Skip to main content
Book cover

pp 1–31Cite as

Psychedelics as Novel Therapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms

Part of the Current Topics in Behavioral Neurosciences book series

Abstract

Serotonin 2A receptor (5-HT2AR) agonist “classic psychedelics” are drawing increasing interest as potential mental health treatments. Recent work suggests psychedelics can exert persisting anxiolytic and antidepressant effects lasting up to several months after a single administration. Data indicate acute subjective drug effects as important psychological factors involved in observed therapeutic benefits. Additionally, animal models have shown an important role for 5-HT2AR agonists in modulating learning and memory function with relevance for Alzheimer’s Disease (AD) and related dementias. A number of biological mechanisms of action are under investigation to elucidate 5-HT2AR agonists’ therapeutic potential, including enhanced neuroplasticity, anti-inflammatory effects, and alterations in brain functional connectivity. These diverse lines of research are reviewed here along with a discussion of AD pathophysiology and neuropsychiatric symptoms to highlight classic psychedelics as potential novel pharmacotherapies for patients with AD. Human clinical research suggests a possible role for high-dose psychedelic administration in symptomatic treatment of depressed mood and anxiety in early-stage AD. Preclinical data indicate a potential for low- or high-dose psychedelic treatment regimens to slow or reverse brain atrophy, enhance cognitive function, and slow progression of AD. In conclusion, rationale and potential approaches for preliminary research with psychedelics in patients with AD are presented, and ramifications of this line of investigation for development of novel AD treatments are discussed.

Keywords

  • Alzheimer’s disease
  • Dementia
  • Hallucinogen
  • Mild cognitive impairment (MCI)
  • Psilocybin
  • Psychedelic

This is a preview of subscription content, access via your institution.

Fig. 1

References

  • Agin-Liebes GI, Malone T, Yalch MM, Mennenga SE, Ponté KL, Guss J, Bossis AP, Grigsby J, Fischer S, Ross S (2020) Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. J Psychopharmacol 34(2):155–166

    Google Scholar 

  • Alzheimer’s Association (2021) Alzheimer’s disease facts and figures. Alzheimers Dement 17(3):327–406. https://doi.org/10.1002/alz.12328

    CrossRef  Google Scholar 

  • Anderson BT, Danforth A, Daroff PR, Stauffer C, Ekman E, Agin-Liebes G, Trope A, Boden MT, Dilley PJ, Mitchell J, Woolley J (2020) Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: an open-label safety and feasibility pilot study. EClinicalMedicine 27. https://doi.org/10.1016/j.eclinm.2020.100538

  • Arancibia S, Silhol M, Moulière F, Meffre J, Höllinger I, Maurice T, Tapia-Arancibia L (2008) Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiol Dis 31(3):316–326. https://doi.org/10.1016/j.nbd.2008.05.012

    CrossRef  Google Scholar 

  • Ayton S (2021) Brain volume loss due to donanemab. Eur J Neurol 28(9):e67–e68. https://doi.org/10.1111/ene.15007

    CrossRef  Google Scholar 

  • Aznar S, Hervig ME-S (2016) The 5-HT2A serotonin receptor in executive function: implications for neuropsychiatric and neurodegenerative diseases. Neurosci Biobehav Rev 64:63–82. https://doi.org/10.1016/j.neubiorev.2016.02.008

    CrossRef  Google Scholar 

  • Balthazar MLF, Pereira FRS, Lopes TM, da Silva EL, Coan AC, Campos BM, Duncan NW, Stella F, Northoff G, Damasceno BP, Cendes F (2014) Neuropsychiatric symptoms in Alzheimer’s disease are related to functional connectivity alterations in the salience network. Hum Brain Mapp 35(4):1237–1246. https://doi.org/10.1002/hbm.22248

    CrossRef  Google Scholar 

  • Banerjee S, Hellier J, Romer R, Dewey M, Knapp M, Ballard C, Baldwin R, Bentham P, Fox C, Holmes C, Katona C, Livingston G, Lawton C, McCrae N, Moniz-Cook E, Murray J, Nurock J, Orrell M, O’Brien J et al (2013) Study of the use of antidepressants for depression in dementia: the HTA -SADD trial – a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine. Health Technol Assess 17(7):Article 7. http://www.hta.ac.uk/research/HTAjournal.shtml

    Google Scholar 

  • Banning LCP, Ramakers IHGB, Rosenberg PB, Lyketsos CG, Leoutsakos J-MS (2021) Alzheimer’s disease biomarkers as predictors of trajectories of depression and apathy in cognitively normal individuals, mild cognitive impairment, and Alzheimer’s disease dementia. Int J Geriatr Psychiatry 36(1):224–234. https://doi.org/10.1002/gps.5418

    CrossRef  Google Scholar 

  • Barrett FS, Carbonaro TM, Hurwitz E, Johnson MW, Griffiths RR (2018) Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition. Psychopharmacology 235(10):2915–2927. https://doi.org/10.1007/s00213-018-4981-x

    CrossRef  Google Scholar 

  • Barrett FS, Doss MK, Sepeda ND, Pekar JJ, Griffiths RR (2020a) Emotions and brain function are altered up to one month after a single high dose of psilocybin. Sci Rep 10(1):1–14. https://doi.org/10.1038/s41598-020-59282-y

    CrossRef  Google Scholar 

  • Barrett FS, Krimmel SR, Griffiths RR, Seminowicz DA, Mathur BN (2020b) Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention. NeuroImage 218:116980. https://doi.org/10.1016/j.neuroimage.2020.116980

    CrossRef  Google Scholar 

  • Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E et al (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367(9):795–804. https://doi.org/10.1056/NEJMoa1202753

    CrossRef  Google Scholar 

  • Bershad AK, Schepers ST, Bremmer MP, Lee R, de Wit H (2019) Acute subjective and behavioral effects of microdoses of lysergic acid diethylamide in healthy human volunteers. Biol Psychiatry 86(10):792–800. https://doi.org/10.1016/j.biopsych.2019.05.019

    CrossRef  Google Scholar 

  • Bloom GS (2014) Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4):505–508. https://doi.org/10.1001/jamaneurol.2013.5847

    CrossRef  Google Scholar 

  • Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PCR, Strassman RJ (2015) Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol 29(3):289–299

    Google Scholar 

  • Bogenschutz MP, Podrebarac SK, Duane JH, Amegadzie SS, Malone TC, Owens LT, Ross S, Mennenga SE (2018) Clinical interpretations of patient experience in a trial of psilocybin-assisted psychotherapy for alcohol use disorder. Front Pharmacol 9. https://doi.org/10.3389/fphar.2018.00100

  • Boulougouris V, Glennon JC, Robbins TW (2008) Dissociable effects of selective 5-HT 2A and 5-HT 2C receptor antagonists on serial spatial reversal learning in rats. Neuropsychopharmacology 33(8):2007–2019. https://doi.org/10.1038/sj.npp.1301584

    CrossRef  Google Scholar 

  • Bouso JC, Fábregas JM, Antonijoan RM, Rodríguez-Fornells A, Riba J (2013) Acute effects of ayahuasca on neuropsychological performance: differences in executive function between experienced and occasional users. Psychopharmacology 230(3):415–424. https://doi.org/10.1007/s00213-013-3167-9

    CrossRef  Google Scholar 

  • Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259. https://doi.org/10.1007/BF00308809

