Psychiatry. 2004;56:101–112. doi: 10.1016/j.biopsych.2004.04.002.10.1016/j.biopsych.2004.04.00215231442Colle R., Cury C., Chupin M., Deflesselle E., Hardy P., Nasser G., Falissard B., Ducreux D., Colliot O., Corruble E. Hippocampal volume predicts antidepressant efficacy in depressed patients without incomplete hippocampal inversion. NeuroImage Clin. 2016;12:949–955. doi: 10.1016/j.nicl.2016.04.009.10.1016/j.nicl.2016.04.009PMC515355727995060Béchade C., d’Andrea I., Etienne F., Verdonk F., Moutkine I., Banas S.M., Kolodziejczak M., Diaz S.L., Parkhurst C.N., Gan W.B. The serotonin 2B receptor is required in neonatal microglia to limit neuroinflammation and sickness behavior in adulthood. Glia. 2020;69:638–654. doi: 10.1002/glia.23918.10.1002/glia.2391833095507Whitford M. Alzheimer’s disease and serotonin: A review. Neuropsychobiology. 1986;15:133–142. doi: 10.1159/000118256.10.1159/0001182563785643Holmes C., Arranz M., Collier D., Powell J., Lovestone S. Depression in Alzheimer’s disease: The effect of serotonin receptor gene variation. Am. J. Med. Genet. Part. B Neuropsychiatr. Genet. 2003;119:40–43.12707936Krebs T.S., Johansen P.-Ø. Psychedelics and mental health: A population study. PLoS ONE. 2013;8:e63972.PMC374724723976938Piert M., Koeppe R.A., Giordani B., Berent S., Kuhl D.E. Diminished glucose transport and phosphorylation in Alzheimer’s disease determined by dynamic FDG-PET. J. Nucl. Med. 1996;37:201–208.8667045Jagust W.J., Seab J.P., Huesman R.H., Valk P.E., Mathis C.A., Reed B.R., Coxson P.G., Budinger T.F. Diminished glucose transport in Alzheimer’s disease: Dynamic PET studies. J. Cereb. Blood Flow. Metab. 1991;11:323–330. doi: 10.1038/jcbfm.1991.65.10.1038/jcbfm.1991.651997504Wirth M., Madison C.M., Rabinovici G.D., Oh H., Landau S.M., Jagust W.J. Alzheimer’s Disease Neurodegenerative Biomarkers Are Associated with Decreased Cognitive Function but Not-Amyloid in Cognitively Normal Older Individuals. J. Neurosci. 2013;33:5553–5563. doi: 10.1523/JNEUROSCI.4409-12.2013.10.1523/JNEUROSCI.4409-12.2013PMC368777723536070Dwyer D.S., Ardizzone T.D., Bradley R.J. Psychoactive drugs affect glucose transport and the regulation of glucose metabolism. Int. Rev. Neurobiol. 2002;51:503–530.12420369Hajduch E., Rencurel F., Balendran A., Batty I.H., Downes C.P., Hundal H.S. Serotonin (5-hydroxytryptamine), a novel regulator of glucose transport in rat skeletal muscle. J. Biol. Chem. 1999;274:13563–13568. doi: 10.1074/jbc.274.19.13563.10.1074/jbc.274.19.1356310224126Lotharius J., Brundin P. Pathogenesis of Parkinson’s disease: Dopamine, vesicles and α-synuclein. Nat. Rev. Neurosci. 2002;3:932–942. doi: 10.1038/nrn983.10.1038/nrn98312461550Pan X., Kaminga A.C., Wen S.W., Wu X., Acheampong K., Liu A. Dopamine and dopamine receptors in Alzheimer’s disease: A systematic review and network meta-analysis. Front. Aging Neurosci. 2019;11:175.PMC663773431354471Cross A.J., Crow T.J., Perry E.K., Perry R.H., Blessed G., Tomlinson B.E. Reduced dopamine-beta-hydroxylase activity in Alzheimer’s disease. Br. Med. J. 1981;282:93–94. doi: 10.1136/bmj.282.6258.93.10.1136/bmj.282.6258.93PMC15038926779929Martorana A., Koch G. Is dopamine involved in Alzheimer’s disease? Front. Aging Neurosci. 2014;6:252.PMC417476525309431Chen J.-Y., Stern Y., Sano M., Mayeux R. Cumulative risks of developing extrapyramidal signs, psychosis, or myoclonus in the course of Alzheimer’s disease. Arch. Neurol. 