Restricted accessResearch articleFirst published online 2023-12
Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers
N-methyl-D-aspartate receptor-mediated dissociatives and serotonergic hallucinogens are being increasingly used in therapeutic interventions that involve nonordinary states of consciousness and may represent a unique mental health paradigm wherein pharmacologically induced experiences are conducive to psychological well-being.
Objective:
The aim of this study was to further understand how the phenomenological and health-promoting effects of high-dose dextromethorphan (DXM) compared to psilocybin in the same participants when administered under experimental conditions that are typical of therapeutic psychedelic trials.
Methods:
Single, acute oral doses of DXM (400 mg/70 kg), psilocybin (10, 20, 30 mg/70 kg), and inactive placebo were administered under double-blind and psychologically supportive conditions to 20 healthy participants with histories of hallucinogen use. Ratings of personal meaning, spiritual significance, psychological challenge, and psychological insight attributed to acute drug experiences were assessed 7 h (at session end) and 1 week after each drug administration. Persisting psychological effects were assessed 1 week after each drug administration.
Results:
High-dose DXM and psilocybin produced similar increases over placebo in ratings of drug experience that was predictive of psychological benefit at 1 week, even when expectancy effects were minimized. These effects tended to favor psilocybin in a dose-dependent manner and were limited by poor physical tolerability for DXM.
Conclusions:
This analysis suggests the utility of exploring clinical applications of dissociatives that occur within the supportive contexts that are characteristic of psychedelic research and that prioritize the optimization of psychologically valuable drug experiences. This study was registered with ClinicalTrials.gov (NCT02033707).
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References
1.
SchenbergEE. Psychedelic-assisted psychotherapy: A paradigm shift in psychiatric research and development. Front Pharmacol, 2018; 9:733.
2.
VollenweiderFX, KometerM. The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders. Nat Rev Neurosci, 2010; 11(9):642–651.
3.
AleksandrovaLR, PhillipsAG. Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends Pharmacol Sci, 2021; 42(11):929–942.
4.
JohnstonJN, KadriuB, AllenJ, et al.Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment. Neuropharmacology, 2023; 226:109422.
5.
StuderusE, GammaA, VollenweiderFX. Psychometric evaluation of the altered states of consciousness rating scale (OAV). PLoS One, 2010; 5(8):e12412.
6.
CarbonaroTM, JohnsonMW, HurwitzE, et al.Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: Similarities and differences in subjective experiences. Psychopharmacology (Berl), 2018; 235(2):521–534.
7.
HaseA, ErdmannM, LimbachV, et al.Analysis of recreational psychedelic substance use experiences classified by substance. Psychopharmacology, 2022; 239(2):643–659.
8.
LepowL, MorishitaH, YehudaR. Critical period plasticity as a framework for psychedelic-assisted psychotherapy. Front Neurosci, 2021; 15:1–8.
9.
MathaiDS, MoraV, Garcia-RomeuA. Toward synergies of ketamine and psychotherapy. Front Psychol, 2022; 13:868103.
10.
RosemanL, NuttDJ, Carhart-HarrisRL. Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol, 2017; 8:974.
11.
RosemanL, HaijenE, Idialu-IkatoK, et al.Emotional breakthrough and psychedelics: Validation of the Emotional Breakthrough Inventory. J Psychopharmacol, 2019; 33(9):1076–1087.
12.
NayakS, JohnsonMW. Psychedelics and psychotherapy. Pharmacopsychiatry, 2021; 54(4):167–175.
13.
Gouzoulis-MayfrankE, HeekerenK, NeukirchA, et al.Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): A double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry, 2005; 38(6):301–311.
14.
SchmidtA, KometerM, BachmannR, et al.The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions. Psychopharmacology (Berl), 2013; 225(1):227–239.
15.
van SchalkwykGI, WilkinsonST, DavidsonL, et al.Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: Analysis of the Clinician Administered Dissociative State Scale. J Affect Disord, 2018; 227:11–16.
16.
MathaiDS, MeyerMJ, StorchEA, et al.The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review. J Affect Disord, 2020; 264:123–129.
17.
MathaiDS, NayakSM, YadenDB, et al.Reconsidering “dissociation” as a predictor of antidepressant efficacy for esketamine. Psychopharmacology (Berl), 2023; 240:827–836.
18.
GriffithsRR, RichardsWA, McCannU, et al.Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 2006; 187(3):268–283.
19.
GriffithsRR, JohnsonMW, RichardsWA, et al.Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects. Psychopharmacology (Berl), 2011; 218(4):649–665.
20.
MillièreR. Looking for the self: Phenomenology, neurophysiology and philosophical significance of drug-induced ego dissolution. Front Hum Neurosci, 2017; 11:1–22.
21.
HartogsohnI. The meaning-enhancing properties of psychedelics and their mediator role in psychedelic therapy, spirituality, and creativity. Front Neurosci, 2018; 12:1–5.
22.
FischmanLG. Seeing without self: Discovering new meaning with psychedelic-assisted psychotherapy. Neuropsychoanalysis, 2019; 21(2):53–78.
23.
AmadaN, LeaT, LethebyC, et al.Psychedelic experience and the narrative self: An exploratory qualitative study. J Conscious Stud, 2020; 27(9–10):6–33.
24.
GashiL, SandbergS, PedersenW. Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences. Int J Drug Policy, 2021; 87:102997.
25.
SumnerR, ChackoE, McMilanR, et al.A qualitative and quantitative account of patient's experiences of ketamine and its antidepressant properties. J Psychopharmacol, 2021; 35(8):946–961.
26.
