Skip to main content

The paradoxical psychological effects of lysergic acid diethylamide (LSD)

  • R. L. Carhart-Harris (a1), M. Kaelen (a1), M. Bolstridge (a1), T. M. Williams (a2), L. T. Williams (a1), R. Underwood (a3), A. Feilding (a4) and D. J. Nutt (a1)...

Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or psychedelic that modulates consciousness in a marked and novel way. This study sought to examine the acute and mid-term psychological effects of LSD in a controlled study.


A total of 20 healthy volunteers participated in this within-subjects study. Participants received LSD (75 µg, intravenously) on one occasion and placebo (saline, intravenously) on another, in a balanced order, with at least 2 weeks separating sessions. Acute subjective effects were measured using the Altered States of Consciousness questionnaire and the Psychotomimetic States Inventory (PSI). A measure of optimism (the Revised Life Orientation Test), the Revised NEO Personality Inventory, and the Peter's Delusions Inventory were issued at baseline and 2 weeks after each session.


LSD produced robust psychological effects; including heightened mood but also high scores on the PSI, an index of psychosis-like symptoms. Increased optimism and trait openness were observed 2 weeks after LSD (and not placebo) and there were no changes in delusional thinking.


The present findings reinforce the view that psychedelics elicit psychosis-like symptoms acutely yet improve psychological wellbeing in the mid to long term. It is proposed that acute alterations in mood are secondary to a more fundamental modulation in the quality of cognition, and that increased cognitive flexibility subsequent to serotonin 2A receptor (5-HT2AR) stimulation promotes emotional lability during intoxication and leaves a residue of ‘loosened cognition’ in the mid to long term that is conducive to improved psychological wellbeing.