1991;48:1141–1143. doi: 10.1001/archneur.1991.00530230049020.10.1001/archneur.1991.005302300490201953398Stern Y., Albert M., Brandt J., Jacobs D., Tang M., Marder K., Bell K., Sano M., Devanand D.P., Bylsma F. Utility of extrapyramidal signs and psychosis as predictors of cognitive and functional decline, nursing home admission, and death in Alzheimer’s disease: Prospective analyses from the Predictors Study. Neurology. 1994;44:2300.7991116Chui H.C., Lyness S.A., Sobel E., Schneider L.S. Extrapyramidal signs and psychiatric symptoms predict faster cognitive decline in Alzheimer’s disease. Arch. Neurol. 1994;51:676–681. doi: 10.1001/archneur.1994.00540190056015.10.1001/archneur.1994.005401900560158018040Mitchell R.A., Herrmann N., Lanctôt K.L. The role of dopamine in symptoms and treatment of apathy in Alzheimer’s disease. CNS Neurosci. Ther. 2011;17:411–427. doi: 10.1111/j.1755-5949.2010.00161.x.10.1111/j.1755-5949.2010.00161.xPMC649383320560994Udo N., Hashimoto N., Toyonaga T., Isoyama T., Oyanagi Y., Narita H., Shiga T., Nakagawa S., Kusumi I. Apathy in Alzheimer’s disease correlates with the dopamine transporter level in the caudate nuclei. Dement. Geriatr. Cogn. Disord. Extra. 2020;10:86–93. doi: 10.1159/000509278.10.1159/000509278PMC754894033082772Nieoullon A. Dopamine and the regulation of cognition and attention. Progress. Neurobiol. 2002;67:53–83. doi: 10.1016/S0301-0082(02)00011-4.10.1016/S0301-0082(02)00011-412126656Goldman-Rakic P.S. The cortical dopamine system: Role in memory and cognition. Adv. Pharmacol. 1997;42:707–711.9327997Wise R.A. Dopamine, learning and motivation. Nat. Rev. Neurosci. 2004;5:483–494. doi: 10.1038/nrn1406.10.1038/nrn140615152198Eisenegger C., Naef M., Linssen A., Clark L., Gandamaneni P.K., Müller U., Robbins T.W. Role of dopamine D2 receptors in human reinforcement learning. Neuropsychopharmacology. 2014;39:2366–2375. doi: 10.1038/npp.2014.84.10.1038/npp.2014.84PMC413874624713613Shiner T., Seymour B., Wunderlich K., Hill C., Bhatia K.P., Dayan P., Dolan R.J. Dopamine and performance in a reinforcement learning task: Evidence from Parkinson’s disease. Brain. 2012;135:1871–1883. doi: 10.1093/brain/aws083.10.1093/brain/aws083PMC335975122508958Xia Q.-P., Cheng Z.-Y., He L. The modulatory role of dopamine receptors in brain neuroinflammation. Int. Immunopharmacol. 2019;76:105908. doi: 10.1016/j.intimp.2019.105908.10.1016/j.intimp.2019.10590831622861Shao L.-X., Liao C., Gregg I., Davoudian P.A., Savalia N.K., Delagarza K., Kwan A.C. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron. 2021;109:2535–2544.e4. doi: 10.1016/j.neuron.2021.06.008.10.1016/j.neuron.2021.06.008PMC837677234228959Gao H.-M., Kotzbauer P.T., Uryu K., Leight S., Trojanowski J.Q., Lee V.M.-Y. Neuroinflammation and oxidation/nitration of α-synuclein linked to dopaminergic neurodegeneration. J. Neurosci. 2008;28:7687–7698. doi: 10.1523/JNEUROSCI.0143-07.2008.10.1523/JNEUROSCI.0143-07.2008PMC270209318650345Zhang L., Zhou F.-M., Dani J.A. Cholinergic drugs for Alzheimer’s disease enhance in vitro dopamine release. Mol. Pharmacol. 2004;66:538–544. doi: 10.1124/mol.104.000299.10.1124/mol.104.00029915322245Li J., Zhu M., Manning-Bog A.B., Di Monte D.A., Fink A.L. Dopamine and L-dopa disaggregate amyloid fibrils: Implications for Parkinson’s and Alzheimer’s disease. FASEB J. 2004;18:962–964. doi: 10.1096/fj.03-0770fje.10.1096/fj.03-0770fje15059976Lawn T., Dipasquale O., Vamvakas A., Tsougos I., Mehta M.A., Howard M.A. Differential contributions of serotonergic and dopaminergic functional connectivity to the phenomenology of LSD. Psychopharmacology. 