MollaahmetogluO, KeelerJ, AshbullbyK, et al.“This Is Something That Changed My Life”: A qualitative study of patients' experiences in a clinical trial of ketamine treatment for alcohol use disorders. Front Psychiatry, 2021; 12:1–17.
27.
BreeksemaJJ, NiemeijerA, KuinB, et al.Holding on or letting go? Patient experiences of control, context, and care in oral esketamine treatment for treatment-resistant depression: A qualitative study. Front Psychiatry, 2022; 13:948115.
28.
BreeksemaJJ, NiemeijerA, KuinB, et al.Phenomenology and therapeutic potential of patient experiences during oral esketamine treatment for treatment-resistant depression: An interpretative phenomenological study. Psychopharmacology (Berl), 2023; 240(7):1547–1560.
29.
MarguilhoM, FigueiredoI, Castro-RodriguesP. A unified model of ketamine's dissociative and psychedelic properties. J Psychopharmacol, 2023; 37(1):14–32.
30.
CarbonaroTM, JohnsonMW, GriffithsRR. Subjective features of the psilocybin experience that may account for its self-administration by humans: A double-blind comparison of psilocybin and dextromethorphan. Psychopharmacology, 2020; 237(8):2293–2304.
31.
BarrettFS, CarbonaroTM, HurwitzE, et al.Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: Effects on cognition. Psychopharmacology (Berl), 2018; 235(10):2915–2927.
32.
JohnsonM, RichardsW, GriffithsR. Human hallucinogen research: Guidelines for safety. J Psychopharmacol, 2008; 22(6):603–620.
33.
DittrichA. The standardized psychometric assessment of altered states of consciousness (ASCs) in humans. Pharmacopsychiatry 1998;31 Suppl, 2:80–84.
34.
BraunV, ClarkeV. Using thematic analysis in psychology. Qual Res Psychol, 2006; 3(2):77–101.
35.
CohenJ. A coefficient of agreement for nominal scales. Educ Psychol Meas, 1960; 20(1):37–46.
36.
De VriesH, ElliottMN, KanouseDE, et al.Using pooled kappa to summarize interrater agreement across many items. Field Methods, 2008; 20:272–282.
37.
KirchW, (ed). Pearson's Correlation Coefficient. In: Encyclopedia of Public Health. Springer. Netherlands: Dordrecht; 2008; pp. 1090–1091.
38.
PearsonES, D'AgostinoRB, BowmanKO. Tests for departure from normality: Comparison of powers. Biometrika, 1977; 64(2):231–246.
39.
McHughML. Interrater reliability: The kappa statistic. Biochem Med (Zagreb), 2012; 22(3):276–282.
40.
van ElkM, YadenDB. Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review. Neurosci Biobehav Rev, 2022; 140:104793.
41.
IosifescuDV, JonesA, O'GormanC, et al.Efficacy and safety of AXS-05 (Dextromethorphan-Bupropion) in patients with major depressive disorder: A Phase 3 Randomized Clinical Trial (GEMINI). J Clin Psychiatry, 2022; 83(4):41226.
42.
BennettR, YavorskyC, BravoG. Ketamine for bipolar depression: Biochemical, psychotherapeutic, and psychedelic approaches. Front Psychiatry, 2022; 13:1–9.
43.
ReissigCJ, CarterLP, JohnsonMW, et al.High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens. Psychopharmacology (Berl), 2012; 223(1):1–15.
44.
Consumer Healthcare Products Association. Dextromethorphan: Briefing Book for the Meeting of the FDA Drug Safety and Risk Management Committee [Internet]; 2010. Available from: https://www.chpa.org/sites/default/files/media/docs/2020-10/Briefing-book-Dextromethorphan-09142010.pdf [Last accessed: May31, 2023].
45.
SilvaAR, Dinis-OliveiraRJ. Pharmacokinetics and pharmacodynamics of dextromethorphan: Clinical and forensic aspects. Drug Metab Rev, 2020; 52(2):258–282.
46.
MorrisH, WallachJ. From PCP to MXE: A comprehensive review of the non-medical use of dissociative drugs. Drug Test Anal, 2014; 6(7–8):614–632.
ButlerLD. Normative dissociation. Psychiatr Clin North Am, 2006;29(1):45–62, viii.
49.
DellPF, O'NeilJA. Dissociation and the Dissociative Disorders: DSM-V and Beyond. Routledge: New York, NY; 2010; p. 899.
50.
SeligmanR, KirmayerLJ. Dissociative experience and cultural neuroscience: Narrative, metaphor and mechanism. Cult Med Psychiatry, 2008; 32(1):31–64.
51.
McIntyreRS, RosenblatJD, NemeroffCB, et al.Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An International Expert Opinion on the Available Evidence and Implementation. Am J Psychiatry, 2021; 178(5):383–399.
52.
FavaM, FreemanMP, FlynnM, et al.Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry, 2020; 25(7):1592–1603.
53.
KrystJ, KawalecP, MitorajAM, et al.Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: A meta-analysis of randomized clinical trials. Pharmacol Rep, 2020; 72(3):543–562.
54.
MathaiDS, McCathernAG, GuzickAG, et al.Parental attitudes toward use of ketamine in adolescent mood disorders and suicidality. J Child Adolesc Psychopharmacol, 2021; 31(8):553–561.
55.
AdayJS, HeifetsBD, PratscherSD, et al.Great expectations: Recommendations for improving the methodological rigor of psychedelic clinical trials. Psychopharmacology (Berl), 2022; 239(6):1989–2010.
56.
Garcia-RomeuA, GriffithsRR, JohnsonMW. Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Curr Drug Abuse Rev, 2014; 7(3):157–164.
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