    CrossRef  Google Scholar 

  • Brier MR, Gordon B, Friedrichsen K, McCarthy J, Stern A, Christensen J, Owen C, Aldea P, Su Y, Hassenstab J, Cairns NJ, Holtzman DM, Fagan AM, Morris JC, Benzinger TLS, Ances BM (2016) Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med 8(338):338ra66. https://doi.org/10.1126/scitranslmed.aaf2362

    CrossRef  Google Scholar 

  • Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25(34):7709–7717. https://doi.org/10.1523/JNEUROSCI.2177-05.2005

    CrossRef  Google Scholar 

  • Butzlaff M, Ponimaskin E (2016) The role of serotonin receptors in Alzheimer’s disease. Opera Med Physiol 2(1):77–86

    Google Scholar 

  • Caccamo A, Magrì A, Medina DX, Wisely EV, López-Aranda MF, Silva AJ, Oddo S (2013) mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 12(3):370–380. https://doi.org/10.1111/acel.12057

    CrossRef  Google Scholar 

  • Cammalleri M, Lütjens R, Berton F, King AR, Simpson C, Francesconi W, Sanna PP (2003) Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1. Proc Natl Acad Sci 100(24):14368–14373. https://doi.org/10.1073/pnas.2336098100

    CrossRef  Google Scholar 

  • Carhart-Harris RL, Leech R, Williams TM, Erritzoe D, Abbasi N, Bargiotas T, Hobden P, Sharp DJ, Evans J, Feilding A, Wise RG, Nutt DJ (2012) Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin. Br J Psychiatry 200(3):238–244. https://doi.org/10.1192/bjp.bp.111.103309

    CrossRef  Google Scholar 

  • Carhart-Harris RL, Bolstridge M, Rucker J, Day CMJ, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ (2016) Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry 3(7):619–627. https://doi.org/10.1016/S2215-0366(16)30065-7

    CrossRef  Google Scholar 

  • Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall MB, Tanner M, Kaelen M, McGonigle J, Murphy K, Leech R, Curran HV, Nutt DJ (2017) Psilocybin for treatment-resistant depression: FMRI-measured brain mechanisms. Sci Rep 7(1):13187. https://doi.org/10.1038/s41598-017-13282-7

    CrossRef  Google Scholar 

  • Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ (2021) Trial of psilocybin versus escitalopram for depression. N Engl J Med 384(15):1402–1411

    Google Scholar 

  • Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F, Vollenweider FX (2005) Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors. J Cogn Neurosci 17(10):1497–1508. https://doi.org/10.1162/089892905774597191

    CrossRef  Google Scholar 

  • Catlow BJ, Song S, Paredes DA, Kirstein CL, Sanchez-Ramos J (2013) Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Exp Brain Res 228(4):481–491. https://doi.org/10.1007/s00221-013-3579-0

    CrossRef  Google Scholar 

  • Cavalleri L, Merlo Pich E, Millan MJ, Chiamulera C, Kunath T, Spano PF, Collo G (2018) Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling. Mol Psychiatry 23(4):812–823. https://doi.org/10.1038/mp.2017.241

    CrossRef  Google Scholar 

  • Chakraborty S, Lennon JC, Malkaram SA, Zeng Y, Fisher DW, Dong H (2019) Serotonergic system, cognition, and BPSD in Alzheimer’s disease. Neurosci Lett 704:36–44. https://doi.org/10.1016/j.neulet.2019.03.050

    CrossRef  Google Scholar 

  • Chen M-K, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin S, Najafzadeh S, Ropchan J, Lu Y, McDonald JW, Michalak HR, Nabulsi NB, Arnsten AFT, Huang Y, Carson RE, van Dyck CH (2018) Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol 75(10):1215. https://doi.org/10.1001/jamaneurol.2018.1836

    CrossRef  Google Scholar 

  • Ciaramella A, Salani F, Bizzoni F, Orfei MD, Langella R, Angelucci F, Spalletta G, Taddei AR, Caltagirone C, Bossù P (2013) The stimulation of dendritic cells by amyloid beta 1–42 reduces BDNF production in Alzheimer’s disease patients. Brain Behav Immun 32:29–32. https://doi.org/10.1016/j.bbi.2013.04.001

    CrossRef  Google Scholar 

  • Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, Finan PH, Griffiths RR (2021) Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiat 78(5):481–489

    Google Scholar 

  • de Quervain DJ-F, Henke K, Aerni A, Coluccia D, Wollmer MA, Hock C, Nitsch RM, Papassotiropoulos A (2003) A functional genetic variation of the 5-HT2a receptor affects human memory. Nat Neurosci 6(11):1141–1142. https://doi.org/10.1038/nn1146

    CrossRef  Google Scholar 

  • Dennis EL, Thompson PM (2014) Functional brain connectivity using fMRI in aging and Alzheimer’s disease. Neuropsychol Rev 24(1):49–62. https://doi.org/10.1007/s11065-014-9249-6

    CrossRef  Google Scholar 

  • Doggrell SA (2021) Still grasping at straws: donanemab in Alzheimer’s disease. Expert Opin Investig Drugs 30(8):797–801. https://doi.org/10.1080/13543784.2021.1948010

    CrossRef  Google Scholar 

  • Donovan LL, Johansen JV, Ros NF, Jaberi E, Linnet K, Johansen SS, Ozenne B, Issazadeh-Navikas S, Hansen HD, Knudsen GM (2021) Effects of a single dose of psilocybin on behaviour, brain 5-HT2A receptor occupancy and gene expression in the pig. Eur Neuropsychopharmacol 42:1–11. https://doi.org/10.1016/j.euroneuro.2020.11.013

    CrossRef  Google Scholar 

  • Dotson VM, Beydoun MA, Zonderman AB (2010) Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology 75(1):27–34. https://doi.org/10.1212/WNL.0b013e3181e62124

    CrossRef  Google Scholar 

  • Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R, Cappa S, Crutch S, Engelborghs S, Frisoni GB, Fox NC, Galasko D, Habert M-O, Jicha GA, Nordberg A et al (2014) Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 13(6):614–629. https://doi.org/10.1016/S1474-4422(14)70090-0

    CrossRef  Google Scholar 

  • Eide FF, Vining ER, Eide BL, Zang K, Wang X-Y, Reichardt LF (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 16(10):3123–3129. https://doi.org/10.1523/JNEUROSCI.16-10-03123.1996

    CrossRef  Google Scholar 

  • Erritzoe D, Roseman L, Nour MM, MacLean K, Kaelen M, Nutt DJ, Carhart-Harris RL (2018) Effects of psilocybin therapy on personality structure. Acta Psychiatr Scand 138(5):368–378. https://doi.org/10.1111/acps.12904

    CrossRef  Google Scholar 

  • Family N, Maillet EL, Williams LTJ, Krediet E, Carhart-Harris RL, Williams TM, Nichols CD, Goble DJ, Raz S (2020) Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers. Psychopharmacology 237(3):841–853. https://doi.org/10.1007/s00213-019-05417-7

    CrossRef  Google Scholar 

  • Flanagan TW, Nichols CD (2018) Psychedelics as anti-inflammatory agents. Int Rev Psychiatry 30(4):363–375. https://doi.org/10.1080/09540261.2018.1481827