2022;239:1797–1808. doi: 10.1007/s00213-022-06117-5.10.1007/s00213-022-06117-5PMC916684635322297Passie T., Seifert J., Schneider U., Emrich H.M. The pharmacology of psilocybin. Addict. Biol. 2002;7:357–364. doi: 10.1080/1355621021000005937.10.1080/135562102100000593714578010Baloyannis S. Dendritic pathology in Alzheimer’s disease. J. Neurol. Sci. 2009;283:153–157.19296966Barrett F.S., Carbonaro T.M., Hurwitz E., Johnson M.W., Griffiths R.R. Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: Effects on cognition. Psychopharmacology. 2018;235:2915–2927.PMC616215730062577Carter O.L., Burr D.C., Pettigrew J.D., Wallis G.M., Hasler F., Vollenweider F.X. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors. J. Cogn. Neurosci. 2005;17:1497–1508. doi: 10.1162/089892905774597191.10.1162/08989290577459719116269092Goldberg S.B., Pace B.T., Nicholas C.R., Raison C.L., Hutson P.R. The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis. Psychiatry Res. 2020;284:112749. doi: 10.1016/j.psychres.2020.112749.10.1016/j.psychres.2020.11274931931272Carhart-Harris R.L., Bolstridge M., Rucker J., Day C.M., Erritzoe D., Kaelen M., Bloomfield M., Rickard J.A., Forbes B., Feilding A. Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. Lancet Psychiatry. 2016;3:619–627. doi: 10.1016/S2215-0366(16)30065-7.10.1016/S2215-0366(16)30065-727210031Carhart-Harris R., Giribaldi B., Watts R., Baker-Jones M., Murphy-Beiner A., Murphy R., Martell J., Blemings A., Erritzoe D., Nutt D.J. Trial of psilocybin versus escitalopram for depression. N. Engl. J. Med. 2021;384:1402–1411. doi: 10.1056/NEJMoa2032994.10.1056/NEJMoa203299433852780Roseman L., Nutt D.J., Carhart-Harris R.L. Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front. Pharmacol. 2018;8:974.PMC577650429387009Griffiths R.R., Johnson M.W., Carducci M.A., Umbricht A., Richards W.A., Richards B.D., Cosimano M.P., Klinedinst M.A. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J. Psychopharmacol. 2016;30:1181–1197. doi: 10.1177/0269881116675513.10.1177/0269881116675513PMC536755727909165Ross S., Bossis A., Guss J., Agin-Liebes G., Malone T., Cohen B., Mennenga S.E., Belser A., Kalliontzi K., Babb J. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial. J. Psychopharmacol. 2016;30:1165–1180. doi: 10.1177/0269881116675512.10.1177/0269881116675512PMC536755127909164Family N., Maillet E.L., Williams L.T.J., Krediet E., Carhart-Harris R.L., Williams T.M., Nichols C.D., Goble D.J., Raz S. Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers. Psychopharmacology. 2020;237:841–853. doi: 10.1007/s00213-019-05417-7.10.1007/s00213-019-05417-7PMC703606531853557Bershad A.K., Schepers S.T., Bremmer M.P., Lee R., de Wit H. Acute subjective and behavioral effects of microdoses of lysergic acid diethylamide in healthy human volunteers. Biol. Psychiatry. 2019;86:792–800. doi: 10.1016/j.biopsych.2019.05.019.10.1016/j.biopsych.2019.05.019PMC681452731331617Carhart-Harris R.L., Kaelen M., Bolstridge M., Williams T., Williams L., Underwood R., Feilding A., Nutt D.J. The paradoxical psychological effects of lysergic acid diethylamide (LSD) Psychol. Med. 2016;46:1379–1390. doi: 10.1017/S0033291715002901.10.1017/S003329171500290126847689Nichols C.D., Sanders-Bush E. A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. Neuropsychopharmacology. 2002;26:634–642. doi: 10.1016/S0893-133X(01)00405-5.10.1016/S0893-133X(01)00405-511927188González-Maeso J., Yuen T., Ebersole B.J., Wurmbach E., Lira A., Zhou M., Weisstaub N., Hen R., Gingrich J.A., Sealfon S.C. Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J. Neurosci. 2003;23:8836–8843. doi: 10.1523/JNEUROSCI.23-26-08836.2003.10.1523/JNEUROSCI.23-26-08836.2003PMC674040114523084Cini F.A., Ornelas I., Marcos E., Goto-Silva L., Nascimento J., Ruschi S., Salerno J., Karmirian K., Costa M., Sequerra E. d-Lysergic acid diethylamide has major potential as a cognitive enhancer. bioRxiv. 