Evidence suggests that serotonergic psychedelics (e.g. psilocybin), have rapid-acting and long-lasting antidepressant effects after a single dose. However, the mechanism underlying these effects remain unclear. One proposed mechanism is that these drugs promote neuroplasticity. However, this has not been conclusively demonstrated in humans.
Aims:
We hypothesized that relative to placebo, psilocybin would: (1) increase electroencephalographic (EEG) correlates of neuroplasticity, (2) reduce depression symptoms, and (3) changes in EEG would correlate with improvements in depression.
Methods:
In this double-blind, placebo-controlled, within-subject study, individuals with major depressive disorder (MDD; n = 19) were administered placebo followed by psilocybin (0.3 mg/kg) in a fixed order (placebo, followed by psilocybin 4 weeks later). EEG indices of neuroplasticity (tetanus-induced long-term potentiation) as assessed via auditory evoked theta (4–8 Hz) power and measures of depression (GRID Hamilton Rating Scale for Depression-17 (GRID-HAM-D-17)) were measured at several time-points after placebo and psilocybin (24 h and 2 weeks after each session).
Results:
EEG theta power doubled in amplitude 2 weeks after a single psychedelic dose of psilocybin but not after placebo. Further, improvements in depression symptoms 2 weeks after psilocybin were correlated with increases in theta power.
Conclusions:
The increased theta power observed represents evidence of sustained changes in the brain following psilocybin. Given the correlation with enhancement in depressive symptoms, changes in theta may represent an EEG biomarker of the sustained effects of psilocybin, and may shed light on potential mechanisms of psilocybin’s antidepressant effect. Taken together, these results complement the emerging notion that psilocybin, and perhaps other psychedelics, can produce long-term alterations in neuroplasticity.
BlissTVCollingridgeGL (1993) A synaptic model of memory: Long-term potentiation in the hippocampus. Nature361: 31–39.
2.
BockerKBHunaultCCGerritsenJ, et al. (2010) Cannabinoid modulations of resting state EEG theta power and working memory are correlated in humans. J Cogn Neurosci22: 1906–1916.
3.
BradshawAJBackmanTARamirez-CruzV, et al. (2022) DNA authentication and chemical analysis of Psilocybe mushrooms reveal widespread misdeterminations in Fungaria and inconsistencies in metabolites. Appl Environ Microbiol88: e0149822.
4.
BrownESWoolstonDJFrolA, et al. (2004) Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biol Psychiat55: 538–545.
5.
Carhart-HarrisRLBolstridgeMRuckerJ, et al. (2016) Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. Lancet Psychiat3: 619–627.
6.
Carhart-HarrisRLErritzoeDHaijenE, et al. (2017) Psychedelics and connectedness. Psychopharmacology235: 547–550.
7.
Carhart-HarrisRLFristonKJ (2019) REBUS and the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacol Rev71: 316–344.
8.
CavusIReinhartRMRoachBJ, et al. (2012) Impaired visual cortical plasticity in schizophrenia. Biol Psychiat71: 512–520.
9.
ClappWCHammJPKirkIJ, et al. (2012) Translating long-term potentiation from animals to humans: A novel method for noninvasive assessment of cortical plasticity. Biol Psychiat71: 496–502.
10.
DavisAKBarrettFSGriffithsRR (2019) Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety. J Context Behav Sci15: 39–45.
11.
De GregorioDEnnsJPNunezNA, et al. (2018) D-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders. Prog Brain Res242: 69–96.
12.
DoddSNormanTREyreHA, et al. (2022) Psilocybin in neuropsychiatry: A review of its pharmacology, safety, and efficacy. CNS Spectr: 1–11. doi:10.1017/S1092852922000888.
13.
Garcia-RomeuAGriffithsRW JohnsonM (2014) Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Curr Drug Abuse Rev7: 157–164.
14.
GotvaldovaKBorovickaJHajkovaK, et al. (2022) Extensive collection of psychotropic mushrooms with determination of their tryptamine alkaloids. Int J Mol Sci23.
15.
GrattonGColesMGDonchinE (1983) A new method for off-line removal of ocular artifact. Electroencephalogr Clin Neurophysiol55: 468–484.
16.
GriffithsRRJohnsonMWCarducciMA, 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 Psychopharmacol30: 1181–1197.
17.
GriffithsRRJohnsonMWRichardsWA, et al. (2011) Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects. Psychopharmacology218: 649–665.
18.
GriffithsRRRichardsWAMcCannU, et al. (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology187: 268–283.
19.
GrobCSDanforthALChopraGS, et al. (2011) Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiat68: 71–78.
20.
GussJKrauseRSloshowerJ (2020) The Yale manual for psilocybin-assisted therapy of depression (using acceptance and commitment therapy as a therapeutic frame). doi:10.31234/osf.io/u6v9y.
21.
HesselgraveNTroppoliTAWulffAB, et al. (2021) Harnessing psilocybin: Antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci USA118. doi:10.1073/pnas.2022489118.
22.
HolmesSEScheinostDFinnemaSJ, et al. (2019) Lower synaptic density is associated with depression severity and network alterations. Nat Commun10: 1–10.
23.
HuangSRozasCTrevinoM, et al. (2014) Associative Hebbian synaptic plasticity in primate visual cortex. J Neurosci34: 7575–7579.