    CrossRef  Google Scholar 

  • Frick LR, Bernardez-Vidal M, Hocht C, Zanutto BS, Rapanelli M (2015) Dual role of serotonin in the acquisition and extinction of reward-driven learning: involvement of 5-HT1A, 5-HT2A and 5-HT3 receptors. Behav Brain Res 277:193–203. https://doi.org/10.1016/j.bbr.2014.06.025

    CrossRef  Google Scholar 

  • Furr A, Lapiz-Bluhm MD, Morilak DA (2012) 5-HT2A receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats. Int J Neuropsychopharmacol 15(9):1295–1305. https://doi.org/10.1017/S1461145711001441

    CrossRef  Google Scholar 

  • Galvão-Coelho NL, de Menezes Galvão AC, de Almeida RN, Palhano-Fontes F, Campos Braga I, Lobão Soares B, Maia-de-Oliveira JP, Perkins D, Sarris J, de Araujo DB (2020) Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca. J Psychopharmacol 34(10):1125–1133

    Google Scholar 

  • Garcia-Romeu A, Griffiths RR, Johnson MW (2014) Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Curr Drug Abuse Rev 7(3):157–164

    Google Scholar 

  • Garcia-Romeu A, Kersgaard B, Addy PH (2016) Clinical applications of hallucinogens: a review. Exp Clin Psychopharmacol 24(4):229

    Google Scholar 

  • Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W (2011) Astrocytes are important mediators of a β-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2(6):e167–e167

    Google Scholar 

  • Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B, Passie T, Brenneisen R (2014) Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis 202(7):513

    Google Scholar 

  • George DR, Hanson R (2019) Imagining a role for psychedelics in dementia care. Am J Geriatr Psychiatry 27(9):1028–1030. https://doi.org/10.1016/j.jagp.2019.03.008

    CrossRef  Google Scholar 

  • González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA (2007) Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron 53(3):439–452. https://doi.org/10.1016/j.neuron.2007.01.008

    CrossRef  Google Scholar 

  • Graff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, Rabinovici GD, Schott JM, Jones DT, Murray ME (2021) New insights into atypical Alzheimer’s disease in the era of biomarkers. Lancet Neurol 20(3):222–234. https://doi.org/10.1016/S1474-4422(20)30440-3

    CrossRef  Google Scholar 

  • Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R (2008) Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol 22(6):621–632

    Google Scholar 

  • Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA (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(12):1181–1197. https://doi.org/10.1177/0269881116675513

    CrossRef  Google Scholar 

  • Griffiths RR, Johnson MW, Richards WA, Richards BD, Jesse R, MacLean KA, Barrett FS, Cosimano MP, Klinedinst MA (2018) Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol 32(1):49–69

    Google Scholar 

  • Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, Greer GR (2011) Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry 68(1):71. https://doi.org/10.1001/archgenpsychiatry.2010.116

    CrossRef  Google Scholar 

  • Grof S, Goodman LE, Richards WA, Kurland AA (1973) LSD-assisted psychotherapy in patients with terminal cancer. Int Pharmacopsychiatry 8:129–144. https://doi.org/10.1159/000467984

    CrossRef  Google Scholar 

  • Grothe M, Heinsen H, Teipel SJ (2012) Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer’s disease. Biol Psychiatry 71(9):805–813. https://doi.org/10.1016/j.biopsych.2011.06.019

    CrossRef  Google Scholar 

  • Hafkemeijer A, van der Grond J, Rombouts SARB (2012) Imaging the default mode network in aging and dementia. Biochim Biophys Acta 1822(3):431–441. https://doi.org/10.1016/j.bbadis.2011.07.008

    CrossRef  Google Scholar 

  • Harvey JA, Quinn JL, Liu R, Aloyo VJ, Romano AG (2004) Selective remodeling of rabbit frontal cortex: relationship between 5-HT2A receptor density and associative learning. Psychopharmacology 172(4):435–442. https://doi.org/10.1007/s00213-003-1687-4

    CrossRef  Google Scholar 

  • Hasselbalch SG, Madsen K, Svarer C, Pinborg LH, Holm S, Paulson OB, Waldemar G, Knudsen GM (2008) Reduced 5-HT2A receptor binding in patients with mild cognitive impairment. Neurobiol Aging 29(12):1830–1838. https://doi.org/10.1016/j.neurobiolaging.2007.04.011

    CrossRef  Google Scholar 

  • He X, Qin W, Liu Y, Zhang X, Duan Y, Song J, Li K, Jiang T, Yu C (2014) Abnormal salience network in normal aging and in amnestic mild cognitive impairment and Alzheimer’s disease. Hum Brain Mapp 35(7):3446–3464. https://doi.org/10.1002/hbm.22414

    CrossRef  Google Scholar 

  • He W, Goodkind D, Kowal P (2016) International population reports, P95/16-1, An aging world: 2015, U.S. Census Bureau. U.S. Government Publishing Office, Washington, DC

    Google Scholar 

  • Healy CJ (2021) The acute effects of classic psychedelics on memory in humans. Psychopharmacology 238(3):639–653. https://doi.org/10.1007/s00213-020-05756-w

    CrossRef  Google Scholar 

  • Herbert J, Lucassen PJ (2016) Depression as a risk factor for Alzheimer’s disease: genes, steroids, cytokines and neurogenesis – what do we need to know? Front Neuroendocrinol 41:153–171. https://doi.org/10.1016/j.yfrne.2015.12.001

    CrossRef  Google Scholar 

  • Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 33(2):67–75. https://doi.org/10.1016/j.tins.2009.11.003

    CrossRef  Google Scholar 

  • Holm P, Ettrup A, Klein AB, Santini MA, El-Sayed M, Elvang AB, Stensbøl TB, Mikkelsen JD, Knudsen GM, Aznar S (2010) Plaque deposition dependent decrease in 5-HT 2A serotonin receptor in AβPPswe/PS1dE9 amyloid overexpressing mice. J Alzheimers Dis 20(4):1201–1213. https://doi.org/10.3233/JAD-2010-100117

    CrossRef  Google Scholar 

  • Hutten NRPW, Mason NL, Dolder PC, Theunissen EL, Holze F, Liechti ME, Feilding A, Ramaekers JG, Kuypers KPC (2020) Mood and cognition after administration of low LSD doses in healthy volunteers: a placebo controlled dose-effect finding study. Eur Neuropsychopharmacol 41:81–91. https://doi.org/10.1016/j.euroneuro.2020.10.002

    CrossRef  Google Scholar 

  • Hutten NRPW, Mason NL, Dolder PC, Theunissen EL, Holze F, Liechti ME, Varghese N, Eckert A, Feilding A, Ramaekers JG, Kuypers KPC (2021) Low doses of LSD acutely increase BDNF blood plasma levels in healthy volunteers. ACS Pharmacol Transl Sci 4(2):461–466. https://doi.org/10.1021/acsptsci.0c00099

    CrossRef  Google Scholar 

  • Ismail Z, Agüera-Ortiz L, Brodaty H, Cieslak A, Cummings J, Fischer CE, Gauthier S, Geda YE, Herrmann N, Kanji J, Lanctôt KL, Miller DS, Mortby ME, Onyike CU, Rosenberg PB, Smith EE, Smith GS, Sultzer DL, Lyketsos C, for the N. P. I. A. of the I. S. of to A. A. R. and T. (NPS-P. of ISTAART) (2017) The mild behavioral impairment checklist (MBI-C): a rating scale for neuropsychiatric symptoms in pre-dementia populations. J Alzheimers Dis 56(3):929–938. https://doi.org/10.3233/JAD-160979