2019:866814.Speth J., Speth C., Kaelen M., Schloerscheidt A.M., Feilding A., Nutt D.J., Carhart-Harris R.L. Decreased mental time travel to the past correlates with default-mode network disintegration under lysergic acid diethylamide. J. Psychopharmacol. 2016;30:344–353. doi: 10.1177/0269881116628430.10.1177/026988111662843026979587Grof S., Goodman L.E., Richards W.A., Kurland A. LSD-assisted psychotherapy in patients with terminal cancer. Int. Pharmacopsychiatry. 1973;8:129–144. doi: 10.1159/000467984.10.1159/0004679844140164Gasser P., Kirchner K., Passie T. LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects. J. Psychopharmacol. 2015;29:57–68. doi: 10.1177/0269881114555249.10.1177/026988111455524925389218Gasser P., Holstein D., Michel Y., Doblin R., Yazar-Klosinski B., Passie T., Brenneisen R. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J. Nerv. Ment. Dis. 2014;202:513–520. doi: 10.1097/NMD.0000000000000113.10.1097/NMD.0000000000000113PMC408677724594678Abbott K.L., Flannery P.C., Gill K.S., Boothe D.M., Dhanasekaran M., Mani S., Pondugula S.R. Adverse pharmacokinetic interactions between illicit substances and clinical drugs. Drug Metab. Rev. 2020;52:44–65. doi: 10.1080/03602532.2019.1697283.10.1080/03602532.2019.169728331826670Halpern J.H., Sherwood A.R., Hudson J.I., Yurgelun-Todd D., Pope Jr H.G. Psychological and cognitive effects of long-term peyote use among Native Americans. Biol. Psychiatry. 2005;58:624–631. doi: 10.1016/j.biopsych.2005.06.038.10.1016/j.biopsych.2005.06.03816271313Dinis-Oliveira R.J., Pereira C.L., da Silva D.D. Pharmacokinetic and pharmacodynamic aspects of peyote and mescaline: Clinical and forensic repercussions. Curr. Mol. Pharmacol. 2019;12:184.PMC686460230318013Carstairs S.D., Cantrell F.L. Peyote and mescaline exposures: A 12-year review of a statewide poison center database. Clin. Toxicol. 2010;48:350–353. doi: 10.3109/15563650903586745.10.3109/1556365090358674520170392Callaway J.C., McKenna D.J., Grob C.S., Brito G.S., Raymon L., Poland R.E., Andrade E., Andrade E., Mash D.C. Pharmacokinetics of Hoasca alkaloids in healthy humans. J. Ethnopharmacol. 1999;65:243–256. doi: 10.1016/S0378-8741(98)00168-8.10.1016/S0378-8741(98)00168-810404423Barker S.A. N, N-Dimethyltryptamine (DMT), an endogenous hallucinogen: Past, present, and future research to determine its role and function. Front. Neurosci. 2018;12:536. doi: 10.3389/fnins.2018.00536.10.3389/fnins.2018.00536PMC608823630127713Shen H.-W., Jiang X.-L., Yu A.-M. Nonlinear pharmacokinetics of 5-methoxy-N, N-dimethyltryptamine in mice. Drug Metab. Dispos. 2011;39:1227–1234. doi: 10.1124/dmd.111.039107.10.1124/dmd.111.039107PMC312723721464174Keiser M.J., Setola V., Irwin J.J., Laggner C., Abbas A.I., Hufeisen S.J., Jensen N.H., Kuijer M.B., Matos R.C., Tran T.B., et al. Predicting new molecular targets for known drugs. Nature. 2009;462:175–181. doi: 10.1038/nature08506.10.1038/nature08506PMC278414619881490Fontanilla D., Johannessen M., Hajipour A.R., Cozzi N.V., Jackson M.B., Ruoho A.E. The hallucinogen N, N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science. 2009;323:934–937. doi: 10.1126/science.1166127.10.1126/science.1166127PMC294720519213917Bourrie B., Bouaboula M., Benoit J.M., Derocq J.M., Esclangon M., Le Fur G., Casellas P. Enhancement of endotoxin-induced interleukin-10 production by SR 31747A, a sigma ligand. Eur. J. Immunol. 