24.
JohannesenJSkosnikPD (2017) Applied EEG. In: SadockBJSadockVARuizP (eds.) Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Philadelphia, PA: Lippincott Williams & Wilkins, A Wolters Kluwer business.
25.
LeiGZhaoZLiY, et al. (2017) A method to induce human cortical long-term potentiation by acoustic stimulation. Acta Otolaryngol137: 1069–1076.
26.
LukasiewiczKBakerJJZuoY, et al. (2021) Serotonergic psychedelics in neural plasticity. Front Mol Neurosci14: 748359.
27.
LuscherCMalenkaRC (2012) NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol4.
28.
LyCGrebACCameronLP, et al. (2018) Psychedelics promote structural and functional neural plasticity. Cell Rep23: 3170–3182.
29.
LyCGrebACVargasMV, et al. (2021) Transient stimulation with psychoplastogens is sufficient to initiate neuronal growth. ACS Pharmacol Transl Sci4: 452–460.
30.
LynchMA (2004) Long-term potentiation and memory. Physiol Rev84: 87–136.
31.
Machado-VieiraRSalvadoreGDiazGranadosN, et al. (2009) Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol Therapeut123: 143–150.
32.
MacLeanKAJohnsonMWGriffithsRR (2011) Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol25: 1453–1461.
33.
MaesMYirmyiaRNorabergJ, et al. (2009) The inflammatory & neurodegenerative (I&ND) hypothesis of depression: Leads for future research and new drug developments in depression. Metabol Brain Dis24: 27–53.
MarazzitiDConsoliGPicchettiM, et al. (2010) Cognitive impairment in major depression. Eur J Pharmacol626: 83–86.
36.
MarsdenW (2013) Synaptic plasticity in depression: Molecular, cellular and functional correlates. Prog Neuro-Psychopharmacol Biol Psychiat43: 168–184.
37.
McLoughlinGGyurkovicsMPalmerJ, et al. (2022) Midfrontal theta activity in psychiatric illness: An index of cognitive vulnerabilities across disorders. Biol Psychiat91: 173–182.
38.
NunezABunoW (2021) The theta rhythm of the hippocampus: From neuronal and circuit mechanisms to behavior. Front Cell Neurosci15: 649262.
39.
RavalNRJohansenADonovanLL, et al. (2021) A single dose of psilocybin increases synaptic density and decreases 5-HT2A receptor density in the pig brain. Int J Mol Sci22. doi:10.3390/ijms22020835
40.
RosemanLHaijenEIdialu-IkatoK, et al. (2019) Emotional breakthrough and psychedelics: Validation of the emotional breakthrough inventory. J Psychopharmacol33: 1076–1087.
41.
RossSBossisAGussJ, 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 Psychopharmacol30: 1165–1180.
42.
SandersPJThompsonBCorballisPM, et al. (2018) A review of plasticity induced by auditory and visual tetanic stimulation in humans. Eur J Neurosci48: 2084–2097.
43.
SandiCBisazR (2007) A model for the involvement of neural cell adhesion molecules in stress-related mood disorders. Neuroendocrinology85: 158–176.
44.
ShaoLXLiaoCGreggI, et al. (2021) Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron109: 2535–2544.
SkosnikPDCortes-BrionesJAHajosM (2016) It’s all in the rhythm: The role of cannabinoids in neural oscillations and psychosis. Biol Psychiat79: 568–577.
47.
SkosnikPDHajosMCortes-BrionesJA, et al. (2018) Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans. Neuropharmacology135: 412–423.
48.
SloshowerJGussJKrauseR, et al. (2019) Psilocybin-assisted therapy of major depressive disorder using acceptance and commitment therapy as a therapeutic frame. J Context Behav Sci15: 12–19.
49.
SumnerRLMcMillanRSpriggsMJ, et al. (2020) Ketamine enhances visual sensory evoked potential long-term potentiation in patients with major depressive disorder. Biol Psychiatry Cogn Neurosci Neuroimag5: 45–55.
50.
TurrigianoG (2012) Homeostatic synaptic plasticity: Local and global mechanisms for stabilizing neuronal function. Cold Spring Harbor Perspect Biol4: a005736.
51.
WangXJ (2010) Neurophysiological and computational principles of cortical rhythms in cognition. Physiol Rev90: 1195–1268.
52.
WeissmanCRDaskalakisZJ (2022) Accelerated intermittent theta burst stimulation: Expediting and enhancing treatment outcomes in treatment-resistant depression. Am J Psychiat179: 85–87.
53.
WilliamsJBKobakKABechP, et al. (2008) The GRID-HAMD: Standardization of the Hamilton depression rating scale. Int Clin Psychopharmacol23: 120–129.
54.
ZaehleTClappWCHammJP, et al. (2007) Induction of LTP-like changes in human auditory cortex by rapid auditory stimulation: An FMRI study. Restor Neurol Neurosci25: 251–259.
55.
ZeifmanRJWagnerACWattsR, et al. (2020) Post-psychedelic reductions in experiential avoidance are associated with decreases in depression severity and suicidal ideation. Front Psychiat11: 782.
56.
ZhengCZhangT (2015) Synaptic plasticity-related neural oscillations on hippocampus-prefrontal cortex pathway in depression. Neuroscience292: 170–180.
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