    CrossRef  Google Scholar 

  • Jack CR Jr, Wiste HJ, Botha H, Weigand SD, Therneau TM, Knopman DS, Graff-Radford J, Jones DT, Ferman TJ, Boeve BF (2019) The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes. Brain 142(10):3230–3242

    Google Scholar 

  • Jarvik ME, Abramson HA, Hirsch MW (1955) Lysergic acid diethylamide (LSD-25): VI. Effect upon recall and recognition of various stimuli. J Psychol 39(2):443–454. https://doi.org/10.1080/00223980.1955.9916194

    CrossRef  Google Scholar 

  • Jaworski J, Sheng M (2006) The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol 34(3):205–219. https://doi.org/10.1385/MN:34:3:205

    CrossRef  Google Scholar 

  • Jefsen OH, Elfving B, Wegener G, Müller HK (2021) Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. J Psychopharmacol 35(4):483–493. https://doi.org/10.1177/0269881120959614

    CrossRef  Google Scholar 

  • Johnson MW, Richards WA, Griffiths RR (2008) Human hallucinogen research: guidelines for safety. J Psychopharmacol 22(6):603–620

    Google Scholar 

  • Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR (2014) Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 28(11):983–992

    Google Scholar 

  • Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE (2018) The abuse potential of medical psilocybin according to the 8 factors of the controlled substances act. Neuropharmacology 142:143–166

    Google Scholar 

  • Joie RL, Perrotin A, Barré L, Hommet C, Mézenge F, Ibazizene M, Camus V, Abbas A, Landeau B, Guilloteau D, Sayette VL, Eustache F, Desgranges B, Chételat G (2012) Region-specific hierarchy between atrophy, hypometabolism, and β-amyloid (Aβ) load in Alzheimer’s disease dementia. J Neurosci 32(46):16265–16273. https://doi.org/10.1523/JNEUROSCI.2170-12.2012

    CrossRef  Google Scholar 

  • Karran E, Hardy J (2014) A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol 76(2):185–205. https://doi.org/10.1002/ana.24188

    CrossRef  Google Scholar 

  • Karran E, Mercken M, Strooper BD (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698–712. https://doi.org/10.1038/nrd3505

    CrossRef  Google Scholar 

  • Karttunen K, Karppi P, Hiltunen A, Vanhanen M, Välimäki T, Martikainen J, Valtonen H, Sivenius J, Soininen H, Hartikainen S, Suhonen J, Pirttilä T (2011) Neuropsychiatric symptoms and quality of life in patients with very mild and mild Alzheimer’s disease. Int J Geriatr Psychiatry 26(5):473–482. https://doi.org/10.1002/gps.2550

    CrossRef  Google Scholar 

  • Killin LOJ, Starr JM, Shiue IJ, Russ TC (2016) Environmental risk factors for dementia: a systematic review. BMC Geriatr 16(1):175. https://doi.org/10.1186/s12877-016-0342-y

    CrossRef  Google Scholar 

  • Kim SYH (2011) The ethics of informed consent in Alzheimer disease research. Nat Rev Neurol 7(7):410–414. https://doi.org/10.1038/nrneurol.2011.76

    CrossRef  Google Scholar 

  • King AR, Martin IL, Seymour KA (1972) Reversal learning facilitated by a single injection of lysergic acid diethylamide (LSD 25) in the rat. Br J Pharmacol 45(1):161P–162P

    Google Scholar 

  • Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT (2018) Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s Dementia Transl Res Clin Interv 4:575–590. https://doi.org/10.1016/j.trci.2018.06.014

    CrossRef  Google Scholar 

  • Klaassens BL, van Gerven J, van der Grond J, de Vos F, Möller C, Rombouts SA (2017) Diminished posterior precuneus connectivity with the default mode network differentiates normal aging from Alzheimer’s disease. Front Aging Neurosci 9:97

    Google Scholar 

  • Knopman DS, Jones DT, Greicius MD (2021) Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement 17(4):696–701. https://doi.org/10.1002/alz.12213

    CrossRef  Google Scholar 

  • Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S et al (2019) Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet 51(3):414–430. https://doi.org/10.1038/s41588-019-0358-2

    CrossRef  Google Scholar 

  • Lai MK, Tsang SW, Alder JT, Keene J, Hope T, Esiri MM, Francis PT, Chen CP (2005) Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease. Psychopharmacology 179(3):673–677. https://doi.org/10.1007/s00213-004-2077-2

    CrossRef  Google Scholar 

  • Lanctôt KL, Amatniek J, Ancoli-Israel S, Arnold SE, Ballard C, Cohen-Mansfield J, Ismail Z, Lyketsos C, Miller DS, Musiek E, Osorio RS, Rosenberg PB, Satlin A, Steffens D, Tariot P, Bain LJ, Carrillo MC, Hendrix JA, Jurgens H, Boot B (2017) Neuropsychiatric signs and symptoms of Alzheimer’s disease: new treatment paradigms. Alzheimer’s Dementia Transl Res Clin Interv 3(3):440–449. https://doi.org/10.1016/j.trci.2017.07.001

    CrossRef  Google Scholar 

  • Langs RJ (1967) Stability of earliest memories under LSD-25 AND PLACEBO. J Nerv Ment Dis 144(3):171–184

    Google Scholar 

  • Leoutsakos J-MS, Forrester SN, Lyketsos CG, Smith GS (2015) Latent classes of neuropsychiatric symptoms in NACC controls and conversion to mild cognitive impairment or dementia. J Alzheimers Dis 48(2):483–493. https://doi.org/10.3233/JAD-150421

    CrossRef  Google Scholar 

  • Li L-B, Zhang L, Sun Y-N, Han L-N, Wu Z-H, Zhang Q-J, Liu J (2015) Activation of serotonin2A receptors in the medial septum-diagonal band of Broca complex enhanced working memory in the hemiparkinsonian rats. Neuropharmacology 91:23–33. https://doi.org/10.1016/j.neuropharm.2014.11.025

    CrossRef  Google Scholar 

  • Lima da Cruz RV, Moulin TC, Petiz LL, Leão RN (2018) A single dose of 5-MeO-DMT stimulates cell proliferation, neuronal survivability, morphological and functional changes in adult mice ventral dentate gyrus. Front Mol Neurosci 11. https://doi.org/10.3389/fnmol.2018.00312

  • Liu Y, Yoo M-J, Savonenko A, Stirling W, Price DL, Borchelt DR, Mamounas L, Lyons WE, Blue ME, Lee MK (2008) Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer’s disease. J Neurosci 28(51):13805–13814. https://doi.org/10.1523/JNEUROSCI.4218-08.2008

    CrossRef  Google Scholar 

  • Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, Burbach KF, Soltanzadeh Zarandi S, Sood A, Paddy MR, Duim WC, Dennis MY, McAllister AK, Ori-McKenney KM, Gray JA, Olson DE (2018) Psychedelics promote structural and functional neural plasticity. Cell Rep 23(11):3170–3182. https://doi.org/10.1016/j.celrep.2018.05.022

    CrossRef  Google Scholar 

  • Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S (2002) Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288(12):1475. https://doi.org/10.1001/jama.288.12.1475