1995;25:2882–2887. doi: 10.1002/eji.1830251026.10.1002/eji.18302510267589087Carayon P., Bouaboula M., Loubet J.F., Bourrie B., Petitpretre G., Le Fur G., Casellas P. The sigma ligand SR 31747 prevents the development of acute graft-versus-host disease in mice by blocking IFN-gamma and GM-CSF mRNA expression. Int. J. Immunopharmacol. 1995;17:753–761. doi: 10.1016/0192-0561(95)00066-B.10.1016/0192-0561(95)00066-B8582787Zhu F., Panwar B., Dodge H.H., Li H., Hampstead B.M., Albin R.L., Paulson H.L., Guan Y. COMPASS: A computational model to predict changes in MMSE scores 24-months after initial assessment of Alzheimer’s disease. Sci. Rep. 2016;6:srep34567. doi: 10.1038/srep34567.10.1038/srep34567PMC505051627703197Szabo A., Rajnavolgyi E. The brain-immune-gut triangle: Innate immunity in psychiatric and neurological disorders. Curr. Immunol. Rev. 2013;9:241–248.Cameron L.P., Benson C.J., DeFelice B.C., Fiehn O., Olson D.E. Chronic, intermittent microdoses of the psychedelic N, N-dimethyltryptamine (DMT) produce positive effects on mood and anxiety in rodents. ACS Chem. Neurosci. 2019;10:3261–3270. doi: 10.1021/acschemneuro.8b00692.10.1021/acschemneuro.8b00692PMC663977530829033Morgan C.J., Curran H.V., Drugs I.S.C.o. Ketamine use: A review. Addiction. 2012;107:27–38. doi: 10.1111/j.1360-0443.2011.03576.x.10.1111/j.1360-0443.2011.03576.x21777321Berman R.M., Cappiello A., Anand A., Oren D.A., Heninger G.R., Charney D.S., Krystal J.H. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry. 2000;47:351–354. doi: 10.1016/S0006-3223(99)00230-9.10.1016/S0006-3223(99)00230-910686270McIntyre R.S., Carvalho I.P., Lui L.M., Majeed A., Masand P.S., Gill H., Rodrigues N.B., Lipsitz O., Coles A.C., Lee Y. The effect of intravenous, intranasal, and oral ketamine/esketamine in mood disorders: A meta-analysis. J. Affect. Disord. 2020;276:576–584. doi: 10.1016/j.jad.2020.06.050.10.1016/j.jad.2020.06.05032871689Short B., Fong J., Galvez V., Shelker W., Loo C.K. Side-effects associated with ketamine use in depression: A systematic review. Lancet Psychiatry. 2018;5:65–78.28757132Malhotra A.K., Pinals D.A., Weingartner H., Sirocco K., Missar C.D., Pickar D., Breier A. NMDA receptor function and human cognition: The effects of ketamine in healthy volunteers. Neuropsychopharmacology. 1996;14:301–307. doi: 10.1016/0893-133X(95)00137-3.10.1016/0893-133X(95)00137-38703299Pfenninger E.G., Durieux M.E., Himmelseher S. Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. J. Am. Soc. Anesthesiol. 2002;96:357–366. doi: 10.1097/00000542-200202000-00022.10.1097/00000542-200202000-0002211818769Morgan C.J., Dodds C.M., Furby H., Pepper F., Fam J., Freeman T.P., Hughes E., Doeller C., King J., Howes O. Long-term heavy ketamine use is associated with spatial memory impairment and altered hippocampal activation. Front. Psychiatry. 2014;5:149. doi: 10.3389/fpsyt.2014.00149.10.3389/fpsyt.2014.00149PMC425551525538631Kessels R., Feijen J., Postma A. Implicit and explicit memory for spatial information in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 2005;20:184–191. doi: 10.1159/000087233.10.1159/00008723316088143Smalheiser N.R. Ketamine: A Neglected Therapy for Alzheimer Disease. Front. Aging Neurosci. 2019;11:186. doi: 10.3389/fnagi.2019.00186.10.3389/fnagi.2019.00186PMC666797531396078Mohammad Shehata I., Masood W., Nemr N., Anderson A., Bhusal K., Edinoff A.N., Cornett E.M., Kaye A.M., Kaye A.D. The Possible Application of Ketamine in the Treatment of Depression in Alzheimer’s Disease. Neurol. Int. 2022;14:310–321. doi: 10.3390/neurolint14020025.10.3390/neurolint14020025PMC903621335466206Carbonaro T.M., Bradstreet M.P., Barrett F.S., MacLean K.A., Jesse R., Johnson M.W., Griffiths R.R. Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. J. Psychopharmacol. 