Corresponding author
* Address for correspondence: R. L. Carhart-Harris, Imperial College London, Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine, London, UK. (Email:
Hide All
Beck, AT, Ward, CH, Mendelson, M, Mock, J, Erbaugh, J (1961). An inventory for measuring depression. Archives of General Psychiatry 4, 561571.
Bhagwagar, Z, Hinz, R, Taylor, M, Fancy, S, Cowen, P, Grasby, P (2006). Increased 5-HT2A receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [11C]MDL 100,907. American Journal of Psychiatry 163, 15801587.
Bogenschutz, MP, Forcehimes, AA, Pommy, JA, Wilcox, CE, Barbosa, P, Strassman, RJ (2015). Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. Journal of Psychopharmacology 29, 289299.
Boulougouris, V, Glennon, JC, Robbins, TW (2008). Dissociable effects of selective 5-HT2A and 5-HT2C receptor antagonists on serial spatial reversal learning in rats. Neuropsychopharmacology 33, 20072019.
Bouso, JC, González, D, Fondevila, S, Cutchet, M, Fernández, X, Ribeiro Barbosa, PC, Alcázar-Córcoles, , Araújo, WS, Barbanoj, MJ, Fábregas, JM, Riba, J (2012). Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of Ayahuasca: a longitudinal study. PLOS ONE 7, e42421.
Bouso, JC, Palhano-Fontes, F, Rodríguez-Fornells, A, Ribeiro, S, Sanches, R, Crippa, JA, Hallak, JE, De Araujo, DB, Riba, J (2015). Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans. European Neuropsychopharmacology 25, 483492.
Branchi, I (2011). The double edged sword of neural plasticity: increasing serotonin levels leads to both greater vulnerability to depression and improved capacity to recover. Psychoneuroendocrinology 36, 339351.
Carhart-Harris, R, Brugger, S, Nutt, D, Stone, J (2013). Psychiatry's next top model: cause for a re-think on drug models of psychosis and other psychiatric disorders. Journal of Psychopharmacology 27, 771778.
Carhart-Harris, R, Kaelen, M, Whalley, M, Bolstridge, M, Feilding, A, Nutt, D (2014 a). LSD enhances suggestibility in healthy volunteers. Psychopharmacology (Berlin) 232, 785794.
Carhart-Harris, RL, Erritzoe, D, Williams, T, Stone, JM, Reed, LJ, Colasanti, A, Tyacke, RJ, Leech, R, Malizia, AL, Murphy, K, Hobden, P, Evans, J, Feilding, A, Wise, RG, Nutt, DJ (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences USA 109, 21382143.
Carhart-Harris, RL, Leech, R, Hellyer, PJ, Shanahan, M, Feilding, A, Tagliazucchi, E, Chialvo, DR, Nutt, D (2014 b). The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Frontiers in Human Neuroscience 8, 20.
Carter, OL, Hasler, F, Pettigrew, JD, Wallis, GM, Liu, GB, Vollenweider, FX (2007). Psilocybin links binocular rivalry switch rate to attention and subjective arousal levels in humans. Psychopharmacology (Berlin) 195, 415424.
Carver, CS, Scheier, MF (2014). Dispositional optimism. Trends in Cognitive Science 18, 293299.
Cohen, S, Ditman, KS (1962). Complications associated with lysergic acid diethylamide (LSD-25). JAMA 181, 161162.
Costa, PT Jr., McCrae, RR (1995). Domains and facets: hierarchical personality assessment using the Revised NEO Personality Inventory. Journal of Personality Assessment 64, 2150.
Dolder, PC, Schmid, Y, Haschke, M, Rentsch, KM, Liechti, ME (2015). Pharmacokinetics and concentration–effect relationship of oral LSD in humans. International Journal of Neuropsychopharmacology. Published online 24 June 2015. doi:10.1093/ijnp/pyv072.
Floyd, M, Scogin, F, Chaplin, WF (2004). The Dysfunctional Attitudes Scale: factor structure, reliability, and validity with older adults. Aging and Mental Health 8, 153160.
Frecska, E, More, CE, Vargha, A, Luna, LE (2012). Enhancement of creative expression and entoptic phenomena as after-effects of repeated ayahuasca ceremonies. Journal of Psychoactive Drugs 44, 191199.
Frokjaer, VG, Mortensen, EL, Nielsen, FA, Haugbol, S, Pinborg, LH, Adams, KH, Svarer, C, Hasselbalch, SG, Holm, S, Paulson, OB, Knudsen, GM (2008). Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder. Biological Psychiatry 63, 569576.
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. Journal of Nervous and Mental Diseases 202, 513520.
Glaesmer, H, Rief, W, Martin, A, Mewes, R, Brahler, E, Zenger, M, Hinz, A (2012). Psychometric properties and population-based norms of the Life Orientation Test Revised (LOT-R). British Journal of Health Psychology 17, 432445.
Glennon, RA, Titeler, M, Mckenney, JD (1984). Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences 35, 25052511.
Gouzoulis-Mayfrank, E, Heekeren, K, Neukirch, A, Stoll, M, Stock, C, Obradovic, M, Kovar, KA (2005). Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry 38, 301311.
Griffiths, R, Richards, W, Johnson, M, McCann, U, Jesse, R (2008). Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. Journal of Psychopharmacology 22, 621632.