    CrossRef  Google Scholar 

  • Lyketsos CG, Colenda CC, Beck C, Blank K, Doraiswamy MP, Kalunian DA, Yaffe K (2006) Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer Disease. Am J Geriatr Psychiatry 14(7):561–573. https://doi.org/10.1097/01.JGP.0000221334.65330.55

    CrossRef  Google Scholar 

  • Lyketsos CG, Carrillo MC, Ryan JM, Khachaturian AS, Trzepacz P, Amatniek J, Cedarbaum J, Brashear R, Miller DS (2011) Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimers Dement 7(5):532–539. https://doi.org/10.1016/j.jalz.2011.05.2410

    CrossRef  Google Scholar 

  • MacLean KA, Johnson MW, Griffiths RR (2011) Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol 25(11):1453–1461

    Google Scholar 

  • Madsen MK, Fisher PM, Stenbæk DS, Kristiansen S, Burmester D, Lehel S, Páleníček T, Kuchař M, Svarer C, Ozenne B, Knudsen GM (2020) A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding. Eur Neuropsychopharmacol 33:71–80. https://doi.org/10.1016/j.euroneuro.2020.02.001

    CrossRef  Google Scholar 

  • Marner L, Frokjaer VG, Kalbitzer J, Lehel S, Madsen K, Baaré WF, Knudsen GM, Hasselbalch SG (2012) 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 33(3):479–487

    Google Scholar 

  • Marucci G, Buccioni M, Ben DD, Lambertucci C, Volpini R, Amenta F (2021) Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 190:108352. https://doi.org/10.1016/j.neuropharm.2020.108352

    CrossRef  Google Scholar 

  • Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW, Morris JC (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56(1):127–129. https://doi.org/10.1212/WNL.56.1.127

    CrossRef  Google Scholar 

  • Mason NL, Kuypers KPC, Müller F, Reckweg J, Tse DHY, Toennes SW, Hutten NRPW, Jansen JFA, Stiers P, Feilding A, Ramaekers JG (2020) Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin. Neuropsychopharmacology 45(12):2003–2011. https://doi.org/10.1038/s41386-020-0718-8

    CrossRef  Google Scholar 

  • Mecca AP (2019) 1ciii - AD molecular: molecular imaging of Alzheimer’s disease: PET imaging of neurotransmitter systems. In: Becker JT, Cohen AD (eds) Progress in molecular biology and translational science, vol vol 165. Academic Press, pp 139–165. https://doi.org/10.1016/bs.pmbts.2019.04.003

    CrossRef  Google Scholar 

  • Mevel K, Chételat G, Eustache F, Desgranges B (2011) The default mode network in healthy aging and Alzheimer’s disease. Int J Alzheimers Dis 2011:e535816. https://doi.org/10.4061/2011/535816

    CrossRef  Google Scholar 

  • Michaelsen K, Zagrebelsky M, Berndt-Huch J, Polack M, Buschler A, Sendtner M, Korte M (2010) Neurotrophin receptors TrkB.T1 and p75NTR cooperate in modulating both functional and structural plasticity in mature hippocampal neurons. Eur J Neurosci 32(11):1854–1865. https://doi.org/10.1111/j.1460-9568.2010.07460.x

    CrossRef  Google Scholar 

  • Miguel-Álvarez M, Santos-Lozano A, Sanchis-Gomar F, Fiuza-Luces C, Pareja-Galeano H, Garatachea N, Lucia A (2015) Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer’s disease: a systematic review and meta-analysis of treatment effect. Drugs Aging 32(2):139–147

    Google Scholar 

  • Minichiello L (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 10(12):850–860. https://doi.org/10.1038/nrn2738

    CrossRef  Google Scholar 

  • Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, Shcherbinin S, Sparks J, Sims JR, Brys M, Apostolova LG, Salloway SP, Skovronsky DM (2021) Donanemab in early Alzheimer’s disease. N Engl J Med 384(18):1691–1704. https://doi.org/10.1056/NEJMoa2100708

    CrossRef  Google Scholar 

  • Nau F Jr, Yu B, Martin D, Nichols CD (2013) Serotonin 5-HT 2A receptor activation blocks TNF-α mediated inflammation in vivo. PLoS One 8(10):e75426

    Google Scholar 

  • Nelson JC, Devanand DP (2011) A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc 59(4):577–585. https://doi.org/10.1111/j.1532-5415.2011.03355.x

    CrossRef  Google Scholar 

  • Nichols DE (2016) Psychedelics. Pharmacol Rev 68(2):264–355. https://doi.org/10.1124/pr.115.011478

    CrossRef  Google Scholar 

  • Nichols DE (2020) Psilocybin: from ancient magic to modern medicine. J Antibiot 73(10):679–686. https://doi.org/10.1038/s41429-020-0311-8

    CrossRef  Google Scholar 

  • Nichols CD, Sanders-Bush E (2002) A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. Neuropsychopharmacology 26(5):634–642. https://doi.org/10.1016/S0893-133X(01)00405-5

    CrossRef  Google Scholar 

  • Nichols CD, Garcia EE, Sanders-Bush E (2003) Dynamic changes in prefrontal cortex gene expression following lysergic acid diethylamide administration. Mol Brain Res 111(1):182–188. https://doi.org/10.1016/S0169-328X(03)00029-9

    CrossRef  Google Scholar 

  • Noorani T, Garcia-Romeu A, Swift TC, Griffiths RR, Johnson MW (2018) Psychedelic therapy for smoking cessation: qualitative analysis of participant accounts. J Psychopharmacol 32(7):756–769. https://doi.org/10.1177/0269881118780612

    CrossRef  Google Scholar 

  • Olson DE (2018) Psychoplastogens: a promising class of plasticity-promoting neurotherapeutics. J Exp Neurosci 12:1179069518800508. https://doi.org/10.1177/1179069518800508

    CrossRef  Google Scholar 

  • Olson DE (2021) The subjective effects of psychedelics may not be necessary for their enduring therapeutic effects. ACS Pharmacol Transl Sci 4(2):563–567. https://doi.org/10.1021/acsptsci.0c00192

    CrossRef  Google Scholar 

  • Ossenkoppele R, Schonhaut DR, Schöll M, Lockhart SN, Ayakta N, Baker SL, O’Neil JP, Janabi M, Lazaris A, Cantwell A, Vogel J, Santos M, Miller ZA, Bettcher BM, Vossel KA, Kramer JH, Gorno-Tempini ML, Miller BL, Jagust WJ, Rabinovici GD (2016) Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain 139(5):1551–1567. https://doi.org/10.1093/brain/aww027

    CrossRef  Google Scholar 

  • Ozben T, Ozben S (2019) Neuro-inflammation and anti-inflammatory treatment options for Alzheimer’s disease. Clin Biochem 72:87–89. https://doi.org/10.1016/j.clinbiochem.2019.04.001

    CrossRef  Google Scholar 

  • Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, Mota-Rolim SA, Osório FL, Sanches R, dos Santos RG, Tófoli LF, Silveira GO, Yonamine M, Riba J, Santos FR, Silva-Junior AA, Alchieri JC, Galvão-Coelho NL, Lobão-Soares B et al (2019) Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med 49(4):655–663. https://doi.org/10.1017/S0033291718001356