2016;30:1268–1278.PMC555167827578767Cameron L.P., Nazarian A., Olson D.E. Psychedelic Microdosing: Prevalence and Subjective Effects. J. Psychoact. Drugs. 2020;52:113–122. doi: 10.1080/02791072.2020.1718250.10.1080/02791072.2020.1718250PMC728293631973684Anderson T., Petranker R., Christopher A., Rosenbaum D., Weissman C., Dinh-Williams L.-A., Hui K., Hapke E. Psychedelic microdosing benefits and challenges: An empirical codebook. Harm Reduct. J. 2019;16:1–10. doi: 10.1186/s12954-019-0308-4.10.1186/s12954-019-0308-4PMC661788331288862Bornemann J. The viability of microdosing psychedelics as a strategy to enhance cognition and well-being-an early review. J. Psychoact. Drugs. 2020;52:300–308. doi: 10.1080/02791072.2020.1761573.10.1080/02791072.2020.176157332362269417079072026070820260708

1873-75445992026Apr06NeuroscienceHallucinogenic Therapy in Alzheimer's Disease targeting Mitochondria-Associated Membranes.162169162-16910.1016/j.neuroscience.2026.02.028S0306-4522(26)00125-9Mitochondrial dysfunction is increasingly recognized as a central driver of Alzheimer's disease (AD), contributing to neuroinflammation, synaptic failure, and energy collapse.Emerging preclinical evidence suggests that classic hallucinogens, such as psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), mescaline, may restore mitochondrial integrity by activating Serotonin 2A (5-HT2A) and sigma-1(Sig-1R) receptors. In experimental models, these pathways are associated with enhanced mitochondrial biogenesis, reduced oxidative stress, and preservation of ER-mitochondrial coupling. DMT and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) specifically engage Sig-1R at mitochondria-associated membranes, improving calcium homeostasis and cellular resilience. While these mechanisms are mechanistically compelling, evidence for clinical efficacy in AD remains limited and largely preclinical. Accordingly, this framework is presented as a hypothesis-generating model suggesting that mitochondrial-centered psychedelic mechanisms warrant further investigation,provided that neuropsychiatric safety, patient selection, and translational feasibility are carefully addressed.Copyright © 2026 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.Minauro-SanmiguelFernandoFUnidad de Investigación Médica en Genética Humana, Hospital de Pediatría, Centro Médico Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.Vargas-PerezHectorHThe Nierika Intercultural Medicine Institute, Ocuilan, Estado de México, Mexico. Electronic address: hectorvargasperez@gmail.com.engJournal ArticleReview20260216

United StatesNeuroscience76050740306-45220Hallucinogens0Receptors, sigma0Sigma-1 ReceptorIMAlzheimer Diseasedrug therapymetabolismHumansAnimalsHallucinogenspharmacologytherapeutic useMitochondria Associated Membranesdrug effectsmetabolismMitochondriadrug effectsmetabolismReceptors, sigmametabolismSigma-1 Receptor5-HT2A receptorAlzheimer’s diseaseMitochondriaNeuroinflammationPsychedelicsSigma-1 receptorSynaptic plasticityDeclaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.202512220261720262152026315536202621913520262181928ppublish4170790710.1016/j.neuroscience.2026.02.028S0306-4522(26)00125-9398928472025031120250525