Griffiths, RR, Richards, WA, McCann, U, Jesse, R (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berlin) 187, 268283, discussion 284–292.
Grinspoon, L, Bakalar, JB (1979). Psychedelic Drugs Reconsidered. Basic Books: New York.
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. Archives of General Psychiatry 68, 7178.
Harvey, JA (2003). Role of the serotonin 5-HT2A receptor in learning. Learning and Memory 10, 355362.
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 (Berlin) 172, 435442.
Hendricks, PS, Thorne, CB, Clark, CB, Coombs, DW, Johnson, MW (2015). Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population. Journal of Psychopharmacology 29, 280288.
Hintzen, A, Passie, T (2010). The Pharmacology of LSD: A Critical Review. Oxford University Press: Oxford.
Hirt, ER, Devers, EE, Mccrea, SM (2008). I want to be creative: exploring the role of hedonic contingency theory in the positive mood–cognitive flexibility link. Journal of Personality and Social Psychology 94, 214230.
Hodgues, WF, Spielberger, CD (1969). An indicant of trait or state anxiety? Journal of Consultancy and Clinical Psychology 33, 430434.
Hofmann, A (1980). LSD: My Problem Child. McGraw-Hill: New York.
Johnson, M, Richards, W, Griffiths, R (2008). Human hallucinogen research: guidelines for safety. Journal of Psychopharmacology 22, 603620.
Johnson, MW, Garcia-Romeu, A, Cosimano, MP, Griffiths, RR (2014). Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. Journal of Psychopharmacology 28, 983992.
Kaelen, M, Barrett, FS, Roseman, L, Lorenz, R, Family, N, Bolstridge, M, Curran, HV, Feilding, A, Nutt, DJ, Carhart-Harris, RL (2015). LSD enhances the emotional response to music. Psychopharmacology (Berlin) 232, 36073614.
Kaiser, S, Heekeren, K, Simon, JJ (2011). The negative symptoms of schizophrenia: category or continuum? Psychopathology 44, 345353.
King, AR, Martin, IL, Seymour, KA (1972). Reversal learning facilitated by a single injection of lysergic acid diethylamide (LSD 25) in the rat. British Journal of Pharmacology 45, 161P162P.
Kometer, M, Schmidt, A, Bachmann, R, Studerus, E, Seifritz, E, Vollenweider, FX (2012). Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biological Psychiatry 72, 898906.
Krebs, TS, Johansen, PO (2013). Psychedelics and mental health: a population study. PLOS ONE 8, e63972.
Krystal, JH, Karper, LP, Seibyl, JP, Freeman, GK, Delaney, R, Bremner, JD, Heninger, GR, Bowers, MB Jr., Charney, DS (1994). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of General Psychiatry 51, 199214.
Lin, WL, Tsai, PH, Lin, HY, Chen, HC (2014). How does emotion influence different creative performances? The mediating role of cognitive flexibility. Cognition and Emotion 28, 834844.
Lebedev, AV, Lovden, M, Rosenthal, G, Feilding, A, Nutt, DJ, Carhart-Harris, RL (2015). Finding the self by losing the self: neural correlates of ego-dissolution under psilocybin. Human Brain Mapping 36, 31373153.
Maclean, KA, Johnson, MW, Griffiths, RR (2011). Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. Journal of Psychopharmacology 25, 14531461.
Mason, O, Morgan, CJ, Dhiman, SK, Patel, A, Parti, N, Curran, HV (2009). Acute cannabis use causes increased psychotomimetic experiences in individuals prone to psychosis. Psychological Medicine 39, 951956.
Mason, O, Wakerley, D (2012). The psychotomimetic nature of dreams: an experimental study. Schizophrenia Research Treatment 2012, 872307.
Mason, OJ, Morgan, CJ, Stefanovic, A, Curran, HV (2008). The Psychotomimetic States Inventory (PSI): measuring psychotic-type experiences from ketamine and cannabis. Schizophrenia Research 103, 138142.
Meyer, JH, McMain, S, Kennedy, SH, Korman, L, Brown, GM, Dasilva, JN, Wilson, AA, Blak, T, Eynan-Harvey, R, Goulding, VS, Houle, S, Links, P (2003). Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. American Journal of Psychiatry 160, 9099.
Moreno, FA, Wiegand, CB, Taitano, EK, Delgado, PL (2006). Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive–compulsive disorder. Journal of Clinical Psychiatry 67, 17351740.
Morrison, PD, Zois, V, Mckeown, DA, Lee, TD, Holt, DW, Powell, JF, Kapur, S, Murray, RM (2009). The acute effects of synthetic intravenous Δ9-tetrahydrocannabinol on psychosis, mood and cognitive functioning. Psychological Medicine 39, 16071616.
Muthukumaraswamy, SD, Carhart-Harris, RL, Moran, RJ, Brookes, MJ, Williams, TM, Errtizoe, D, Sessa, B, Papadopoulos, A, Bolstridge, M, Singh, KD, Feilding, A, Friston, KJ, Nutt, DJ (2013). Broadband cortical desynchronization underlies the human psychedelic state. Journal of Neuroscience 33, 1517115183.
Osmond, H, Smythies, J (1952). Schizophrenia: a new approach. Journal of Mental Science 98, 309315.
Ott, U, Reuter, M, Hennig, J, Vaitl, D (2005). Evidence for a common biological basis of the absorption trait, hallucinogen effects, and positive symptoms: epistasis between 5-HT2a and COMT polymorphisms. American Journal of Medical Genetics. Part B, Biological Neuropsychiatric Genetics 137B, 2932.