    CrossRef  Google Scholar 

  • Palmqvist S, Schöll M, Strandberg O, Mattsson N, Stomrud E, Zetterberg H, Blennow K, Landau S, Jagust W, Hansson O (2017) Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat Commun 8(1):1214. https://doi.org/10.1038/s41467-017-01150-x

    CrossRef  Google Scholar 

  • Palop JJ, Mucke L (2016) Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci 17(12):777–792. https://doi.org/10.1038/nrn.2016.141

    CrossRef  Google Scholar 

  • Pasquini L, Rahmani F, Maleki-Balajoo S, La Joie R, Zarei M, Sorg C, Drzezga A, Tahmasian M (2019) Medial temporal lobe disconnection and hyperexcitability across Alzheimer’s disease stages. J Alzheimer’s Dis Rep 3(1):103–112. https://doi.org/10.3233/ADR-190121

    CrossRef  Google Scholar 

  • Pasquini L, Palhano-Fontes F, Araujo DB (2020) Subacute effects of the psychedelic ayahuasca on the salience and default mode networks. J Psychopharmacol 34(6):623–635. https://doi.org/10.1177/0269881120909409

    CrossRef  Google Scholar 

  • Peng S, Wuu J, Mufson EJ, Fahnestock M (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 93(6):1412–1421. https://doi.org/10.1111/j.1471-4159.2005.03135.x

    CrossRef  Google Scholar 

  • Peters ME, Schwartz S, Han D, Rabins PV, Steinberg M, Tschanz JT, Lyketsos CG (2015) Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s dementia and death: the cache county dementia progression study. Am J Psychiatr 172(5):460–465. https://doi.org/10.1176/appi.ajp.2014.14040480

    CrossRef  Google Scholar 

  • Pokorny T, Duerler P, Seifritz E, Vollenweider FX, Preller KH (2020) LSD acutely impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision-making. Psychol Med 50(13):2255–2264. https://doi.org/10.1017/S0033291719002393

    CrossRef  Google Scholar 

  • Preller KH, Duerler P, Burt JB, Ji JL, Adkinson B, Stämpfli P, Seifritz E, Repovš G, Krystal JH, Murray JD, Anticevic A, Vollenweider FX (2020) Psilocybin induces time-dependent changes in global functional connectivity. Biol Psychiatry 88(2):197–207. https://doi.org/10.1016/j.biopsych.2019.12.027

    CrossRef  Google Scholar 

  • Putcha D, Brickhouse M, O’Keefe K, Sullivan C, Rentz D, Marshall G, Dickerson B, Sperling R (2011) Hippocampal hyperactivation associated with cortical thinning in Alzheimer’s disease signature regions in non-demented elderly adults. J Neurosci 31(48):17680–17688. https://doi.org/10.1523/JNEUROSCI.4740-11.2011

    CrossRef  Google Scholar 

  • Raval NR, Johansen A, Donovan LL, Ros NF, Ozenne B, Hansen HD, Knudsen GM (2021) A single dose of psilocybin increases synaptic density and decreases 5-HT2A receptor density in the pig brain. Int J Mol Sci 22(2):835. https://doi.org/10.3390/ijms22020835

    CrossRef  Google Scholar 

  • Reiff CM, Richman EE, Nemeroff CB, Carpenter LL, Widge AS, Rodriguez CI, Kalin NH, McDonald WM (2020) Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatr 177(5):391–410. https://doi.org/10.1176/appi.ajp.2019.19010035

    CrossRef  Google Scholar 

  • Revenga MF, Zhu B, Guevara CA, Naler LB, Saunders JM, Zhou Z, Toneatti R, Sierra S, Wolstenholme JT, Beardsley PM, Huntley GW, Lu C, González-Maeso J (2021) Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice. BioRxiv 2021(02):24.432725. https://doi.org/10.1101/2021.02.24.432725

    CrossRef  Google Scholar 

  • Rice 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. https://doi.org/10.1016/j.ejrad.2017.07.014

    CrossRef  Google Scholar 

  • Rich JB, Rasmusson DX, Folstein MF, Carson KA, Kawas C, Brandt J (1995) Nonsteroidal anti-inflammatory drugs in Alzheimer’s disease. Neurology 45(1):51–55. https://doi.org/10.1212/WNL.45.1.51

    CrossRef  Google Scholar 

  • Richards WA, Rhead JC, DiLeo FB, Yensen R, Kurland AA (1977) The peak experience variable in DPT-assisted psychotherapy with cancer patients. J Psychedelic Drugs 9(1):1–10

    Google Scholar 

  • Romano AG, Quinn JL, Li L, Dave KD, Schindler EA, Aloyo VJ, Harvey JA (2010) Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit, Romano et al. Psychopharmacology 212(3):441–448. https://doi.org/10.1007/s00213-010-2004-7

    CrossRef  Google Scholar 

  • Roseman L, Nutt DJ, Carhart-Harris RL (2018) Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol 8:974

    Google Scholar 

  • Rosenberg PB, Martin BK, Frangakis C, Mintzer JE, Weintraub D, Porsteinsson AP, Schneider LS, Rabins PV, Munro CA, Meinert CL, Lyketsos CG, Drye LT (2010) Sertraline for the treatment of depression in Alzheimer disease. Am J Geriatr Psychiatry 18(2):136–145. https://doi.org/10.1097/JGP.0b013e3181c796eb

    CrossRef  Google Scholar 

  • Ross 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 (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(12):1165–1180. https://doi.org/10.1177/0269881116675512

    CrossRef  Google Scholar 

  • Ruthirakuhan M, Herrmann N, Vieira D, Gallagher D, Lanctôt KL (2019) The roles of apathy and depression in predicting Alzheimer disease: a longitudinal analysis in older adults with mild cognitive impairment. Am J Geriatr Psychiatry 27(8):873–882. https://doi.org/10.1016/j.jagp.2019.02.003

    CrossRef  Google Scholar 

  • Sala Frigerio C, De Strooper B (2016) Alzheimer’s disease mechanisms and emerging roads to novel therapeutics. Annu Rev Neurosci 39(1):57–79. https://doi.org/10.1146/annurev-neuro-070815-014015

    CrossRef  Google Scholar 

  • Sampedro F, de la Fuente Revenga M, Valle M, Roberto N, Domínguez-Clavé E, Elices M, Luna LE, Crippa JAS, Hallak JEC, de Araujo DB, Friedlander P, Barker SA, Álvarez E, Soler J, Pascual JC, Feilding A, Riba J (2017) Assessing the psychedelic “after-glow” in Ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities. Int J Neuropsychopharmacol 20(9):698–711. https://doi.org/10.1093/ijnp/pyx036

    CrossRef  Google Scholar 

  • Scarmeas N, Brandt J, Albert M, Hadjigeorgiou G, Papadimitriou A, Dubois B, Sarazin M, Devanand D, Honig L, Marder K, Bell K, Wegesin D, Blacker D, Stern Y (2005) Delusions and hallucinations are associated with worse outcome in Alzheimer disease. Arch Neurol 62(10). https://doi.org/10.1001/archneur.62.10.1601

  • Schindler EAD, Sewell RA, Gottschalk CH, Luddy C, Flynn LT, Lindsey H, Pittman BP, Cozzi NV, D’Souza DC (2021) Exploratory controlled study of the migraine-suppressing effects of psilocybin. Neurotherapeutics 18(1):534–543. https://doi.org/10.1007/s13311-020-00962-y