1878-42161372025Mar20Prog Neuropsychopharmacol Biol PsychiatryPsychedelics in neuroinflammation: Mechanisms and therapeutic potential.11127811127810.1016/j.pnpbp.2025.111278S0278-5846(25)00032-6Neuroinflammation is a critical factor in the pathogenesis of various neurodegenerative and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, and major depressive disorder. Psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT), have demonstrated promising therapeutic effects on neuroinflammation, primarily through interactions with serotonin (5-HT) receptors, particularly the 5-HT2A receptor. Activation of these receptors by psychedelics modulates the production of pro-inflammatory cytokines, regulates microglial activity, and shifts the balance between neurotoxic and neuroprotective metabolites. Additionally, psychedelics affect critical signaling pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and mechanistic target of rapamycin (mTOR) pathways, promoting neuroplasticity and exerting anti-inflammatory effects. Beyond the serotonergic system, other neurotransmitter systems-including the glutamatergic, dopaminergic, noradrenergic, gamma-aminobutyric acid (GABAergic), and cholinergic systems-also play significant roles in mediating the effects of psychedelics. This review examines the intricate mechanisms by which psychedelics modulate neuroinflammation and underscores their potential as innovative therapeutic agents for treating neuroinflammatory and neuropsychiatric disorders.Copyright © 2025 Elsevier Inc. All rights reserved.de DeusJunia LaraJLDepartment of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC, USA; Department of Oral and Basic Biology Ribeirão Preto, Dental School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.MaiaJuliana MarinoJMDepartment of Medicine, Federal University of Juiz de Fora, Governador Valadares,MG, Brazil.SorianoRenato NeryRNDivision of Physiology and Biophysics, Department of Basic Life Sciences, Federal University of Juiz de Fora, Governador Valadares, MG, Brazil.AmorimMateus RMRDepartment of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC, USA; Program of Physiology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.BrancoLuiz G SLGSDepartment of Oral and Basic Biology Ribeirão Preto, Dental School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; Program of Physiology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. Electronic address: branco@forp.usp.br.engJournal ArticleReview20250131

EnglandProg Neuropsychopharmacol Biol Psychiatry82116170278-58460HallucinogensIMHumansNeuroinflammatory Diseasesdrug therapymetabolismHallucinogenstherapeutic usepharmacologyAnimalsSignal Transductiondrug effectsAstrocytesMacrophagesMicrogliaNeurodegenerative diseasesSerotonin systemDeclaration of competing interest The authors acknowledge the financial support from FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior). Their contributions were essential for the development of this research. The authors also appreciate the institutional support provided for the execution of the study.20247312025132025127202531211332025225112025211921ppublish3989284710.1016/j.pnpbp.2025.111278S0278-5846(25)00032-6351582302022050920220524

1873-7862582022MayEur NeuropsychopharmacolLSD, afterglow and hangover: Increased episodic memory and verbal fluency, decreased cognitive flexibility.7197-1910.1016/j.euroneuro.2022.01.114S0924-977X(22)00124-9Psychedelics acutely impair cognitive functions, but these impairments decline with growing experiences with psychedelics and microdoses may even exert opposing effects. Given the recent evidence that psychedelics induce neuroplasticity, this explorative study aimed at investigating the potential of psychedelics to sub-acutely change cognition. For this, we applied a randomized, double-blind, placebo-controlled, crossover study with 24 healthy volunteers receiving 50 μg lysergic acid diethylamide (LSD) or an inactive placebo. Sub-acute changes in cognition were measured 24 h after