Peters, ER, Joseph, SA, Garety, PA (1999). Measurement of delusional ideation in the normal population: introducing the PDI (Peters et al. Delusions Inventory). Schizophrenia Bulletin 25, 553576.
Petri, G, Expert, P, Turkheimer, F, Carhart-Harris, R, Nutt, D, Hellyer, PJ, Vaccarino, F (2014). Homological scaffolds of brain functional networks. Journal of the Royal Society Interface 11, 20140873.
Petrovsky, N, Ettinger, U, Hill, A, Frenzel, L, Meyhofer, I, Wagner, M, Backhaus, J, Kumari, V (2014). Sleep deprivation disrupts prepulse inhibition and induces psychosis-like symptoms in healthy humans. Journal of Neuroscience 34, 91349140.
Reich, P, Hepps, RB (1972). Homicide during a psychosis induced by LSD. JAMA 219, 869871.
Roelofs, J, Muris, P, Huibers, M, Peeters, F, Arntz, A (2006). On the measurement of rumination: a psychometric evaluation of the ruminative response scale and the rumination on sadness scale in undergraduates. Journal of Behavior Therapy and Experimental Psychiatry 37, 299313.
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 (Berlin) 212, 441448.
Roseman, L, Leech, R, Nutt, DJ, Feilding, A, Carhart-Harris, RL (2014). The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers. Frontiers in Human Neuroscience 8, 204.
Rush, AJ, Trivedi, MH, Ibrahim, HM, Carmody, TJ, Arnow, B, Klein, DN, Markowitz, JC, Ninan, PT, Kornstein, S, Manber, R, Thase, ME, Kocsis, JH, Keller, MB (2003). The 16-item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biological Psychiatry 54, 573583.
Scheier, MF, Carver, CS, Bridges, MW (1994). Distinguishing optimism from neuroticism (and trait anxiety, self-mastery, and self-esteem): a reevaluation of the Life Orientation Test. Journal of Personality and Social Psychology 67, 10631078.
Schmid, Y, Enzler, F, Gasser, P, Grouzmann, E, Preller, KH, Vollenweider, FX, Brenneisen, R, Muller, F, Borgwardt, S, Liechti, ME (2014). Acute effects of lysergic acid diethylamide in healthy subjects. Biological Psychiatry 78, 544553.
Stokes, PR, Mehta, MA, Curran, HV, Breen, G, Grasby, PM (2009). Can recreational doses of THC produce significant dopamine release in the human striatum? NeuroImage 48, 186190.
Studerus, E, Gamma, A, Vollenweider, FX (2010). Psychometric evaluation of the altered states of consciousness rating scale (OAV). PLoS ONE 5, e12412.
Studerus, E, Kometer, M, Hasler, F, Vollenweider, FX (2011). Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. Journal of Psychopharmacology 25, 14341452.
Tagliazucchi, E, Carhart-Harris, R, Leech, R, Nutt, D, Chialvo, DR (2014). Enhanced repertoire of brain dynamical states during the psychedelic experience. Human Brain Mapping 35, 54425456.
Tellegen, A, Atkinson, G (1974). Openness to absorbing and self-altering experiences (“absorption”), a trait related to hypnotic susceptibility. Journal of Abnormal Psychology 83, 268277.
Turecki, G, Briere, R, Dewar, K, Antonetti, T, Lesage, AD, Seguin, M, Chawky, N, Vanier, C, Alda, M, Joober, R, Benkelfat, C, Rouleau, GA (1999). Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. American Journal of Psychiatry 156, 14561458.
Umbricht, D, Vollenweider, FX, Schmid, L, Grubel, C, Skrabo, A, Huber, T, Koller, R (2003). Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia. Neuropsychopharmacology 28, 170181.
Van Wel, JH, Kuypers, KP, Theunissen, EL, Bosker, WM, Bakker, K, Ramaekers, JG (2012). Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors. PLOS ONE 7, e40187.
Vollenweider, FX, Csomor, PA, Knappe, B, Geyer, MA, Quednow, BB (2007). The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval. Neuropsychopharmacology 32, 18761887.
Vollenweider, FX, Vollenweider-Scherpenhuyzen, MF, Babler, A, Vogel, H, Hell, D (1998). Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9, 38973902.
Weisstaub, NV, Zhou, M, Lira, A, Lambe, E, Gonzalez-Maeso, J, Hornung, JP, Sibille, E, Underwood, M, Itohara, S, Dauer, WT, Ansorge, MS, Morelli, E, Mann, JJ, Toth, M, Aghajanian, G, Sealfon, SC, Hen, R, Gingrich, JA (2006). Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313, 536540.
Williams, GV, Rao, SG, Goldman-Rakic, PS (2002). The physiological role of 5-HT2A receptors in working memory. Journal of Neuroscience 22, 28432854.
Zarate, CA Jr., Singh, JB, Carlson, PJ, Brutsche, NE, Ameli, R, Luckenbaugh, DA, Charney, DS, Manji, HK (2006). A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry 63, 856864.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 394
Total number of PDF views: 1423 *
Loading metrics...

Abstract views

Total abstract views: 14087 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 22nd May 2018. This data will be updated every 24 hours.