    CrossRef  Google Scholar 

  • Schmid Y, Liechti ME (2018) Long-lasting subjective effects of LSD in normal subjects. Psychopharmacology 235(2):535–545. https://doi.org/10.1007/s00213-017-4733-3

    CrossRef  Google Scholar 

  • Schott BH, Seidenbecher CI, Richter S, Wüstenberg T, Debska-Vielhaber G, Schubert H, Heinze H-J, Richardson-Klavehn A, Düzel E (2011) Genetic variation of the serotonin 2a receptor affects hippocampal novelty processing in humans. PLoS One 6(1):e15984. https://doi.org/10.1371/journal.pone.0015984

    CrossRef  Google Scholar 

  • Schwindt GC, Chaudhary S, Crane D, Ganda A, Masellis M, Grady CL, Stefanovic B, Black SE (2013) Modulation of the default-mode network between rest and task in Alzheimer’s disease. Cereb Cortex 23(7):1685–1694. https://doi.org/10.1093/cercor/bhs160

    CrossRef  Google Scholar 

  • Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298(5594):789–791. https://doi.org/10.1126/science.1074069

    CrossRef  Google Scholar 

  • Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011a) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1(1):a006189. https://doi.org/10.1101/cshperspect.a006189

    CrossRef  Google Scholar 

  • Serrano-Pozo A, Mielke ML, Gómez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT (2011b) Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 179(3):1373–1384. https://doi.org/10.1016/j.ajpath.2011.05.047

    CrossRef  Google Scholar 

  • Sestieri C, Corbetta M, Romani GL, Shulman GL (2011) Episodic memory retrieval, parietal cortex, and the default mode network: functional and topographic analyses. J Neurosci 31(12):4407–4420. https://doi.org/10.1523/JNEUROSCI.3335-10.2011

    CrossRef  Google Scholar 

  • Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM et al (2016) The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537(7618):50–56. https://doi.org/10.1038/nature19323

    CrossRef  Google Scholar 

  • Shao L-X, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, Kwan AC (2021) Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron. https://doi.org/10.1016/j.neuron.2021.06.008

  • Shin I-S, Carter M, Masterman D, Fairbanks L, Cummings JL (2005) Neuropsychiatric symptoms and quality of life in Alzheimer disease. Am J Geriatr Psychiatry 13(6):469–474. https://doi.org/10.1097/00019442-200506000-00005

    CrossRef  Google Scholar 

  • Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, Read S, Satyamurthy N, Petric A, Huang S-C, Barrio JR (2002) Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 10(1):24–35. https://doi.org/10.1097/00019442-200201000-00004

    CrossRef  Google Scholar 

  • Smigielski L, Kometer M, Scheidegger M, Krähenmann R, Huber T, Vollenweider FX (2019a) Characterization and prediction of acute and sustained response to psychedelic psilocybin in a mindfulness group retreat. Sci Rep 9(1):14914. https://doi.org/10.1038/s41598-019-50612-3

    CrossRef  Google Scholar 

  • Smigielski L, Scheidegger M, Kometer M, Vollenweider FX (2019b) Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. NeuroImage 196:207–215. https://doi.org/10.1016/j.neuroimage.2019.04.009

    CrossRef  Google Scholar 

  • Smith GS, Barrett FS, Joo JH, Nassery N, Savonenko A, Sodums DJ, Marano CM, Munro CA, Brandt J, Kraut MA, Zhou Y, Wong DF, Workman CI (2017) Molecular imaging of serotonin degeneration in mild cognitive impairment. Neurobiol Dis 105:33–41. https://doi.org/10.1016/j.nbd.2017.05.007

    CrossRef  Google Scholar 

  • Soto M, Andrieu S, Nourhashemi F, Ousset PJ, Ballard C, Robert P, Vellas B, Lyketsos CG, Rosenberg PB (2015) Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design. Int Psychogeriatr 27(2):181–197. https://doi.org/10.1017/S1041610214001720

    CrossRef  Google Scholar 

  • Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):280–292. https://doi.org/10.1016/j.jalz.2011.03.003

    CrossRef  Google Scholar 

  • Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, Breitner JCS, Steffens DC, Tschanz JT (2008) Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry 23(2):170–177. https://doi.org/10.1002/gps.1858

    CrossRef  Google Scholar 

  • Stewart WF, Kawas C, Corrada M, Metter EJ (1997) Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48(3):626–632. https://doi.org/10.1212/WNL.48.3.626

    CrossRef  Google Scholar 

  • Stopford CL, Snowden JS, Thompson JC, Neary D (2008) Variability in cognitive presentation of Alzheimer’s disease. Cortex 44(2):185–195. https://doi.org/10.1016/j.cortex.2005.11.002

    CrossRef  Google Scholar 

  • Swift TC, Belser AB, Agin-Liebes G, Devenot N, Terrana S, Friedman HL, Guss J, Bossis AP, Ross S (2017) Cancer at the dinner table: experiences of psilocybin-assisted psychotherapy for the treatment of cancer-related distress. J Humanist Psychol 57(5):488–519

    Google Scholar 

  • Szabo A, Kovacs A, Frecska E, Rajnavolgyi E (2014) Psychedelic N, N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PLoS One 9(8):e106533

    Google Scholar 

  • Sze C-I, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56(8):933–944. https://doi.org/10.1097/00005072-199708000-00011

    CrossRef  Google Scholar 

  • Tang L, Wang Y, Chen Y, Chen L, Zheng S, Bao M, Xiang J, Luo H, Li J, Li Y (2017) The association between 5HT2A T102C and behavioral and psychological symptoms of dementia in Alzheimer’s disease: a meta-analysis. Biomed Res Int 2017:e5320135. https://doi.org/10.1155/2017/5320135

    CrossRef  Google Scholar 

  • Tanila H (2017) The role of BDNF in Alzheimer’s disease. Neurobiol Dis 97:114–118. https://doi.org/10.1016/j.nbd.2016.05.008

    CrossRef  Google Scholar 

  • Tanzi RE (2012) The genetics of Alzheimer disease. Cold Spring Harb Perspect Med 2(10):a006296. https://doi.org/10.1101/cshperspect.a006296

    CrossRef  Google Scholar 

  • Tayeb HO, Yang HD, Price BH, Tarazi FI (2012) Pharmacotherapies for Alzheimer’s disease: beyond cholinesterase inhibitors. Pharmacol Ther 134(1):8–25. https://doi.org/10.1016/j.pharmthera.2011.12.002

    CrossRef  Google Scholar 

  • Theofilas P, Ehrenberg AJ, Dunlop S, Di Lorenzo Alho AT, Nguy A, Leite REP, Rodriguez RD, Mejia MB, Suemoto CK, Ferretti-Rebustini REDL, Polichiso L, Nascimento CF, Seeley WW, Nitrini R, Pasqualucci CA, Jacob Filho W, Rueb U, Neuhaus J, Heinsen H, Grinberg LT (2017) Locus coeruleus volume and cell population changes during Alzheimer’s disease progression: a stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement 13(3):236–246. https://doi.org/10.1016/j.jalz.2016.06.2362

    CrossRef  Google Scholar 

  • Tomasi D, Volkow ND (2012) Aging and functional brain networks. Mol Psychiatry 17(5):549–558. https://doi.org/10.1038/mp.2011.81