dosing, including memory (Rey-Osterrieth Complex Figure, ROCF; 2D Object-Location Memory Task, OLMT; Rey Auditory-Verbal Learning Test, RAVLT), verbal fluency (phonological; semantic; switch), design fluency (basic; filter; switch), cognitive flexibility (Wisconsin Card Sorting Test, WCST), sustained and switching attention (Trail Making Test, TMT), inhibitory control (Stroop Task) and perceptual reasoning (Block Design Test, BDT). The results show that when compared to placebo and corrected for Body Mass Index (BMI) and abstinence period from psychedelics, LSD sub-acutely improved visuospatial memory (ROCF immediate recall points and percentage, OLMT consolidation percentage) and phonological verbal fluency and impaired cognitive flexibility (WCST: fewer categories achieved; more perseveration, errors and conceptual level responses). In conclusion, the low dose of LSD moderately induced both "afterglow" and "hangover". The improvements in visuospatial memory and phonological fluency suggest that LSD-assisted therapy should be explored as a novel treatment perspective in conditions involving memory and language declines such as brain injury, stroke or dementia.Copyright © 2022. Published by Elsevier B.V.WießnerIsabelIDepartment of Psychiatry, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil; Interdisciplinary Cooperation for Ayahuasca Research and Outreach (ICARO), School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil. Electronic address: isabel.wiessner@gmail.com.OlivieriRodolfoRDepartment of Psychiatry, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil; Interdisciplinary Cooperation for Ayahuasca Research and Outreach (ICARO), School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.FalchiMarceloMDepartment of Psychiatry, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil; Interdisciplinary Cooperation for Ayahuasca Research and Outreach (ICARO), School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.Palhano-FontesFernandaFBrain Institute, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil.Oliveira MaiaLucasLDepartment of Psychiatry, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil; Interdisciplinary Cooperation for Ayahuasca Research and Outreach (ICARO), School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.FeildingAmandaAThe Beckley Foundation, Beckley Park, Oxford, United Kingdom.B AraujoDraulioDBrain Institute, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil.RibeiroSidartaSBrain Institute, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil.TófoliLuís FernandoLFDepartment of Psychiatry, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil; Interdisciplinary Cooperation for Ayahuasca Research and Outreach (ICARO), School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.engJournal ArticleRandomized Controlled Trial20220211

NetherlandsEur Neuropsychopharmacol91113900924-977X0Hallucinogens8NA5SWF92OLysergic Acid DiethylamideIMCognitionCross-Over StudiesHallucinogenspharmacologyHumansLysergic Acid DiethylamidepharmacologyMemory, EpisodicNeuropsychological TestsCognitive FlexibilityExecutive FunctionsPhonological Verbal FluencyPsycholytic DoseSub-acute LSD EffectsVisuospatial MemoryDeclaration of competing interest SR declares the following patent application as a competing interest: a) Patent applicants (The Beckley Foundation, Universidade Federal do Rio Grande do Norte); b) Name of inventors: Not yet listed; c) Application number: 1 911 024.6; d) Status of application: pending.20211022022126202212920222156020225106020222142014ppublish3515823010.1016/j.euroneuro.2022.01.114S0924-977X(22)00124-9