    CrossRef  Google Scholar 

  • Tramutola A, Lanzillotta C, Domenico FD (2017) Targeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies. Expert Rev Neurother 17(1):33–45. https://doi.org/10.1080/14737175.2017.1244482

    CrossRef  Google Scholar 

  • Tromp D, Dufour A, Lithfous S, Pebayle T, Després O (2015) Episodic memory in normal aging and Alzheimer disease: insights from imaging and behavioral studies. Ageing Res Rev 24:232–262. https://doi.org/10.1016/j.arr.2015.08.006

    CrossRef  Google Scholar 

  • Tsybko AS, Ilchibaeva TV, Filimonova EA, Eremin DV, Popova NK, Naumenko VS (2020) The chronic treatment with 5-HT2A receptor agonists affects the behavior and the BDNF system in mice. Neurochem Res 45(12):3059–3075. https://doi.org/10.1007/s11064-020-03153-5

    CrossRef  Google Scholar 

  • Vann Jones SA, O’Kelly A (2020) Psychedelics as a treatment for Alzheimer’s disease dementia. Front Synapt Neurosci 12. https://doi.org/10.3389/fnsyn.2020.00034

  • Versijpt J, Van Laere KJ, Dumont F, Decoo D, Vandecapelle M, Santens P, Goethals I, Audenaert K, Slegers G, Dierckx RA, Korf J (2003) Imaging of the 5-HT2A system: age-, gender-, and Alzheimer’s disease-related findings. Neurobiol Aging 24(4):553–561. https://doi.org/10.1016/S0197-4580(02)00137-9

    CrossRef  Google Scholar 

  • Wang W-Y, Tan M-S, Yu J-T, Tan L (2015) Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 3(10). https://doi.org/10.3978/j.issn.2305-5839.2015.03.49

  • Watts R, Day C, Krzanowski J, Nutt D, Carhart-Harris R (2017) Patients’ accounts of increased “connectedness” and “acceptance” after psilocybin for treatment-resistant depression. J Humanist Psychol 57(5):520–564. https://doi.org/10.1177/0022167817709585

    CrossRef  Google Scholar 

  • Weintraub S, Wicklund AH, Salmon DP (2012) The neuropsychological profile of Alzheimer disease. Cold Spring Harb Perspect Med 2(4):a006171. https://doi.org/10.1101/cshperspect.a006171

    CrossRef  Google Scholar 

  • Williams GV, Rao SG, Goldman-Rakic PS (2002) The physiological role of 5-HT2A receptors in working memory. J Neurosci 22(7):2843–2854. https://doi.org/10.1523/JNEUROSCI.22-07-02843.2002

    CrossRef  Google Scholar 

  • Wimo A, Ballard C, Brayne C, Gauthier S, Handels R, Jones RW, Jonsson L, Khachaturian AS, Kramberger M (2014) Health economic evaluation of treatments for Alzheimer′s disease: impact of new diagnostic criteria. J Intern Med 275(3):304–316. https://doi.org/10.1111/joim.12167

    CrossRef  Google Scholar 

  • Wittmann M, Carter O, Hasler F, Cahn BR, Grimberg U, Spring P, Hell D, Flohr H, Vollenweider FX (2007) Effects of psilocybin on time perception and temporal control of behaviour in humans. J Psychopharmacol 21(1):50–64. https://doi.org/10.1177/0269881106065859

    CrossRef  Google Scholar 

  • Yaden DB, Griffiths RR (2021) The subjective effects of psychedelics are necessary for their enduring therapeutic effects. ACS Pharmacol Transl Sci 4(2):568–572. https://doi.org/10.1021/acsptsci.0c00194

    CrossRef  Google Scholar 

  • Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD (2008) Serotonin 5-HT2A receptor activation suppresses TNF-α-induced inflammation with extraordinary potency. J Pharmacol Exp Ther. https://doi.org/10.1124/jpet.108.143461

  • Yuede CM, Wallace CE, Davis TA, Gardiner WD, Hettinger JC, Edwards HM, Hendrix RD, Doherty BM, Yuede KM, Burstein ES, Cirrito JR (2021) Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer’s disease. J Neurochem 156(5):658–673. https://doi.org/10.1111/jnc.15260

    CrossRef  Google Scholar 

  • Yuki D, Sugiura Y, Zaima N, Akatsu H, Takei S, Yao I, Maesako M, Kinoshita A, Yamamoto T, Kon R, Sugiyama K, Setou M (2014) DHA-PC and PSD-95 decrease after loss of synaptophysin and before neuronal loss in patients with Alzheimer’s disease. Sci Rep 4(1):7130. https://doi.org/10.1038/srep07130

    CrossRef  Google Scholar 

  • Zhang G, Stackman RW Jr (2015) The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol 6:225

    Google Scholar 

  • Zhang G, Ásgeirsdóttir HN, Cohen SJ, Munchow AH, Barrera MP, Stackman RW (2013) Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Neuropharmacology 64:403–413. https://doi.org/10.1016/j.neuropharm.2012.06.007

    CrossRef  Google Scholar 

  • Zhang G, Cinalli D, Cohen SJ, Knapp KD, Rios LM, Martínez-Hernández J, Luján R, Stackman RW (2016) Examination of the hippocampal contribution to serotonin 5-HT2A receptor-mediated facilitation of object memory in C57BL/6J mice. Neuropharmacology 109:332–340. https://doi.org/10.1016/j.neuropharm.2016.04.033

    CrossRef  Google Scholar 

  • Zhao Q-F, Tan L, Wang H-F, Jiang T, Tan M-S, Tan L, Xu W, Li J-Q, Wang J, Lai T-J, Yu J-T (2016) The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord 190:264–271. https://doi.org/10.1016/j.jad.2015.09.069

    CrossRef  Google Scholar 

  • Zhou J, Seeley WW (2014) Network dysfunction in Alzheimer’s disease and frontotemporal dementia: implications for psychiatry. Biol Psychiatry 75(7):565–573. https://doi.org/10.1016/j.biopsych.2014.01.020

    CrossRef  Google Scholar 

  • Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D (2010) Inflammation in Alzheimer’s disease: relevance to pathogenesis and therapy. Alzheimers Res Ther 2(1):1. https://doi.org/10.1186/alzrt24

    CrossRef  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Matthew W. Johnson, Ph.D., Roland R. Griffiths, Ph.D., Frederick S. Barrett, Ph.D., William A. Richards, Ph.D., Mary Cosimano, M.S.W., Annie Umbricht, M.D., and Natalie Gukasyan, M.D. for their support in this work.

Declaration of Interest

AGR serves as a scientific advisor to ETHA Natural Botanicals and NeonMind Biosciences.

Funding/Support

Funding for this research was provided by the Pineapple Fund, CSP Fund, Heffter Research Institute, and by Tim Ferriss, Matt Mullenweg, Blake Mycoskie, Craig Nerenberg, and the Steven and Alexandra Cohen Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Albert Garcia-Romeu .

Rights and permissions

Reprints and Permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Verify currency and authenticity via CrossMark

Cite this chapter

Garcia-Romeu, A., Darcy, S., Jackson, H., White, T., Rosenberg, P. (2021). Psychedelics as Novel Therapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms. In: Current Topics in Behavioral Neurosciences. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2021_267

Download citation

  • DOI: https://doi.org/10.1007/7854_2021_267

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg