Psychedelics and cognitive function: A systematic review

Abstract

Introduction: With the progressive advancement of clinical and experimental trials aimed at investigating the pharmacotherapeutic potential of psychedelic substances, there is also the development of other conceptions of use, not only for the treatment of psychiatric disorders, but also for the improvement of emotional/cognitive functions. Objective: The present study is a systematic review of investigations aimed at evaluating the effects of psychedelics on cognitive functions in healthy volunteers. Methods: A search was performed in PubMed database, using the search terms “psychedelics and cognitive enhancement” and “psychedelics and cognitive performance”. Results and conclusions: Of the experimental studies analyzed, only forty-six (46) met the inclusion criteria. The results obtained showed that 3,4-methylenedioxy-methamphetamine (MDMA) was the most studied drug, with eighteen (18) articles. Fourteen (14) articles were published with psilocybin. Lysergic acid diethylamide (LSD) ranked third, with six (6) articles; other two (2) studies focused on investigating the beverage ayahuasca, and another (1) its psychoactive-containing molecule: dimethyltryptamine (DMT). Eight (8) studies investigated the effects of other psychedelic drugs, like S-ketamine, mescaline, 3,4-methylenedioxy-amphetamine (MDE), and ibogaine. Although there were no serious adverse effects resulting from the use of the investigated psychedelic drugs, rigorous assessment of the potential risks of long-term use and of the advantages of the continuous use of these drugs through neuropsychological assessments are still warranted.

Full text

Research, Society and Development, v. 12, n. 14, e16121444436, 2023
(CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v12i14.44436
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Psychedelics and cognitive function: A systematic review
Psicodélicos e funções cognitivas: Uma revisão sistemática
Psicodélicos y funciones cognitivas: Una revisión sistemática
Received: 12/01/2023 | Revised: 12/09/2023 | Accepted: 12/10/2023 | Published: 12/13/2023
Caíque Gois Cardoso
ORCID: https://orcid.org/0009-0008-3903-0270
Universidade Federal de São Paulo, Brasil
E-mail: caiquegois@gmail.com
Milena de Barros Viana
ORCID: https://orcid.org/0000-0002-2465-3183
Universidade Federal de São Paulo, Brasil
E-mail: milenabv@gmail.com
Abstract
Introduction: With the progressive advancement of clinical and experimental trials aimed at investigating the
pharmacotherapeutic potential of psychedelic substances, there is also the development of other conceptions of use, not
only for the treatment of psychiatric disorders, but also for the improvement of emotional/cognitive functions. Objective:
The present study is a systematic review of investigations aimed at evaluating the effects of psychedelics on cognitive
functions in healthy volunteers. Methods: A search was performed in PubMed database, using the search terms
“psychedelics and cognitive enhancement” and “psychedelics and cognitive performance”. Results and conclusions: Of
the experimental studies analyzed, only forty-six (46) met the inclusion criteria. The results obtained showed that 3,4-
methylenedioxy-methamphetamine (MDMA) was the most studied drug, with eighteen (18) articles. Fourteen (14)
articles were published with psilocybin. Lysergic acid diethylamide (LSD) ranked third, with six (6) articles; other two
(2) studies focused on investigating the beverage ayahuasca, and another (1) its psychoactive-containing molecule:
dimethyltryptamine (DMT). Eight (8) studies investigated the effects of other psychedelic drugs, like S-ketamine,
mescaline, 3,4-methylenedioxy-amphetamine (MDE), and ibogaine. Although there were no serious adverse effects
resulting from the use of the investigated psychedelic drugs, rigorous assessment of the potential risks of long-term use
and of the advantages of the continuous use of these drugs through neuropsychological assessments are still warranted.
Keywords: Psychedelics; Healthy volunteers; Cognitive function.
Resumo
Introdução: Com o recente retorno e progressivo avanço dos ensaios clínicos e experimentais voltados para a
investigação do potencial farmacoterapêutico de substâncias psicodélicas, surge o desenvolvimento também de outras
concepções de uso, não apenas para o tratamento de transtornos psíquicos, mas também para aprimoramento de funções
emocionais/cognitivas. Objetivo: O objeto deste estudo foi realizar uma revisão sistemática de trabalhos que avaliaram
a utilização de drogas psicodélicas sobre processos cognitivos em voluntários saudáveis. Método: Foi realizada uma
busca na base de dados PubMed, utilizando os termos de busca “psychedelics and cognitive enhancement”; e
“psychedelics and cognitive performance”. Resultados e conclusões: Dos estudos experimentais analisados, verificou-
se que somente quarenta e seis (46) preenchiam os critérios de inclusão. Os resultados obtidos mostraram que o
metilenodioximetanfetamina (MDMA) foi a droga mais estudada, encontrada em dezoito (18) artigos. Quatorze (14)
artigos foram publicados com a psilocibina. Seis (6) artigos investigaram os efeitos da dietilamida do ácido lisérgico
(LSD); dois (2) estudos investigaram os efeitos da ayahuasca, e outro (1) de sua molécula psicoativa: a dimetiltriptamina
(DMT). Oito (8) artigos investigaram os efeitos de outras drogas psicodélicas: a S-cetamina, mescalina,
metilenodioxianfetamina (MDE) e a ibogaína. Embora não tenham sido verificados efeitos adversos graves decorrentes
da utilização das substâncias psicodélicas e medicinas tradicionais investigadas, estudos adicionais sobre o potencial de
risco de uso a longo prazo e sobre o nível de abrangência das variáveis presentes nas avaliações neuropsicológicas
apresentadas ainda são necessários.
Palavras-chave: Substâncias psicodélicas; Voluntários saudáveis; Cognição.
Resumen
Introducción: Con el progresivo avance de los ensayos clínicos y experimentales direccionados a investigar el potencial
farmacoterapéutico de las sustancias psicodélicas, también se desarrollan otras concepciones de uso, no sólo para el
tratamiento de trastornos psiquiátricos, sino también para la mejora de funciones emocionales/cognitivas. Objetivo: El
presente estudio es una revisión sistemática de investigaciones destinadas a evaluar los efectos de los psicodélicos sobre
las funciones cognitivas en voluntarios sanos. Métodos: Se realizó una búsqueda en la base de datos PubMed, utilizando

Research, Society and Development, v. 12, n. 14, e16121444436, 2023
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los términos de búsqueda ““psychedelics and cognitive enhancement”; y “psychedelics and cognitive performance”.
Resultados y conclusiones: De los estudios experimentales analizados, sólo quarenta y seis (46) cumplieron los criterios
de inclusión. Los resultados obtenidos mostraron que la 3,4-metilendioximetanfetamina (MDMA) fue la droga más
estudiada, con dieciocho (18) artículos. Se publicaron catorce (14) artículos con psilocibina. La dietilamida del ácido
lisérgico (LSD) ocupó el tercer lugar, con seis (6) artículos; otros dos (2) estudios se centraron en investigar la bebida
ayahuasca, y outro (1) su molécula que contiene psicoactivos: dimetiltriptamina (DMT). Ocho (8) estudios investigaron
los efectos de otras drogas psicodélicas, como S-ketamina, mescalina, 3,4-metilendioxianfetamina (MDE) e ibogaína.
Aunque no se produjeron efectos adversos graves derivados del uso de las drogas psicodélicas investigadas, todavía se
justifica una evaluación rigurosa de los riesgos potenciales del uso a largo plazo y de las ventajas del uso contínuo de
estas drogas mediante evaluaciones neuropsicológicas.
Palabras clave: Sustancias psicodélicas; Voluntarios sanos; Cognición.
1. Introduction
The growth of scientific research with psychedelics, which has been called the “Psychedelic Renaissance” (Carhart-
Harris, et al., 2018), has become evident during the last years. Contemporary research with psychedelics applied together with
new theoretical-methodological approaches, shows therapeutic efficacy and few adverse side effects on a wide variety of
neuropsychiatric disorders, namely: drug addiction (Johnson, et al., 2014; Bogenschutz, et al., 2015), post-traumatic stress
disorder (PTSD) (Mithoefer, et al., 2019; Schenberg, et al., 2020; Mitchell, et al., 2021), anxiety disorders (Grob, et al., 2010;
Gasser, et al., 2014; Danforth, et al., 2016) and depression (Carthart-Harris, et al., 2016; Ross, et al., 2016). Currently, institutions
in several countries have gained legal status to carry out clinical-investigative work on the therapeutic potential of psychedelic
drugs. Recently, the US Food and Drug Administration (FDA) assigned 3,4-methylenedioxy-methamphetamine (MDMA) and
psilocybin to the “breakthrough therapy” category (Jardim, et al., 2020; Reiff, et al., 2020; Schenberg, et al., 2020), granting
these substances the status of “innovative therapies” for the treatments of PTSD and depression, respectively (Rodrigues, 2019).
With the resurgence of studies with psychedelic drugs and the dissemination of successful results in scientific journals,
another indication for the use of these drugs emerges: the idea that these substances may promote cognitive/emotional benefits
for healthy volunteers. This is the idea that supposedly justifies the use of extremely low dosages over several days, the so-called
microdoses (Cameron, et al., 2020). Regarding the motivation underlying the use of microdoses, studies (Fadiman & Korb, 2019;
Andersson & Kjellgren, 2019; Hutten, et al., 2020) identified three categories of interest: (a) interest in improving oneself
cognitively and/or spiritually; (b) intention to promote well-being (in the sense of promoting health and pleasure or the relief of
symptoms, generally related to psychological suffering); (c) as a substitute therapy for psychiatric medication.
Nevertheless, knowledge about the effects of psychedelics on cognitive functions is still relatively limited. Although
some psychedelics may improve cognition, in particularly when administered to patients with compromised cognitive functions
(Magaraggia, et al., 2021), such association not necessarily applies to non-clinical populations. Therefore, there is an urge to
gather evidence from empirical studies looking at the effects of psychedelics in cognitive functions in healthy subjects.
The purpose of the present study was to perform a systematic review of the literature aimed at investigating: 1) which
psychedelics have been evaluated for cognitive improvement; 2) the results obtained on different cognitive aspects, i.e. memory,
emotional processing, social cognition, creativity; 3) possible side effects.
2. Research Methods and Reporting
The present review was conducted according to the preferred reporting items for systematic reviews (PRISMA)
guidelines (Selçuk, 2019). To comply with the principles of these guidelines, we tried to avoid selective reporting by gathering
all relevant data that conformed to the specified eligibility criteria described below. All studies published until October 2023
were included, without any language restriction.

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2.1 Eligibility criteria
The inclusion criteria were: 1) original articles, comparative studies, and clinical trials that directly dealt with the
administration and effects of psychedelics as cognitive enhancers; 2) articles written in any language.
Editorial texts, reviews, comments, conference articles, anecdotal reports and duplicate studies were excluded. In
addition, articles that were not conducted with cognitive, psychotechnical and/or neuroimaging tests in their experimental design
were withdrawn. Besides, those in which the experiments were conducted on healthy volunteers, as well as those that researchers
did not reach knowledge about the concentration of the administered dosage or control of the quality of the drug, were also
removed. At last, studies performed with Cannabis sativa or cannabinoids were not included in the present review.
2.2 Information sources
The search was conducted in PubMed database, for all kinds of articles published between 1966 to October 2023.
2.3 Search strategy and data collection process
Search strategies consisted in the crossing of the terms psychedelics AND cognitive enhancement, OR psychedelics
AND cognitive performance.
The reviewers collected the data independently in three different phases. Phase 1: Titles were carefully read to exclude
articles outside the scope of this research. The reviewers were not blinded to authorship information or the name of the journals.
Studies that did not deal with the research questions raised by this review were excluded. Phase 2: the reviewers analyzed the
abstracts of the remaining studies independently. In this phase, abstracts not addressing the subject of interest, literature reviews,
case reports, and congress abstracts were excluded. Phase 3, the full text of the articles selected in phase 2 were assessed. Then,
the articles were evaluated by the reviewers to verify whether they met the full inclusion criteria. The studies were excluded, and
the reasons recorded. Relevant papers that conformed to the pre-specified eligibility criteria were identified.
After applying the search, inclusion, and exclusion criteria, 46 articles were selected.
2.4 Data items
The following information was compiled to characterize the studies in Table 1: drug(s), authors/year of study, subjects,
instruments/measures used to evaluate the performance or cognitive enhancement potential, and main results.
3. Results
3.1 Study Selection
The initial online data search identified one hundred and ninety-three (193) articles. After the exclusion criteria, forty-
six (46) articles were selected. The results of the search strategy are shown in Figure 1.

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Figure 1 - Flowchart of the search criteria performed.
Source: Authors.
Identification
Records identified by PubMed database:
193.
Non-specific articles: 123
Duplicate articles: 10
Records removed: 133
Screening
Registration of articles
evaluated for eligibility: 60.
Registration of articles evaluated for eligibility and
excluded for the following reasons:
Fifteen (15) articles did not provide explicit
information about drug quality/dosage control or
participants health status in the context of the study or
did not investigate cognitive
performance/enhancement.
Registration of selected
controlled experimental articles:
46
Inclusion
Studies included: 46.

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3.2 General characteristics of the included studies
Tables 1-4 identify and characterize the included studies. The following drugs were tested for cognitive functions: 3,4-
methylenedioxymethamphetamine (MDMA), and its analogue 3,4-methylenedioxyethylamphetamine (MDE), in eighteen (18)
and three (3) studies, respectively (Table 1).
Table 1 - 3,4-methylenedioxy-methamphetamine (MDMA) and methylenedioxyamphetamine (MDA).
Drug(s)
Authors/Year
Sample
(N/Age/Gender
Methods
Measurements
Results
MDMA
Gabay et al. 2019
20 healthy
subjects
± 21-37 years
10M/10F
Randomized, double-blind, placebo-
controlled study to investigate the
effects of MDMA on social
decision-making. Participants
played a trust game with trusted and
untrusted opponents during fMRI.
The density of receptors in the
participants' nervous systems using
PET imaging was also measured.
MDMA and placebo were
administered orally in two separate
sessions, with a one-week interval
between sessions. The order of drug
administration was counterbalanced
among participants.
Trust game; 5D-
ASC; PD;
Affective Bias
task; MET; ASL
fMRI.
The results suggest that MDMA
can increase cooperative behavior
in social decision-making
contexts. This effect was
associated with changes in
neuronal activity in regions linked
to social cognition. However, the
study also highlights the context-
specific nature of MDMA's effects
on decision-making. The study
found no evidence to support the
hypothesis that MDMA's
dopaminergic modulation was
responsible for the observed
results.
MDMA;
MPH;
Modafinil
Schmidt et al.
2018a
24 healthy
subjects
±19-29 years
12M/12F
Cross-over, double-blind,
randomized, within-subject,
placebo-controlled study to compare
the acute effects of methylphenidate,
modafinil, and MDMA on neural
correlates of facial fear processing.
60 mg of methylphenidate, 600 mg
of modafinil, and 125 mg of MDMA
were administered to the subjects
while performing an event-related
fMRI task to assess neural activation
in response to fearful faces. Negative
mood states were assessed with the
STAI and subjective ratings.
FERT; STAI;
AMRS.
Results showed that MDMA,
when compared with modafinil,
did not increase neuronal activity
of the amygdala in responses to
fearful faces. The study found no
significant effect of
methylphenidate or MDMA on
brain activation during facial fear
processing.
MDMA
Kuypers et al.
2018
20 healthy
subjects
±21.2 years
12M/8F
Placebo-controlled within-subject
study. Participants were given
placebo or the 5-HT2A antagonist
ketanserin as a pretreatment,
followed by MDMA or placebo as
treatment. Participants then
completed two behavioral tests
(PAST/AAT) that assessed
processing of emotional and social
stimuli. Self-reported mood and
oxytocin concentrations were also
identified at various time points
throughout the study.
POMS; PAST;
AAT.
Results showed that MDMA
reduced arousal levels elicited by
negative sounds. This effect was
neutralized by pre-treatment with
ketanserin, indicating the
involvement of the 5-HT. MDMA
does not increase response
towards emotional and social
stimuli, but increased positive and
negative mood ratings and
elevated plasma concentrations of
oxytocin. The reduction in arousal
levels upon hearing negative
sounds was not related to
heightened subjective arousal. It is
suggested that this decrease in
arousal to negative stimuli
potentially reflects a decrease in
defenses, a process that may play
a role in the therapeutic process.
MDMA
Haijen et al. 2018
20 healthy
subjects
±21.2 years
12M/8F
Two-by-two double-blind, placebo-
controlled within-subject design
with pretreatment (ketanserin 40 mg
or placebo) preceding the treatment
(MDMA 75 mg or placebo) by 30
min. A double-dummy procedure
was used to control for differences in
Tmax between both drugs.
30-word learning
task; NART; GSS;
Social behavior
tests (Approach
Avoidance Test
with emotional
and social
situation stimuli,
Processing of
Sounds Task) and
questionnaires
(Dissociative
Experiences Scale,
MDMA caused memory
impairment in the verbal word
learning task. MDMA did not
affect endocannabinoid
concentrations nor did ketanserin
block the MDMA-induced
memory impairment. Thus,
MDMA-induced memory
impairment seems to be unrelated
to the endocannabinoid system.

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Clinician
Administered
Dissociative
States Scale,
POMS)
MDMA;
MPH;
modafinil.
Dolder et al. 2018
24 healthy
subjects
± 24.5 years
12M/12F
Double-blind, randomized,
crossover study to investigate the
acute effects of single doses of
MDMA, methylphenidate,
modafinil and placebo. The study
was developed in four experimental
sessions, with at least one week
between sessions. Acute drug effects
were tested using psychometric
scales. The study monitored the
autonomic, subjective, endocrine
and emotional effects of the drugs.
AMRS; FERT;
STAI; ARCI;
5D-ASC; VAS;
SADI.
Results suggest that all active
drugs produced comparable
hemodynamic and adverse effects.
However, MDMA produced
greater increases in pupil dilation,
good subjective effects, drug
liking, happiness, confidence,
well-being, and changes in
consciousness than either
methylphenidate or modafinil.
MDMA reduced anxiety, but
impaired fear recognition and led
to incorrect classifications of
emotions. In SADI, only MDMA
produced sexual arousal-like
effects. Only MDMA produced
marked increases in cortisol,
prolactin and oxytocin.
MDMA;
MPH;
Modafinil
Schmidt et al.
2017
21 healthy
subjects
±21-30 years
10M/11F
The study compared the effects of
the three drugs on the neural
mechanisms underlying response
inhibition in healthy subjects. The
methods used in this article were a
double-blind, randomized, within-
subject placebo-controlled trial. The
three drugs were administered while
performing an fMRi test related to
the Go/No-Go exam to assess brain
activation during motor response
inhibition.
AMRS; Go/No-go
task.
Results suggest that MDMA did
not improve inhibitory
performance. While the three
drugs activated fronto-parietal
regions, fMRI results showed that
MDMA significantly increased
activation in the right
middle/inferior frontal gyrus and
superior parietal lobule compared
with placebo.
MDMA
Kuypers et al.
2016
65 MDMA users
and 65 healthy
subjects
± 18-28 years
40M/25F
The study compared a control group
of healthy volunteers, with no
history of drug use, with MDMA
users.
WLT-IR; WLT-
DR
Results suggest that although
memory impairment is clinically
present during MDMA use, it is
absent during withdrawal. Verbal
memory performance of placebo-
treated subjects did not differ from
controls. History of MDMA use
was not predictive of memory
impairment. During MDMA use
by users, verbal memory was
impaired.
MDMA;
MPH
Schmid et al. 2015
30 healthy
subjects
± 18-32 years
15M/15F
Double-blind, randomized, placebo-
controlled, crossover study. The
study involved the administration of
methylphenidate and MDMA and
the evaluation of their effects on
subjective sexual arousal through
viewing erotic images and on the
perception of romantic relationships
of unknown couples. Participants
were asked to rate their level of
sexual arousal when viewing explicit
and implicit sexual stimuli and
increase the time of presentation of
implicit sexual stimuli by pressing
the button. Plasma levels of
testosterone, estrogen and
progesterone were also measured.
SAT; CAT.
Compared with methylphenidate,
MDMA did not increase rates of
sexual arousal to overt sexual
stimuli. However, none of the
drugs altered the others'
assessment of their romantic
relationships. The study also
found that plasma levels of
testosterone, estrogen and
progesterone were not associated
with rates of sexual arousal.
MDMA
Kirkpatrick et al.
2015
Study 1:
361 healthy
subjects
±34.5 years
Both gender
(57%F)
Study 2:
32 healthy
subjects
± 27.6 years
23M/9F
In Study 1, the WTT was
administered to participants to
examine their performance against
measures of personality and
socioeconomic status. In Study 2,
MDMA-experienced participants
completed the WTT after
administration of MDMA (0, 0.5, or
1.0 mg/kg) to examine effects on
generosity. Drug conditions were
administered in randomized order,
under double-blind conditions.
NEO-FFI; WTT
Results showed that participants
were more generous to a close
friend than to an acquaintance or
stranger in both studies. In Study
1, WTT generosity was related to
family income and the trait
“Kindness”. In Study 2, MDMA
(1.0 mg/kg) increased generosity
to a friend but not to a stranger,
while MDMA (0.5mg/kg) slightly
increased generosity to a stranger,
especially among study

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participants. women. Findings
suggest that MDMA produces
prosocial effects that depend on
the social closeness of
relationships.
MDMA;
MPH
Schmid et al. 2014
30 healthy
subjects
± 24.5 years
15M/15F
Double-blind, randomized, placebo-
controlled, crossover study to
investigate the acute effects of
MDMA, methylphenidate, and
placebo on various aspects of social
cognition. The study used a variety
of cognitive tests to assess different
dimensions of social cognition. The
study also measured the subjective,
autonomic, pharmacokinetic,
endocrine, and adverse effects of the
drugs. Finally, the study combined
current and previously published
data into a pooled analysis of the
effects of MDMA and
methylphenidate in a larger sample.
FERT; MET;
SVO; MJT;
AMRS;
5D-ASC.
Results suggest that MDMA
increased emotional empathy for
positive emotional situations and
tended to reduce recognition of
sad faces. MDMA had no effects
on cognitive empathy or social
cognitive inferences. MDMA
produced subjective
"empathogenic" effects such as
liking the drug, closeness to
others, openness, and confidence.
MDMA, but not methylphenidate,
increased plasma levels of
oxytocin and prolactin. None of
the drugs influenced moral
judgment.
MDMA;
Pindolol
Kuypers et al.
2014
20 healthy
subjects
±18-26 years
12M/8F
Placebo-controlled within-subject
study to investigate the effects of
MDMA on empathy and social
interaction. The study included four
treatment conditions: MDMA (75
mg), with or without pindolol (20
mg), oxytocin nasal spray, or
placebo. Participants received the
treatments and then rated cognitive
and emotional empathy using the
RMET and MET tests. Social
interaction was assessed using a trust
game and a ball-throwing game.
Hormone analysis was also
performed to measure cortisol and
oxytocin levels.
RMET; MET; IRI;
Trust Game;
SBTGQ; WLT;
GSS; POMS;
NART
Results showed that MDMA (75
mg) selectively increased
emotional empathy, leaving
cognitive empathy, trust, and
reciprocity unchanged. The effects
of MDMA on emotional empathy
were not influenced by pindolol or
oxytocin. Oxytocin did not affect
measures of empathy and social
interaction. The Trust Game
showed that participants threw
more balls to the good player
compared to the neutral player.
MDMA
Hysek et al. 2014
32 healthy
subjects
± 24.6 years
16M/16F
Cross-over, double-blind,
randomized, placebo-controlled
study to investigate the acute effects
of MDMA on empathy and social
behavior in volunteers. Tests were
used to assess empathy and social
behavior. The study also measured
plasma levels of hormones involved
in social behavior, including
cortisol, prolactin and oxytocin.
VAS; AMRS;
MET; IRI; SVO;
FERT
Results showed that MDMA
increased emotional empathy and
social behavior in male
participants but impaired the
identification of negative
emotions on a test (FERT),
particularly in female participants.
MDMA also increased plasma
levels of cortisol, prolactin, and
oxytocin. The study did not report
any serious adverse effects of
MDMA on participants.
MDMA;
ethanol;
THC
Lansbergen et al.
2011
Study 1:
14 healthy
subjects
± 18-29 years
8M/6F
Study 2:
14 healthy
subjects
± 18-27 years
11M/3F
The aim of the present report was to
examine the effects of MDMA alone
and in combination with THC or
ethanol on ongoing EEG
oscillations. Four-way, double-
blind, randomized, crossover and
placebo-controlled design.
EEG.
Results showed that the
attenuation of power when drugs
were taken in combination appears
to be considerably less than the
sum of the drugs alone. There was
significant MDMA-alone effects
for theta and lower-1 alpha power.
Increased individual alpha peak
frequency, and theta oscillations
and lower-1 alpha oscillations,
which overlap the traditional theta
frequency band, were attenuated
after the administration of MDMA
alone.
MDMA
Bedi et al. 2010
21 healthy
subjects
± 18-38 years
12M/9F
Four-sessions, within-subject,
randomized, double-blind, placebo-
controlled design. Self-report data of
affective states and tasks to identify
emotions from images of faces,
pictures of eyes, and vocal cues were
collected.
VAS; POMS;
FERT; RMET;
DANVA-2.
Results showed that MDMA (1.5
mg/kg only) altered a behavioral
indicator of social cognition.
Specifically, it robustly reduced
recognition of fearful faces,
without changing recognition of
other emotions from facial or
vocal cues. MDMA produced self-
reports of loving feelings and
friendliness but decreased the
accuracy of subjects in identifying
fear in others. A decreased ability

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to identify negative emotions,
particularly threat-related signals
such as fear, might facilitate social
approach behavior.
MDMA;
Pindolol
Hasler et al. 2009
15 healthy
subjects
± 20-36 years
Only male
Within-subject, double-blind,
placebo-controlled study to
investigate the effects of MDMA
and pindolol on cognitive
performance and subjective
experiences. The study examined
participants under four different
conditions: placebo, pindolol,
MDMA, and MDMA after
pretreatment with pindolol.
Cognitive performance was assessed
using Cambridge Automated
Neuropsychological Test Battery
(CANTAB) tasks and subjective
experiences were measured using
psychometric questionnaires to
assess the central dimensions of
EAC's, mood and state of anxiety.
AMRS; STAI;
5D-ASC; PAL.
Results showed that MDMA
significantly impaired sustained
attention and visual-spatial
memory but did not affect
executive functions. Pindolol
pretreatment did not significantly
alter MDMA-induced cognitive
performance impairment and only
exerted a minor modulatory effect
on two psychometric scales
affected by MDMA treatment
(‘positive derealization’ and
‘dreaming’).
MDMA;
ethanol
Dumont et al.
2008
14 healthy
subjects
± 18-29 years
8M/6F
Four-way, double-blind,
randomized, crossover, placebo-
controlled design.
SDRT; Switch
task; Pursuit Task;
Point Task; Tangle
Task; SDST;
BLMRS.
The study demonstrates that the
effects of 100mg MDMA on
cognitive function are no greater
than the effects of a relatively low
dose of ethanol. MDMA by itself
did not significantly affect
subjective alertness. However,
MDMA did significantly reduce
subjective calmness, for example,
subjects felt more excited after the
use. Impaired memory function
was consistently observed after all
drug conditions, whereas
impairment of psychomotor
function and attention was less
consistent across drug conditions.
MDMA
Vollenweider et al.
2005
42 healthy
subjects
± 21-38 years
32M/10F
Cross-over, randomized study,
where participants received either a
placebo or 1.5 mg/kg of MDMA.
Decision-making characteristics
were evaluated, and results were
obtained with error rates of 20%,
50% and 80%. Decision-making
characteristics were analyzed using
mutual information and mean
dynamic entropy. Self-assessment of
MDMA-induced psychological state
was also obtained.
AMRS; ASC;
two-choice
prediction task.
Results suggest that acute MDMA
administration affects response
selection related to success during
decision-making. Specifically,
MDMA increased the degree to
which the previous response
predicted the current response and
the average predictability of the
response sequence with low error
rates. MDMA also increased the
degree to which the previous
stimulus influenced current
response selection at all error
rates. However, MDMA did not
significantly alter basic response
characteristics such as latency or
response switching. Self-
assessment of MDMA-induced
psychological state did not predict
MDMA-induced decision-making
patterns.
MDMA;
ethanol
Lamers et al. 2003
12 healthy
subjects
-
8M/4F
Three-way crossover, double-blind,
double-dummy, placebo-controlled
study to evaluate the effects of a
single dose of MDMA, and alcohol
on cognitive function, psychomotor
performance, and driving-related
task performance.
SDT; TOL; CTT;
DAT; OMEDA;
MCRT;
Word Fluency.
The results showed that a single
dose of MDMA improved
psychomotor performance such as
movement speed and tracking
performance in a test (DAT).
However, MDMA impaired the
ability to predict object motion
under divided attention, which
may indicate impairment of
specific performance skills
relevant to driving. There was no
effect of MDMA on visual search,
planning or semantic memory
retrieval. The study found no
serious adverse effects and none of
the subjects required special care

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during or after the experimental
sessions.
MDE
Spitzer et al. 2001
5 healthy subjects
-
Only males
Randomized double-blind design
WCST; visual
pop-out search
task; semantic
priming task;
colour and
semantic
discrimination
task; self-rating
scales.
The study demonstrated
differential effects on various
measures assessing alterations of
psychopathology,
neuropsychological performance
and brain activation patterns after
ingestion of (R)- and (S)-MDE.
Together with the differential
psychological effects of the agent,
it is suggested that any future
medical applications of MDE
within the framework of
psychotherapeutic interventions
should make use of the (S)-
enantiomer only.
MDE;
Psilocybin;
d-
methampheta
mine
Gouzoulis-
Mayfrank et al.
1999
32 healthy
subjects
27-47 years
21M/11F
Double-blind, placebo-controlled
neurometabolic design w/ FDG PET
study.
Word association
task (activation
scan) and word
repetition task
(control scan).
There were no diferences in the
total number of overtly spoken
words in repetition tasks. In the
association task, subjects on
psilocybin produced fewer words
than the placebo group. Subjects
on MDE produced slightly fewer.
However, these deficits were not
significant. There were no
significant deficits between the
number of words produced in the
three equal parts of the deficit
activation periods.
MDE
Schreckenberer et
al. 1998
16 healthy
subjects
Randomized double-blind trial.
18-FDG PET
The study used 18-FDG PET to
measure cerebral glucose deficit
and compared the results between
the MDE and placebo groups. It
was showed a significantly
decreased in the bilateral frontal
córtex under MDE. However, was
concluded that the PET use
provides indirect measurements of
cerebral glucose deficit and may
have limitations in accurately
capturing complex metabolic
processes in the brain.
Abbreviations: M: male subjects; F: female subjects; mg: milligrams; μg/mcg: micrograms; 5-HT2A: serotonergic receptor; MDMA: 3,4-methylenedioxymethamphetamine; MPH:
methylphenidate; THC: ∆9-tetrahydrocannabinol; 5D-ASC: 5-Dimensional Altered States of Consciousness Rating Scale; ASC: Alteration of Consciousness Questionnaire; RMET:
Reading the Mind in the Eyes Test; SBTGQ: Social Ball Tossing Game Questionnaire; WLT: Word Learning Task; NART: National Adult Reading Test; SDT: Signal Detection Task;
TOL: Tower of London; CTT: Critical Screening Test; DAT: Divided Attention Test; OMEDA: Moving Object Estimation Test under Divided Attention; MCRT: Motor Choice
Reaction Time; PAL: Pair Associative Learning Task; AMRS: Adjective Mood Rating Scale; MET: Multifaceted Empathy Test; IRI: Interpersonal Reactivity Index; SVO: Social
Values Orientation; FERT: Facial Expression Recognition Task; MJT: Moral Judgement Task; AAT: Approach -Avoidance Task; PET: Positron emission tomography; fMRI:
Functional magnetic resonance imaging; WTT: Welfare Trade-Off Task; SAT: Sexual Satisfaction Inventory; CAT: Couples Appraisal Task; POMS: Profile of Mood States; PAST:
Affective Sound Processing Task; ARCI: Addiction Research Central Inventory; SADI: Sexual Satisfaction and Desire Inventory; PD: The prisoner's dilemma; EAC's: Altered States
of Consciousness; BLMRS: Bond and Lader Mood Rating Scale; SDST: Symbol Digit Substitution Test; SDRT: Symbol Digit Recall Test; STAI: State-Trait Anxiety Questionnaire;
EEG: Electroencephalogram; VAS: Visual Analogue Scale; NEO-FFI: Neuroticism, Extraversion, Openness-Five Factor, Mood States; PAST: Affective Sound Processing Task;
ARCI: Addiction Research Central Inventory; SADI: Sexual Satisfaction and Desire Inventory; PD: The prisoner's dilemma; EAC's: Altered States of Consciousness; BLMRS: Bond
and Lader Mood Rating Scale; SDST: Symbol Digit Substitution Test; SDRT: Symbol Digit Recall Test; STAI: State-Trait Anxiety Questionnaire; EEG: Electroencephalogram;
ANOVA: analysis of variance; VAS: Visual Analogue Scale; NEO-FFI: Neuroticism, Extraversion, Openness-Five Factor; WCST: Wisconsin Card Sorting Test. Source: Authoors.
Psilocybin was investigated in fourteen (14) studies (Table 2).

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Table 2 - Psilocybin.
Drug(s)
Authors/Year
Sample (N/Age/
Gender)
Methods
Measurements
Results
Psilocybin
Mescaline;
LSD
Ley et al. 2023
32 healthy
subjects
25-44 years
16M/16F
Randomized, double-blind,
placebo-controlled, cross-
over design
VASs; AMRS;
5D-ASC;
SOCQ.
The study compared the acute effects of
mescaline, LSD, and psilocybin in healthy
participants. The subjective effects of the
three substances were found to be comparable
at psychoactive-equivalent doses. The study
found no evidence of qualitative differences
in altered states of consciousness induced by
equally doses of mescaline, LSD, and
psilocybin. The subjective experience did not
significantly differ between the three
substances. The study supports dose finding
for research and psychedelic-assisted therapy,
indicating that these substances can be used
in a controlled and monitored setting for
therapeutic purposes.
Psilocybin
Cavanna et al.
2022
34 healthy
subjects
± 18-65 years
23M/11F
Double-blind placebo-
controlled experimental
study to investigate the
acute and short-term effects
of microdosing with
psilocybin mushrooms. The
study measured subjective
experience, behavior,
creativity, perception,
cognition, and neuronal
activity in response to a low
dose of psilocybin
mushrooms (0.5 g of dried
mushrooms).
Go/no-go test;
Stroop test; BFI;
STAI-T; STAI-
S; SSS;
PANAS; MWQ;
PSS; TAS;
BIEPS; FSS;
CPS; TECA;
CFS; RAT;
AUT; WK.
Low doses of psilocybin mushrooms may
result in noticeable subjective effects and
altered EEG rhythms, but without evidence to
support increased well-being, creativity, and
cognitive function. The reported acute effects
were significantly more intense for the active
dose compared to placebo, but only for
participants who correctly identified their
experimental condition. According to the
results, the expectation underlies at least
some of the anecdotal benefits attributed to
microdosing with psilocybin mushrooms.
Psilocybin
Mason et al.
2021
60 healthy
subjects
Double-blind, placebo-
controlled, parallel-group
study. Sixty participants
were randomly assigned to
receive psilocybin or
placebo. Participants were
screened for any medical or
psychiatric conditions and
that they were not taking
any substances that could
interfere with the study.
The effects of psilocybin on
creative thinking have been
measured using a variety of
tests. Brain imaging has
also been used to
investigate the neural
mechanisms underlying
psilocybin's effects on
creative thinking.
PCT;
AUT;
5D-ASC;
fMRi.
Psilocybin induced a differentiation of effects
related to time and the construction of
creative thinking. Acutely, psilocybin
increased ratings of spontaneous creative
insights while decreasing deliberate task-
based creativity. Seven days after psilocybin,
the number of new ideas increased.
Furthermore, the study found that acute and
persistent effects were predicted by
connectivity within and between networks of
the default mode network.
Psilocybin
Smigielski et al.
2020
17 healthy
subjects
± 25.1 years
9M/8F
Double-blind, placebo-
controlled, within-subject
design with a
counterbalanced order of
administration. A verbal
self-monitoring task
involving vocalizations and
participant identification of
real-time auditory source-
(self/other) and pitch-
modulating feedback.
Subjective experience and
task performance were
analyzed, with time-point-
by-time-point assumption-
free multivariate
randomization statistics
applied to the
spatiotemporal dynamics of
event-related potentials.
5D-ASC; EEG.
The study found that psilocybin induce shifts
in perception and alter self-referential
processing. Also, it was showed that
psilocybin abolishes distinctiveness of self-
related scalp configurations via P300-related
mechanisms. Moreover, psilocybin affected
self-other processing by modulating the
activity in the supragenual cingulate cortex
and insula.
Psilocybin
Prochazkova
et al. 2018
38 healthy
subjects
The study investigated the
effects of microdosing
RPM; PCT;
AUT.
Results showed that convergent and divergent
thinking performance improved after a non-

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±31.5 years
23M/15F
psychedelic mushrooms on
creativity-related problem-
solving tests. The study was
conducted during a
microdosing event
organized by the Dutch
Psychedelic Society.
Participants were tested
once before taking a
microdose and once while
waiting for the effects to
manifest. Two creativity-
related problem-solving
tasks were used to assess
convergent and divergent
thinking performance,
respectively. Changes in
fluid intelligence were also
assessed. The mushrooms
were subsequently
analyzed to quantify active
psychedelic alkaloids,
including psilocin,
psilocybin, norbaeocystin,
and baeocystin. The study
was unblinded, meaning
participants were aware
they were taking a
microdose.
blind microdose of psychedelic mushrooms,
while fluid intelligence was unaffected. The
effect of time point was significant, due to
better performance in the second than in the
first session. The study provides quantitative
support for the cognitive-enhancing
properties of microdosed psychedelics, but
future research is needed to confirm these
preliminary findings in more rigorous
placebo-controlled study designs. Based on
these preliminary results, the authors
speculate that psychedelics may affect
cognitive metacontrol policies by optimizing
the balance between cognitive persistence
and flexibility.
Psilocybin;
DXM
Barrett et al.
2018
20 healthy
subjects
± 28.5 years
9M/11F
Double-blind, placebo-
controlled, within-subject
study in which participants
completed
neuropsychological
assessments during five
blind drug administration
sessions (10, 20 and 30
mg/70 kg psilocybin; 400
mg/70 kg DXM; and
placebo). The study
evaluated effects across
several cognitive as well as
subjective domains that
have been reported
elsewhere.
6-point
confidence
scale; Circular
lights task;
balance task;
CNB; Stroop
Test; PLOT;
DSST; MMSE;
mpraxis task;
word-encoding
and recognition
task; letter n-
back task
Psilocybin exerted D-D effects across
multiple cognitive domains, including
psychomotor performance, working memory,
episodic memory, associative learning, and
visual perception. However, there was no
evidence of psychological impairment or
delirium with psilocybin or DXM. DXM had
greater effects than all doses of psilocybin on
balance, episodic memory, response
inhibition, and executive control. The study
reported no significant adverse effects of
psilocybin or DXM on cognitive function.
Psilocybin
Pokorny et al.
2017
32 healthy
subjects
±20-38 years
17M/15F
Double-blind, randomized,
placebo-controlled, within-
subject design.
MET; MDT;
IRI; 5D-ASC;
PANAS.
The study found that psilocybin increased
emotional empathy but did not affect
cognitive empathy or moral behavior in
healthy subjects. Furthermore, the increase in
emotional empathy scores was predicted by
the changed meaning of percepts scores, as
measured by the 5D-ASC scale. These
findings suggests that psilocybin have
potential therapeutic benefits for individuals
with déficits in social skills and empathy.
Psilocybin
Kometer et al.
2013
15 healthy
subjects
≅ 26 years
11M/4F
Double-blind, placebo-
controlled, within-subject,
randomized design.
5D-ASC; EEG
Psilocybin strongly decreased prestimulus
parieto-occipital alpha power values, thus
precluding a subsequent stimulus-induced
alpha power decrease. Furthermore,
psilocybin strongly decreased N170
potentials associated with the appearance of
visual perceptual alterations, including visual
hallucinations. All of these effects were
blocked by pretreatment with the 5-HT2A
antagonist ketanserin, indicating that
activation of 5-HT2A receptors by psilocybin
profoundly modulates the neurophysiological
and phenomenological indices of visual
processing.
Psilocybin
Carhart-Harris
et al. 2012a
15 healthy
subjects
≅ 34 years
10M/5F (ASL)
13M/2F (BOLD)
Functional MRI (fMRI)
techniques and a protocol to
designed to image the
transition from normal
waking consciousness to
the psychedelic state.
ASL perfusion,
BOLD
Psilocybin significantly decreased brain
blood flow and venous oxygenation in a
manner that correlated with its subjective
effects, and significantly decreased the
positive coupling of two key structural hubs.
It is therefore possible that phasic or

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shortterm effects of psilocybin show some
rebound that is detected by longer-term
changes in glucose metabolism. The
pharmaco-physiological interaction results
were particularly intriguing, revealing
significant decreases in the positive coupling
between the the posterior cingulate cortex
(PCC), and medial prefrontal cortex (mPFC)
after psilocybin. The results suggest
decreased activity and connectivity in the
brain’s connector hubs, permitting an
unconstrained style of cognition.
Psilocybin
Carhart-Harris
et al. 2012b
10 healthy
subjects
≅ 31 years
9M/1F
Placebo-controlled cross-
over study.
Fifteen memory
cues were
presented in a
blocked
paradigm,
interleaved with
rest and an
auditory
attention task
with two
functional
magnetic
resonance
imaging scans
(fMRI)
separated by
seven days.
Robust activations to autobiographical
memory cues were found after both placebo
and psilocybin, but greater late phase sensory
activations and more intense subjective
effects were seen after psilocybin. Greater
activations were observed in the bilateral
auditory cortex, somatosensory cortex,
superior parietal cortex, left visual association
regions and the occipital pole after
psilocybin, and post-hoc tests confirmed that
visual and other sensory regions were
uniquely activated under psilocybin. These
effects may have implications for the use of
psilocybin in psychotherapy.
Psilocybin
Wittmann et al.
2007
12 healthy
subjects
-
-
Double-blind experimental
study to investigate the
effects of psilocybin on
temporal processing. The
study employed tests of
temporal reproduction,
sensorimotor
synchronization, and
rhythm tapping to evaluate
the impact of psilocybin on
timing performance.
Various tests were used to
evaluate the subjective
effects of psilocybin. The
study also assessed spatial
working memory and
conscious experience to
control for cognitive and
subjective changes.
SSP; 5D-ASC;
AMRS.
Psilocybin significantly impairs the ability to
reproduce intervals lasting longer than 2.5
seconds, to synchronize interbeat intervals
longer than 2 seconds, and causes subjects to
be slower at their preferred beat rate. These
objective effects on time performance were
accompanied by working memory
impairments and subjective changes in
conscious state, i.e., increased reports of
'depersonalization' and 'derealization'
phenomena, including disturbances in the
subjective 'sense of time'. The study suggests
that the serotonergic system is selectively
involved in processing interval durations
longer than 2 to 3 seconds and in voluntary
control of movement speed.
Psilocybin
Hasler et al.
2004
8 healthy subjects
22-44 years
4M/4F
The study investigated the
effects of administering
different doses of
psilocybin to participants
and measuring the effects
on various psychological
and physiological
parameters. The study was
based on a double-blind,
placebo-controlled
experiment, and the
different doses of
psilocybin were
administered in random
order. Psychological
parameters were assessed
using several tests.
Physiological parameters
measured included blood
pressure,
electrocardiogram, and
plasma levels of various
hormones and clinical
chemical parameters.
5D-ASC;
AMRS; FAIR.
The results of the article showed that
psilocybin increased the D-D shape scores of
all core dimensions of the EACs. Only one
subject reacted with transient anxiety to the
high dose of psilocybin. Compared to
placebo, medium and high doses of
psilocybin led to a 50% reduction in
performance on the FAIR test. “General
inactivation,” “emotional arousal,” and
“dreaminess” were the only domains of the
AMRS scale showing increased scores after
medium and high doses of psilocybin. Mean
arterial pressure was moderately elevated 60
minutes after administration of the high dose
of psilocybin. Neither electrocardiogram nor
body temperature were affected by any dose
of psilocybin. Plasma levels of thyroid-
stimulating hormone, adrenocorticotropic
hormone, and cortisol were elevated during
the peak effects of high-dose psilocybin,
while plasma prolactin levels increased after
medium and high doses of psilocybin.
Psilocybin;
Gouzoulis-
Mayfrank et al.
1999
32 healthy
subjects
27-47 years
Double-blind, placebo-
controlled neurometabolic
design w/ FDG PET study.
Word
association task
(activation scan)
There were no diferences in the total number
of overtly spoken words in repetition tasks. In
the association task, subjects on psilocybin

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MDE; d-
methampheta
mine
21M/11F
and word
repetition task
(control scan).
produced fewer words than the placebo
group. Subjects on MDE produced slightly
fewer. However, these deficits were not
significant. There were no significant deficits
between the number of words produced in the
three equal parts of the deficit activation
periods.
Psilocybin
Dextro-
amphetamine
Duke; Keeler,
1968
8 healthy subjects
-
Only male
Randomized double-blind,
placebo-controlled trial
Trail Making
Test
The study shows that psilocybin produces a
deficit in performance as compared to
placebo. In addition, the demonstration that
psilocybin significantly impairs performance
of the complex task as compared to the simple
task suggests that drug induced muscular
incoordination is not responsible for
decrements in performance.
Abbreviations: M: male subjects; F: female subjects; mg: milligrams; 5-HT2A: serotonergic receptor; MDE: 3,4-methylenedioxyethylamphetamine; LSD: lysergic acid diethylamide;
5D-ASC: 5-Dimensional Altered States of Consciousness Rating Scale; n-back task: Continuous Performance Task; AMRS: Adjective Mood Rating Scale; MET: Multifaceted Empathy
Test; IRI: Interpersonal Reactivity Index;PANAS: Positive and Negative Affect Scale; DXM: dextromethorphan; D-D: dose-dependent; PLOT: Penn Line Orientation Test; DSST:
Digit Symbol Substitution Task; MMSE: Mini Mental State Examination; BOLD: blood-oxygen level-dependent; PCT: Picture-Concept Task; AUT: Alternative Uses Task; BFI: Five
Personalities Inventory; STAI: State-Trait Anxiety Questionnaire; SSS: Short Suggestionability Scale; MWQ: Distraction Scale; PSS: Perceived Stress Scale; FSS: Flow State Scale;
CPS: Creative Personality Scale; TECA: Cognitive-Affective Empathy Test; CFS: Cognitive Flexibility Scale; RAT: Remote Association Test; WK: Wallach-Kogan Test; EEG:
Electroencephalogram; VAS: Visual Analogue Scale. Source: Authors.
Lysergic acid diethylamide (LSD-25) appeared in six (6) studies analyzed (Table 3).
Table 3 - Lysergic acid diethylamide (LSD).
Drug(s)
Authors/Year
Sample
(N/Age/Gender)
Methods
Measurements
Results
LSD
Mescaline
Psilocybin
Ley et al. 2023
32 healthy
subjects
25-44 years
16M/16F
Randomized, double-
blind, placebo-controlled,
cross-over design
VASs; AMRS;
5D-ASC;
SOCQ.
The study compared the acute effects of mescaline, LSD,
and psilocybin in healthy participants. The subjective
effects of the three substances were found to be
comparable at psychoactive-equivalent doses. The study
found no evidence of qualitative differences in altered
states of consciousness induced by equally doses of
mescaline, LSD, and psilocybin. The subjective
experience did not significantly differ between the three
substances. The study supports dose finding for research
and psychedelic-assisted therapy, indicating that these
substances can be used in a controlled and monitored
setting for therapeutic purposes.
LSD
De Wit et al.
2022
56 healthy
subjects
± 19-35 years
37M/19F
Double-blind controlled
study to investigate the
effects of repeated low
doses of LSD on mood,
cognitive performance and
responses to emotional
tests. The study involved
four 5-hour drug
administration sessions
separated by 3-4 days,
followed by a drug-free
follow-up session 3-4 days
after the last session.
Participants were
randomly assigned to one
of three groups: placebo,
13 μg LSD, or 26 μg LSD.
The drug's effects were
measured using subjective
assessments, cognitive and
emotional tests.
POMS;
PANAS;
DASS; ARCI;
5-ASC;
End-of-Session
Questionnaire;
Drug Effects
Questionnaire
Repeated low doses of LSD (13 or 26 μg) produced no
significant changes in participants' mood or cognitive
performance. LSD (26 μg) produced modest subjective
effects, including ratings of enhancement in 'feeling a
drug high' and stimulant-like and LSD-like effects, but
did not improve mood or affect performance on
psychomotor or emotional tests. No residual effects were
detected on mood or test performance in the drug-free
follow-up session. The study concluded that, in the
context of a controlled environment and with a limited
number of administrations, repeated low doses of LSD are
safe but produce negligible changes in mood or cognition
in healthy individuals.
LSD
Hutten et al.
2020
24 healthy
subjects
± 22.8 years
12M/12F
Placebo-controlled,
within-subject study to
evaluate the acute effects
of three different doses of
LSD (5, 10, and 20 mcg)
on measures of cognition,
mood, and subjective
experience. Participants
completed a battery of
cognitive tests and
questionnaires to assess
PVT; DSST;
CCT; POMS;
VAS;
5D-ASC; EDI;
GSS.
Results showed that low doses of LSD (5, 10, and 20 mg)
had selective and beneficial effects on mood and
cognition in most observations. Positive effects included
an improvement in positive mood, friendliness,
excitement, and a decrease in lapses in attention. Negative
effects included an increase in confusion and anxiety.
Psychedelic-induced changes in waking consciousness
were also present. Overall, the study demonstrated that
low doses of LSD can have positive effects on mood and
cognition, but more research is needed to determine the
long-term effects and safety of microdosing with LSD.

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their mood and subjective
experience up to 6 hours
after LSD administration.
LSD
Schmidt et al.
2018b
18 healthy
subjects
±25-58 years
9M/9F
Double-blind,
randomized, placebo-
controlled, crossover
study. The study
administered LSD (100
µg) and placebo to
participants and evaluated
response inhibition with
tests (Go/No-Go) and
fMRi. The study also used
the 5D-ASC questionnaire
to measure LSD-induced
"visual hallucinations."
5D-ASC;
Go/No-go
Task; fMRI.
The results showed that LSD administration impaired
inhibitory performance and reduced neuronal activity in
several regions, including the right middle temporal
gyrus, superior/middle/inferior frontal gyrus, left anterior
cingulate and superior frontal cortex, and left postcentral
gyrus and cerebellum. The study also found that
parahippocampal activation during response inhibition
was differentially related to inhibitory performance after
placebo and LSD administration. Finally, activation in the
left superior frontal gyrus under LSD exposure was
negatively related to LSD-induced cognitive and visual
imagery impairments. These findings suggest that
activation of 5-HT2A by LSD leads to a disruption of
inhibitory processing mediated by the hippocampal
prefrontal cortex, which may subsequently promote LSD-
induced visual image formation.
LSD
Roseman et al.
2016
10 healthy
subjects
-
6M/4F
Subjects attended to two
scanning days (LSD and
placebo) at least 2 weeks
apart in a balanced order,
within-subjects design.
RSFC;
ASL; BOLD;
ASC.
The study found that under the influence of LSD, the
visual cortex behaves as if it is processing spatially
localized visual information. LSD altered eyes-closed
functional connectivity within the early visual cortex in a
retinopic fashion. Patches of visual cortex with congruent
retinotopic representation showed greater resting-state
functional connectivity (RSFC) than patches with
incongruent representations.
LSD
Goldberger,
L., 1966
42 healthy
subjects
-
-
Randomized double-blind,
placebo-controlled trial
Digit Span;
Iowa Silent
Reading Test;
Robinson
Tests; Word-
naming; Serial
Sevens; Simple
Rhyming.
Results showed no similarity between isolation and LSD
effects, at least on a quantitative basis. Therefore, the
quality and intensity differed: the loss of time sense, and
concentration difficulties would be more profound in
LSD. The study conclude that eight (8) hours of isolation
does not produce significant group effects of either
impairment or improvement, at least not with the kinds of
tests so far employed.
Abbreviations: M: male subjects; F: female subjects; μg/mcg: micrograms; 5-HT2A: serotonergic receptor; LSD: lysergic acid diethylamide; 5D-ASC: 5-Dimensional Altered States
of Consciousness Rating Scale; ASC: Alteration of Consciousness Questionnaire; RSFC: Resting-state functional connectivity; BOLD: blood-oxygen level-dependent; ASL: Arterial
Spin Labelling; fMRI: Functional magnetic resonance imaging; MLG: Generalized Linear Model; ANOVA: analysis of variance; GSS: Groeninger Sleep Scale; EDI: Ego Dissolution
Inventory; PVT: Psychomotor Vigilance Task; DSST: Digit Symbol Substitution Task; POMS: Profile of Mood States; CCT: Cognitive Control Test; VAS: Visual Analogue Scale;
PANAS: Positive and Negative Affect Scale; DASS: Depression, Anxiety and Stress Scale; ARCI: Addiction Research Central Inventory; AMRS: Adjective Mood Rating Scale;
SOCQ: States of Consciousness Questionnaire. Source: Authors.
Traditional indigenous medicine and other substances were also investigated: mescaline (2 studies), S-ketamine (1
study), ketamine (1 study), dimethyltryptamine (DMT) (1 study), ibogaine (1 study), and ayahuasca (2 studies) (Table 4).
Table 4 - Ayahuasca and N,N-dimethyltryptamine (DMT), Ketamine, Ibogaine and Mescaline.
Drug(s)
Authors/Year
Sample
(N/Age/Gender)
Method
Measurements
Results
Ayahuasca
Rossi et al.
2023
17 healthy
subjects
± 20-36 years
-
Proof-of-concept,
randomized, double-blind,
placebo-controlled design
evaluated the effects in
social cognition variables,
subjective measurements,
safety, and tolerability after
administration of CBD or
placebo, followed by a
single dose of ayahuasca.
REFE task; MET;
VAMS.
The study found significant reductions in
reaction times for emotion recognition tasks in
both the ayahuasca and CBD groups without
significant differences between the groups.
Both groups showed significant reduction in
anxiety, sedation, cognitive deterioration, and
discomfort. The study suggests that both drugs
could be applied to clinical populations with
anxiety disorders, and further trials with larger
samples are needed to confirm these findings.
Ayahuasca
Rocha et al.
2021
22 healthy
subjects
± 28.5 years
15M/7F
Randomized, double-blind,
placebo-controlled, parallel-
group study. The study
evaluated the effects of a
single dose of ayahuasca
during a cognitive test of
emotion recognition in facial
expressions, as well as
subjective effects,
tolerability measures and
plasma BDNF levels. The
test was performed before
and after drug ingestion, and
REFE.
Results showed that a single dose of ayahuasca
did not significantly modify the recognition of
emotions in facial expressions compared to
placebo. The study also found that ayahuasca
was well tolerated, mainly producing nausea,
gastrointestinal discomfort and vomiting.
Participants reported visual effects,
tranquility/relaxation, and well-being, with few
reports of anxiety and transient confusion. No
significant effects were observed on
cardiovascular measures and BDNF levels. The
study also found a significant deterioration of

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again at various times up to
3 months after drug
ingestion. The study also
evaluated the stability of
ayahuasca alkaloids during
the study period.
alkaloids, especially for dimethyltryptamine
(DMT), dependent on metabolization time.
DMT;
S-ketamine
Daumann
et al. 2010
14 healthy
subjects
± 26-42 years
8M/6F
An event-related,
randomized, double-blind,
crossover, fMRi study was
designed to investigate the
effects of DMT and S-
ketamine during alert states.
A target detection test with
visual and auditory cues
was used to capture
neuronal correlates of
phasic alertness. The effects
of DMT and
S-ketamine on alertness in
participants were
investigated using a target
detection test with visual and
auditory cues.
HRS; APZ-OAV.
Results showed that DMT administration led to
decreased neuronal activation during task
performance, particularly in extrastriate regions
during visual alerting and in temporal regions
during auditory alerting. In contrast, S-ketamine
administration led to increased cortical
activation in the left insula and precentral gyrus
in the auditory modality.
Ketamine
Lofwall et al.
2006
18 healthy
subjects
± 24 years
8M/10F
Single doses of
intramuscular injections of
ketamine or placebo were
administered to participants
in a double-blind, placebo-
controlled, crossover study.
The effects of ketamine on
memory, working memory,
time estimation,
psychomotor performance,
and subjective experience
were assessed repeatedly for
5 hours after drug
administration. Various
cognitive tests were used to
evaluate the effects of
ketamine on memory,
attention, and psychomotor
performance. The study also
evaluated the subjective
effects of ketamine using
questionnaires.
n-back task; VAS;
6-point confidence
scale; Goodman
Kruskal gamma
correlation; HRS;
M-Scale; Episodic
Memory Task;
DSST.
Results showed that ketamine selectively
impaired encoding while sparing retrieval
(Episodic Memory Task), working memory
while sparing attention, and Digit Symbol
Substitution Test (DSST) speed while sparing
accuracy. Ketamine did not significantly impair
recognition or source memory, metamemory, or
time estimation. The study also found that
memory measures were less sensitive to the
effects of ketamine than subjective or
psychomotor measures. The subjective effects
lasted longer than memory and most
psychomotor impairments. Overall, the study
suggests that ketamine produces selective,
transient, dose- and time-related effects on
memory, attention, psychomotor performance,
and subjective experience.
Ibogaine
Forsyth et al.
2016
21 healthy
subjects
± 20-40 years
Only male
Randomized, double-blind,
placebo-controlled study
with participants who
received a single dose of 20
mg of ibogaine after 6 days
of pre-treatment with
paroxetine, double-blind or
placebo. The study
evaluated the influence of
ibogaine on psychological
variables that reflect mood
and cognitive functions
using a battery of
psychometric tests.
The article does
not specify the
evaluation method
but reports that
responses were
compared to a
battery of
psychometric tests
and subjective
mood ratings
performed before
and 2 hours after
ibogaine dosing.
Psychological tests
were chosen based
on the
responsiveness to
opioid and
serotonergic
ligands.
Results suggest that a single 20 mg dose of
ibogaine had minimal influence on
psychological tests and mood assessments. The
ability to selectively ignore distracting spatial
information showed some evidence of
modulation; however, this effect was limited to
the least challenging condition, which casts
doubt on the reliability of this result. The study
was unable to identify stimulant effects after
single doses of 20 mg of ibogaine.
Mescaline;
LSD;
Psilocybin
Ley et al. 2023
32 healthy
subjects
25-44 years
16M/16F
Randomized, double-blind,
placebo-controlled, cross-
over design
VASs; AMRS;
5D-ASC; SOCQ.
The study compared the acute effects of
mescaline, LSD, and psilocybin in healthy
participants. The subjective effects of the three
substances were found to be comparable at
psychoactive-equivalent doses. The study found
no evidence of qualitative differences in altered
states of consciousness induced by equally
doses of mescaline, LSD, and psilocybin. The
subjective experience did not significantly
differ between the three substances. The study

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supports dose finding for research and
psychedelic-assisted therapy, indicating that
these substances can be used in a controlled and
monitored setting for therapeutic purposes.
Mescaline
Halpern et al.
2005
3 groups of the
Navajo ethnic
group, in which:
61 belong to the
NAC religion
and consume
peyote regularly.
36 individuals
with alcohol
dependence, but
sober for 2
months.
79 individuals
who use peyote,
alcohol, or
another
substance.
± 18-45 years
Only male
The study recruited three
groups of Navajo Indians,
including NAC members
who regularly ingested
peyote, individuals with
alcohol dependence, and a
comparison group reporting
minimal use of any
substance. The researchers
then administered a
screening interview and ten
neuropsychological tests of
memory and
attentional/executive
functions to each participant.
The study was a cross-
sectional design, and all
assessments were conducted
on the Navajo Nation
reservation.
Stroop test; RMHI;
WRAT-3;
WAIS- R; ROCF;
WCST; WMS;
RPM; Trails Make
A and B
The results of the article showed that Navajo
Indians who regularly ingested peyote in a
religious setting did not exhibit significant
cognitive impairments compared to those with
minimal substance use. However, individuals
with past alcohol dependence showed
significant deficits on the RMHI and two
neuropsychological measures. The study
suggests that peyote use in a religious context
may not have long-term residual psychological
or cognitive effects.
Abbreviations: M: male subjects; F: female subjects; mg: milligrams; μg/mcg: micrograms; CBD: Cannabidiol; DMT: N,N-dimethyltryptamine; LSD: lysergic acid diethylamide;
BDNF: brain-derived neurotrophic factor; REFE: Facial Expression Emotion Recognition Test; MET: Multifaceted Empathy Test; APZ-OAV: Mental Abnormality Status Test;
VAMS: Visual Analog Mood Scale; HRS: Hallucinatory Rating Scale; fMRI: Functional magnetic resonance imaging; n-back task: Continuous Performance Task; VAS: Visual
Analogue Scale; DSST: Digit Symbol Substitution Task; 5-HT2A: serotonergic receptor; 5D-ASC: 5-Dimensional Altered States of Consciousness Rating Scale; WAIS- R: Wechsler
Adult Intelligence Scale – Revised; RMHI: Mental Health Status Assessment Inventory; RPM: Raven Progressive Matrices; WRAT-3: Wide Range Achievement Test-3; ROCF: Rey-
Osterreith Complex Figure Test; WMS: Wechsler Memory Scale; RSFC: Resting-state functional connectivity; NAC: Native American Church; AMRS: Adjective Mood Rating Scale;
SOCQ: States of Consciousness Questionnaire. Source: Authors.
Eleven (11) studies compared psychedelic serotoninergic drugs with each other, or with another type of drug, like
modafinil, pindolol, ethanol, methylphenidate (MPH), ∆9-tetrahydrocannabinol (THC), among others.
Thirty-six (36) studies investigated male and female subjects, with prevalence for male subjects. Five (5) studies were
performed with male subjects. The ages of the subjects ranged from 18-65 years of age. Thirty-six (36) articles chose the double-
blind, randomized, placebo-controlled clinical trial strategy as their main evaluation method (Ley, et al., 2023; Rossi, et al., 2023;
De Wit, et al., 2022; Cavanna, et al., 2022; Rocha, et al., 2021; Mason, et al., 2021; Holze, et al., 2021; Smigielski, et al., 2020;
Gabay, et al., 2019; Schmidt, et al., 2018a; Schmidt, et al., 2018b; Haijen, et al., 2018; Dolder, et al., 2018; Barrett, et al., 2018;
Schmidt, et al., 2017; Pokorny, et al., 2017; Forsyth, et al., 2016; Kirkpatrick, et al., 2015; Schmid, et al., 2015; Schmid, et al.,
2014; Hysek, et al., 2014; Kometer, et al., 2013; Lansbergen, et al., 2011; Daumann, et al., 2010; Bedi, et al., 2010; Hasler, et
al., 2009; Dumont, et al., 2008; Wittmann, et al., 2007; Lofwall, et al., 2006; Hasler, et al., 2004; Lamers, et al., 2003; Spitzer,
et al., 2001; Gouzoulis-Mayfrank, et al., 1999; Schreckenberger, et al., 1998; Duke & Keeler, 1968; Goldberger, L., 1966). Some
studies added other interventions to research in order to more rigorously assess the levels of safety or effectiveness of the aspects
studied, for example: sixteen (16) studies used crossing techniques (cross-over design) to compare the effects of different
treatments or interventions in the same group of participants (Ley, et al., 2023; Holze, et al., 2021; Schmidt, et al., 2018a;
Schmidt, et al., 2018b; Dolder, et al., 2018; Schmid, et al., 2015; Schmid, et al., 2014; Hysek, et al., 2014; Carhart-Harris, et al.,
2012b; Lansbergen, et al., 2011; Daumann, et al., 2010; Dumont, et al., 2008; Lofwall, et al., 2006; Vollenweider, et al., 2005;
Halpern, et al., 2005; Lamers, et al., 2003).
Thirteen (13) studies used within-subject procedures (Smigielski, et al., 2020; Hutten, et al., 2020; Schmidt, et al.,
2018a; Kuypers, et al., 2018; Haijen, et al., 2018; Barrett, et al., 2018; Schmidt, et al., 2017; Pokorny, et al., 2017; Roseman, et
al., 2016; Kuypers, et al., 2014; Kometer, et al., 2013; Bedi, et al., 2010; Hasler, et al., 2009), in which each participant is exposed
to all independent variable levels in random order. This intervention allows each participant to serve as their own control, thus

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increasing the statistical power of the study and reducing the effects of individual differences between participants. Three (3)
studies used dose-response/dose-effect design techniques to gradually assess psychological and physiological effects (Holze, et
al., 2021; Barrett, et al., 2018; Hasler, et al., 2004). Two (2) studies used the double-dummy technique, in which the inactive
placebo has similar perceptual effects to the studied drug, for example: smell or taste, with the intention of further reducing the
possibility of bias (Haijen, et al., 2018; Lamers, et al., 2003). Three (3) studies used the counterbalanced technique (Smigielski,
et al., 2020; Gabay, et al., 2019; Vollenweider, et al., 2005), in which the order of presentation of the experimental conditions is
systematically varied between participants to ensure that each condition displayed an equal number of times in each position.
3.3 Main results
Tables 1-4 also present the main results found. Forty-six (46) studies were selected and included different cognitive and
subjective task-based evaluations with healthy subjects. Fifteen (15) studies used the 5-Dimensional Altered States of
Consciousness Rating Scale (5D-ASC), to assess the subjective effects of hallucinogenic substances in experimental sessions.
The 5D-ASC is a standardized questionnaire composed of 94 items to be answered on visual analogue scales where there are
items that address concepts about: experience of unity with the whole, spiritual experience, state of bliss, perspicacity,
disincarnation, control and cognition impaired, anxiety, complex images, elementary images, audiovisual synesthesia and altered
meaning of perceptions (Ley, et al., 2023; De Wit, et al., 2022; Mason, et al., 2021; Holze, et al., 2021; Smigielski, et al., 2020;
Hutten, et al., 2020; Gabay, et al., 2019; Schmidt, et al., 2018b; Dolder, et al., 2018; Pokorny, et al., 2017; Schmid, et al., 2014;
Kometer, et al., 2013; Hasler, et al., 2009; Wittmann, et al., 2007; Hasler, et al., 2004). Ten (10) studies used the Adjective Mood
Rating Scale (AMRS), which assesses mood states based on a self-assessment with the help of adjectives (Ley, et al., 2023;
Schmidt, et al., 2018a; Dolder, et al., 2018; Schmidt, et al., 2017; Schmid, et al., 2014; Hysek, et al., 2014; Hasler, et al., 2009;
Wittmann, et al., 2007; Vollenweider, et al., 2005; Hasler, et al., 2004). The Visual Analog Scale (VAS) test was repeatedly used
in seven (7) studies to assess subjective effects related to sociability, including categories such as: “feeling happy”, “open” and
“close to others” (Ley, et al., 2023; Holze, et al., 2021; Hutten, et al., 2020; Dolder, et al., 2018; Hysek, et al., 2014; Bedi, et al.,
2010; Lofwall, et al., 2006). The Multifaceted Empathy Test (MET), which is a task that assesses different aspects of empathy,
classified as: “cognitive and emotional”, was the instrument used in six (6) studies (Rossi, et al., 2023; Gabay, et al., 2019;
Pokorny, et al., 2017; Schmid, et al., 2014; Kuypers, et al., 2014; Hysek, et al., 2014). Four (4) studies also applied the
psychometric test State/Trait Anxiety Questionnaire (STAI), used to measure emotional states of anxiety, and in one (1) study
the STAI-T, which evaluates trait anxiety, and the STAI-S, which measures state anxiety, were used (Cavanna, et al., 2022;
Schmidt, et al., 2018a; Dolder, et al., 2018; Hasler, et al., 2009). Also, the Facial Expression Emotion Recognition Test (FERT),
which assesses the effects of substances on the recognition of basic facial emotions (i.e., happiness, sadness, anger, and fear)
(Schmidt, et al., 2018a; Dolder, et al., 2018; Schmid, et al., 2014; Hysek, et al., 2014), as well as the mood self-assessment
questionnaire Profile of Mood States (POMS), used to assess various mood states, such as tension, depression, anger, vigor,
fatigue, and confusion (De Wit, et al., 2022; Hutten, et al., 2020; Kuypers, et al., 2018; Kuypers, et al., 2014; Bedi, et al., 2010);
and the Positive and Negative Affect Scale (PANAS), a standardized questionnaire used to measure positive and negative affect,
understood as two independent dimensions of mood (De Wit, et al., 2022; Cavanna, et al., 2022; Holze, et al., 2021; Pokorny, et
al., 2017). The n-back task, or Continuous Performance Test, which consists of the sequential visual presentation of single letters,
where subjects need to press a button when a target stimulus appears – the definition of the target differs in relation to the
experimental conditions –, which appeared in two other articles (Barrett, et al., 2018; Lofwall, et al., 2006). The Interpersonal
Reactivity Index (IRI), a self-assessment questionnaire used to measure notions of empathy (Pokorny, et al., 2017; Kuypers, et
al., 2014; Hysek, et al., 2014); the Stroop Test, a neuropsychological test that measures concepts of selective attention and
cognitive flexibility (Cavanna, et al., 2022; Barrett, et al., 2018; Halpern, et al., 2005); and the Go/No-go task, a computerized

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test used to assess inhibitory control by the ability to inhibit an overbearing response to digital stimuli (Cavanna, et al., 2022;
Schmidt, et al., 2018b; Schmidt, et al., 2017) were also adopted in three studies. In addition, the following instruments were
used: Alternative Uses Task (AUT), used to assess the notion of “divergent thinking” (Cavanna, et al., 2022; Mason, et al., 2021;
Prochazkova, et al., 2018); Moral Dilemma Task (MDT), a test that measures the extent to which research participants prioritize
utilitarian (maximizing the greater good) or deontological (following rules and moral principles) considerations in their decision-
making (Pokorny, et al., 2017); Social Value Orientation (SVO), which assesses an individual's social preferences, specifically
their tendency to cooperate or compete with others in social situations. The test assesses an individual's willingness to share
resources and make decisions that benefit themselves and others (Schmid, et al., 2014; Hysek, et al., 2014); Picture Concept
Task (PCT), which is an instrument used to measure creative thinking, through notions of divergent and convergent thinking
(Mason, et al., 2021; Prochazkova, et al., 2018); Digit symbol substitution task (DSST), which deals with neuropsychological
assessment used to measure executive function, mental flexibility and associative learning (Hutten, et al., 2020; Barrett, et al.,
2018; Lofwall, et al., 2006); Groninger Sleep Scale (GSS), this scale helps to assess the quality and quantity of sleep from the
previous night (Hutten, et al., 2020; Haijen, et al., 2018; Kuypers, et al., 2014); Hallucinogenic Rating Scale (HRS), a self-rating
scale on the psychological effects experienced by hallucinogenic drugs (Daumann, et al., 2010; Lofwall, et al., 2006); The Trust
Game, which was used to assess the ability to infer another person's mental state and their ability to cooperate to make beneficial
choices (Gabay, et al., 2019; Kuypers, et al., 2014); The Tower of London (TOL), a neuropsychological test used to assess
planning and problem-solving skills (Lamers, et al., 2003). Apart from behavioral and subjective measurements, seventeen (17)
of the selected studies also used neuroimaging methods such as functional magnetic resonance imaging (fMRi), positron emission
tomography (PET), and Arterial Spin Labeling (ASL) to evaluate brain activity after drug or placebo administration (Ley, et al.,
2023; Cavanna, et al., 2022; Mason, et al., 2021; Smigielski, et al., 2020; Gabay, et al., 2019; Schmidt, et al., 2018a; Schmidt, et
al., 2018b; Schmidt, et al., 2017; Roseman, et al., 2016; Carhart-Harris, et al., 2012a; Carhart-Harris, et al., 2012b; Lansbergen,
et al., 2011; Daumann, et al., 2010; Daumann, et al., 2003; Spitzer, et al., 2001; Gouzoulis-Mayfrank, et al., 1999;
Schreckenberger, et al., 1998). One (1) study (Kirkpatrick, et al., 2015) applied a five-variable personality trait test, the
Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI), which intended to examine scales of neuroticism,
extraversion, openness, agreeableness, and conscientiousness.
In some studies (Mason, et al., 2021; Dolder, et al., 2018; Forsyth, et al., 2016), the cognitive tests used were not
specifically detailed in the information provided. However, the procedures mostly focused on measuring working memory,
selective attention, verbal memory, psychological well-being, and associative memory using fMRI or self-rating scales of
psychological states. In one study (Hasler, et al., 2009), measures were applied with the intention of assessing cognitive
performance. These are part of the battery of neuropsychological tests developed by the University of Cambridge, the CANTAB
– Cambridge Neuropsychological Test Automated Battery. It is a battery of digital tests that aims to assess different cognitive
domains, including attention, memory, and executive functions.
Some studies used criteria to ensure that the recruited subjects could be considered healthy: a) The practice of abstinence
by the participants was requested in twenty-eight (28) of the analyzed studies (Ley, et al., 2023; Rossi, et al., 2023; De Wit, et
al., 2022; Rocha, et al., 2021; Mason, et al., 2021; Holze, et al., 2021; Hutten, et al., 2020; Gabay, et al., 2019; Schmidt, et al.,
2018a; Schmidt, et al., 2018b; Kuypers, et al., 2018; Haijen, et al., 2018; Schmidt, et al., 2017; Pokorny, et al., 2017; Roseman,
et al., 2016; Schmid, et al., 2015; Kirkpatrick, et al., 2015; Schmid, et al., 2014; Kuypers, et al., 2014; Hysek, et al., 2014;
Kometer, et al., 2013; Carhart-Harris, et al., 2012a; Carhart-Harris, et al., 2012b; Lansbergen, et al., 2011; Bedi, et al., 2010;
Dumont, et al., 2008; Lofwall, et al., 2006; Vollenweider, et al., 2005). Depending on the conditions of each methodological
procedure, the abstinence time varied between hours before the tests started and could reach up to 3 months. In general,
abstinence from licit drugs, such as alcohol, nicotine and caffeine were required. b) Two (2) articles did not admit subjects who

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had gone through episodes of suicide attempts (De Wit, et al., 2022; Pokorny, et al., 2017); c) One (1) study left out people who
had a criminal history (Lamers, et al., 2003); d) Another did not include people who had a formal job during the night period
(Kirkpatrick, et al., 2015). e) Interestingly, some studies considered polydrug-using participants as healthy people (Kuypers, et
al., 2018; Haijen, et al., 2018; Kuypers, et al., 2014; Lansbergen, et al., 2011; Lamers, et al., 2003); f) Eight (8) studies had as
exclusion criteria volunteers who consumed more than 10 cigarettes per day (Dolder, et al., 2018; Schmidt, et al., 2018a; Schmidt,
et al., 2017; Kirkpatrick, et al., 2015; Schmid, et al., 2015; Schmid, et al., 2014; Hysek, et al., 2014; Lofwall, et al., 2006).
Broadly speaking, researchers considered participants healthy based on their medical (cardiopathies, hypertension, chronic
diseases, chemical dependency, traumas) and psychiatric history, acquired either through self-report, interviews or through
physical and laboratory examination.
The participation of female volunteers who were pregnant or breastfeeding was excluded for safety reasons in twenty-
one (21) articles (Ley, et al., 2023; Rossi, et al., 2023; De Wit, et al., 2022; Rocha, et al., 2021; Holze, et al., 2021; Hutten, et al.,
2020; Schmidt, et al., 2018b; Haijen, et al., 2018; Barrett, et al., 2018; Schmidt, et al., 2017; Pokorny, et al., 2017; Roseman, et
al., 2016; Schmid, et al., 2015; Kirkpatrick, et al., 2015; Kuypers, et al., 2014; Carhart-Harris, et al., 2012a; Carhart-Harris, et
al., 2012b; Lansbergen, et al., 2011; Bedi, et al., 2010; Lofwall, et al., 2006; Lamers, et al., 2003). The menstrual cycle conditions
of female volunteers were mentioned in twelve (12) articles (De Wit, et al., 2022; Mason, et al., 2021; Holze, et al., 2021; Hutten,
et al., 2020; Dolder, et al., 2018; Schmidt, et al., 2017; Kirkpatrick, et al., 2015; Schmid, et al., 2014; Hysek, et al., 2014; Hasler,
et al., 2009; Vollenweider, et al., 2005; Hasler, et al., 2004).
Thirty-four (34) studies had participants who had previous experiences with psychedelic substances at least one time in
life (Rossi, et al., 2023; Ley, et al., 2023; De Wit, et al., 2022; Cavanna, et al., 2022; Rocha, et al., 2021; Mason, et al., 2021;
Holze, et al., 2021; Hutten, et al., 2020; Gabay, et al., 2019; Schmidt, et al., 2018a; Schmidt, et al., 2018b; Prochazkova, et al.,
2018; Kuypers, et al., 2018; Dolder, et al., 2018; Haijen, et al., 2018; Barrett, et al., 2018; Schmidt, et al., 2018; Pokorny, et al.,
2017; Roseman, et al., 2016; Schmid, et al., 2015; Kirkpatrick, et al., 2015; Schmid, et al., 2014; Kuypers, et al., 2014; Hysek,
et al., 2014; Carhart-Harris, et al., 2012a; Carhart-Harris, et al., 2012b; Lansbergen, et al., 2011; Bedi, et al., 2010; Hasler, et al.,
2009; Dumont, et al., 2008; Wittmann, et al., 2007; Halpern, et al., 2005; Hasler, et al., 2004; Lamers, et al., 2003).
Five (5) studies addressed the phenomenon of microdosing, specifically analyzing the practice with the use of psilocybin
mushrooms (2) and microdoses of LSD (3), apart from using batteries of cognitive tests in order to assess various self-reported
measures of psychological traits such as mood, anxiety, depression, stress, well-being, and mindfulness (De Wit, et al., 2022;
Cavanna, et al., 2022; Holze, et al., 2021; Hutten, et al., 2020; Prochazkova, et al., 2018).
Twenty-eight (28) articles highlighted the use of the “washout period” technique, that is, a rest interval between testing
sessions to ensure that the effects of the previous treatment disappeared before the next test was administered and the participants
did not develop a possible tolerance (Ley, et al., 2023; De Wit, et al., 2022; Cavanna, et al., 2022; Holze, et al., 2021; Smigielski,
et al., 2020; Hutten, et al., 2020; Schmidt, et al., 2018a; Schmidt, et al., 2018b; Kuypers, et al., 2018; Haijen, et al., 2018; Barrett,
et al., 2018; Dolder, et al., 2018; Pokorny, et al., 2017; Schmidt, et al., 2017; Schmid, et al., 2015; Kirkpatrick, et al., 2015;
Schmid, et al., 2014; Hysek, et al., 2014; Kometer, et al., 2013; Carhart-Harris, et al., 2012b; Lansbergen, et al., 2011; Dumont,
et al., 2008; Wittmann, et al., 2007; Lofwall, et al., 2006; Vollenweider, et al., 2005; Halpern, et al., 2005; Spitzer, et al., 2001;
Duke & Keeler, 1968).
Sixteen (16) studies also used other substances to verify the potential for performance or cognitive enhancement in
comparison or interaction with another psychedelic. Among the most used drugs are: modafinil, methylphenidate, alcohol, and
dextromethorphan (DXM) (Rossi, et al., 2023; Dolder, et al., 2018; Haijen, et al., 2018; Barrett, et al., 2018; Kuypers, et al.,
2018; Schmidt, et al., 2018a; Schmidt, et al., 2017; Schmid, et al., 2015; Schmid, et al., 2014; Kuypers, et al., 2014; Lansbergen,

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et al., 2011; Daumann, et al., 2010; Hasler, et al., 2009; Dumont, et al., 2008; Lamers, et al., 2003; Gouzoulis-Mayfrank, et al.,
1999).
Exams to certify the consumption of other drugs, mostly made from urine, hair, and saliva analyses, were also performed
in thirty-four (34) studies (Ley, et al., 2023; De Wit, et al., 2022; Cavanna, et al., 2022; Mason, et al., 2021; Holze, et al., 2021;
Rocha, et al., 2021; Hutten, et al., 2020; Gabay, et al., 2019; Barrett, et al., 2018; Dolder, et al., 2018; Schmidt, et al., 2018a;
Kuypers, et al., 2018; Pokorny, et al., 2017; Schmidt, et al., 2017; Roseman, et al., 2016; Kuypers, et al., 2016; Forsyth, et al.,
2016; Kirkpatrick, et al., 2015; Schmid, et al., 2015; Kuypers, et al., 2014; Schmid, et al., 2014; Hysek, et al., 2014; Kometer, et
al., 2013; Carhart-Harris, et al., 2012a; Lansbergen, et al., 2011; Bedi, et al., 2010; Daumann, et al., 2010; Hasler, et al., 2009;
Dumont, et al., 2008; Wittmann, et al., 2007; Lofwall, et al., 2006; Vollenweider, et al., 2005; Hasler, et al., 2004; Lamers, et
al., 2003). In general, moderate use of marijuana (Cannabis) was accepted.
Of the forty-six (46) selected articles, the race/ethnicity of the participants were mentioned only in five (5) articles (De
Wit, et al., 2022; Hutten, et al., 2020; Barrett, et al., 2018; Kirkpatrick, et al., 2015; Bedi, et al., 2010). Among the juxtaposed
racial and ethnic categories, there were: 454 Caucasians; 8 Asians; 4 Blacks; 14 Mestizos; 7 Hispanic and 1 Indian.
It is also possible to note that the form of recruitment of participants was carried out mostly within the spaces where the
scientific studies themselves were projected, that is, within the Universities. The presence of volunteers who came from academic
spaces was verified in nineteen (19) articles (Holze, et al., 2021; Hutten, et al., 2020; Kuypers, et al., 2018; Barrett, et al., 2018;
Dolder, et al., 2018; Schmidt, et al., 2018b; Haijen, et al., 2018; Pokorny, et al., 2017; Schmidt, et al., 2017; Kuypers, et al.,
2016; Schmid, et al., 2015; Schmid, et al., 2014; Kuypers, et al., 2014; Hysek, et al., 2014; Hasler, et al., 2009; Wittmann, et al.,
2007; Vollenweider, et al., 2005; Hasler, et al., 2004; Lamers, et al., 2003). Other forms of recruitment were based on contact in
the dance scene, mostly in raves, online advertisements, or social networks and “word of mouth”.
4. Discussion
The present study is a systematic review of investigations aimed at evaluating the effects of psychedelics in cognitive
functions in healthy volunteers. Of the experimental studies analyzed, only forty-six (46) met the inclusion criteria. The results
obtained showed that MDMA was the most studied drug, with eighteen (18) articles (Gabay, et al., 2019; Dolder, et al., 2018;
Haijen, et al., 2018; Kuypers, et al., 2018; Schmidt, et al., 2018a; Schmidt, et al., 2017; Kuypers, et al., 2016; Schmid, et al.,
2015; Kirkpatrick, et al., 2015; Schmid, et al., 2014; Kuypers, et al., 2014; Hysek, et al., 2014; Lansbergen, et al., 2011; Bedi, et
al., 2010; Hasler, et al., 2009; Dumont, et al., 2008; Vollenweider, et al., 2005; Lamers, et al., 2003). Fourteen (14) articles were
published with psilocybin (Ley, et al., 2023; Cavanna, et al., 2022; Mason, et al., 2021; Smigielski, et al., 2020; Prochazkova, et
al., 2018; Barrett, et al., 2018; Pokorny, et al., 2017; Kometer, et al., 2013; Carhart-Harris, et al., 2012a; Carhart-Harris, et al.,
2012b; Wittmann, et al., 2007; Hasler, et al., 2004; Gouzoulis-Mayfrank, et al., 1999; Duke & Keeler, 1968). There were six (6)
studies performed with LSD (Ley, et al., 2023; De Wit, et al., 2022; Hutten, et al., 2020; Schmidt, et al., 2018b; Roseman, et al.,
2016; Goldberger, L., 1966). Other two (2) studies (Rossi, et al., 2023; Rocha, et al., 2021) focused on investigating the effects
of ayahuasca, and one (1) its psychoactive-containing molecule, DMT (Daumann, et al., 2010). Eight (8) studies investigated the
effects of other psychedelic drugs: S-ketamine (Daumann, et al., 2010) and ketamine (Lofwall, et al., 2006), mescaline (Ley, et
al., 2023; Halpern, et al., 2005), 3,4-methylenedioxy-amphetamine (MDE) (Spitzer, et al., 2001; Gouzoulis-Mayfrank, et al.,
1999; Schreckenberger, et al., 1998), and ibogaine (Forsyth, et al., 2016).
Results from the studies performed with each one of these substances are discussed in the next sections.

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4.1 MDMA
Schmid and coworkers (2014) used the FERT to investigate whether healthy volunteers developed empathy for
situations they considered positive. MDMA enhanced emotional empathy for positive emotionally charged situations and tended
to reduce the recognition of sad faces. However, the drug had no effects on cognitive empathy in the MET or social cognitive
inferences in the Movie for the Assessment of Social Cognition (MASC). MDMA produced subjective ‘empathogenic’ effects,
such as drug liking, closeness to others, openness, and trust.
In other studies, MDMA also produced effects classified as “empathogenics”, ie. pupil dilation, subjective effects related
to well-being, drug liking, closeness to others, openness, happiness, confidence, sexual arousal, changes in consciousness
(Dolder, et al., 2018; Schmid, et al., 2014) and psychomotor performance (Lamers, et al., 2003). Interesting, MDMA reduced
arousal levels elicited by negative sounds (Kuypers, et al., 2018). One article (Hysek, et al., 2014) found that MDMA increased
“emotional empathy” and social behavior in male participants but impaired the identification of negative emotions on the FERT,
particularly in female participants. In contrast, the results of another study showed that although MDMA, at a low dose (75 mg),
induced greater empathy, attitudes such as trust, and reciprocity remained unchanged (Kuypers, et al., 2014).
Another finding (Gabay, et al., 2019) showed that MDMA can increase cooperative behavior in social decision-making
contexts when playing with trusted opponents. This effect was associated with changes in neuronal activity in regions linked to
social cognition. Nevertheless, the study highlights the context-specific nature of MDMA's effects on decision-making. Also,
the study found no evidence to support the hypothesis that MDMA's dopaminergic modulation was responsible for the observed
results. Similarly, Kirkpatrick and coworkers (2015) suggest that MDMA produces prosocial effects that depend on the social
closeness of relationships.
Bedi and coworkers (2010) found that MDMA (1.5 mg/kg) altered a behavioral indicator of social cognition.
Specifically, it robustly reduced recognition of fearful faces, without changing recognition of other emotions from facial or vocal
cues. MDMA also produced self-reports of loving feelings and friendliness but decreased the accuracy of subjects in identifying
fear in others.
Another study (Schmidt, et al., 2018a) compared the effects of MDMA, modafinil and methylphenidate in negative
emotional processing in healthy subjects and used fMRI to evaluate brain activation. Fearful faces induced significant activation
in various brain regions, including the amygdala, fusiform gyrus, anterior cingulate and orbitofrontal cortex, calcarine sulcus,
dorsal striatum, and insula and inferior frontal gyrus. Modafinil increased brain activation in response to fearful faces within the
limbic-cortical-striatal-pallidal-thalamic circuit relative to placebo. The drug also increased amygdala responses to fearful faces
compared with MDMA, thus suggesting the positive behavioral and neurobiological effects of MDMA on emotional processing.
MDMA was also shown to increase positive and negative mood ratings and elevate plasma concentrations of oxytocin
(Kuypers, et al., 2018; Schmid, et al., 2014; Hysek, et al., 2014), prolactin (Schmid, et al., 2014; Hysek, et al., 2014), and cortisol
(Hysek, et al., 2014). In addition, Haijen and coworkers (2018) demonstrated that MDMA did not affect endocannabinoid
concentrations, and that the MDMA-induced memory impairment which has consistently been demonstrated in human placebo-
controlled studies seems to be unrelated to the endocannabinoid system.
Lansbergen and coworkers (2011) showed that the combined ingestion of MDMA and THC affects induces continuous
electroencephalographic (EEG) oscillations differently than the sum of each drug alone, indicating potential interactions between
these substances. The changes in continuous EEG oscillations observed may be related to the impairment of task performance
often reported following drug ingestion, highlighting the importance of considering EEG measurements when evaluating the
cognitive effects of drug use.
One study (Schmidt, et al., 2017) showed that MDMA did not improve inhibitory performance, although fMRI results
indicated that MDMA significantly increased activation in the right middle/inferior frontal gyrus and superior parietal lobule

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compared with placebo. Additionally, it significantly reduced subjective calmness, i.e subjects felt more excited after the use
(Schmidt, et al., 2017).
The previous history of MDMA use was not predictive of memory impairment, but during MDMA use, verbal memory
was impaired (Kuypers, et al., 2016). Other results also showed that MDMA can significantly impair the level of sustained
attention and visual-spatial memory, but no evidence was found that the substance negatively affected functions related to
thought and emotions, when compared with modafinil and methylphenidate (Hasler, et al., 2009). The drug had no effects on
visual perception, planning ability and semantic memory retrieval (Lamers, et al., 2003). However, Dumont and coworkers
(2008) consistently observed impaired memory function after drug conditions, whereas impairment of psychomotor function and
attention was less consistent across the drug conditions.
Adverse effects were found after administration of the substance, as we could see, the main side effects reported were
lack of appetite, dry mouth, headache, negative subjective effects linked to fear (Dolder, et al., 2018) and significant impairments
in attention and memory, for example, in the ability to predict movements under divided attention (Lamers, et al., 2003).
Taken together, the results gathered above show no conclusive evidence that MDMA can improve cognition or on which
regions encephalic disorders are specifically related to their effects (Kuypers, et al., 2018; Kirkpatrick, et al., 2015; Vollenweider,
et al., 2005). One of the studies even explicitly warns that the use of the substance for cognitive enhancement purposes is not
recommended, as there is no rigorous assessment of the potential risks of long-term use (Vollenweider, et al., 2005).
4.2 3,4-methylenedioxyethylamphetamine (MDE)
Gouzoulis-Mayfrank and coworkers (1999) investigated the neurometabolic effects of MDE, psilocybin, and d-
methamphetamine in healthy volunteers. In the MDE group, frontal hypometabolism was more pronounced, except for the
anterior cingulate, which showed hyperactivity. The drug showed less attenuation of cognitive activation-related increases in left
frontocortical regions compared to psilocybin, indicating a potentially milder effect on cognitive function. Cognitive disturbances
were associated with both diminished activity in the bilateral frontal region and increased activity in the right anterior cingulate.
Spitzer and coworkers (2001) investigated differential effects of (R)- and (S)-MDE on measurements of
psychopathology, neuropsychological performance, and brain activation. Results showed that (S)-MDE induced increases in
mood, impairments in cognition and activated the right frontal cortex. (R)-MDE, on the other hand, increased depression, visual
feature processing, and activated the visual cortical and left frontal areas. The authors concluded that the entactogenic effects of
MDE are likely to be caused by the (S)-enantiomer, while (R)-MDE seems to respond for the neurotoxic effects of the drug. A
significant decrease in bilateral frontal cortex activity after MDE treatment was also found. However, the authors argue that PET
provides indirect measurements of cerebral glucose deficits and may have limitations in accurately capturing complex metabolic
processes in the brain (Schreckenberger, et al., 1998).
4.3 Psilocybin
One of the earlier studies included in the present review was performed by Duke & Keeler (1968). The authors showed
that both psilocybin and dextro-amphetamine produced a deficit in cognitive performance as compared to placebo. Psilocybin
significantly impaired performance of a complex task as compared to a simple task, suggesting that drug-induced muscular
incoordination was not responsible for decrements in performance.
Several years later, Gouzoulis-Mayfrank and coworkers (1999) showed that psilocybin increased regional metabolic
glucose utilization (rMRGlu) in distinct right hemispheric frontotemporal cortical regions, particularly in the anterior cingulate,
and decreased rMRGlu in the thalamus, suggesting a potential impact on cognitive functioning.

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In the beginning of the years 2000, Hasler and coworkers (2004) showed that the altered states of consciousness induced
by psilocybin, in a dose-dependent manner, are generally well tolerated and integrated by healthy individuals. However, it should
be noted that some participants reported adverse effects such as anxiety, confusion, and changes in time perception and working
memory (Wittmann, et al., 2007; Hasler, et al., 2004).
Psilocybin also significantly decreased cerebral blood flow and venous oxygenation in a way that correlated with its
subjective effects (Carhart-Harris, et al., 2012a). The pharmacophysiological interaction results revealed significant reductions
in positive coupling between the posterior cingulate cortex and the medial prefrontal cortex following ingestion (Carhart-Harris,
et al., 2012a). It was suggested that decreased activity and connectivity in the brain's connecting centers allows for an
unconstrained style of cognition (Carhart-Harris, et al., 2012a).
Carhart-Harris and coworkers (2012b) also showed greater sensory activation and more intense subjective effects after
psilocybin when compared to placebo. Greater activations were observed in the bilateral auditory cortex, somatosensory cortex,
superior parietal cortex, left visual association regions and the occipital pole after psilocybin. The drug also induced changes in
perception and altered self-referential processing, affecting self-other processing by modulating activity in the supragenual
cingulate cortex and insula (Smigielski, et al., 2020).
Kometer and coworkers (2013) used EEG to investigate psilocybin effects on alpha waves oscillations that regulate
cortical excitability and early visual-evoked P1 and N170 potentials in healthy human subjects. Results showed that the drug
strongly decreased pre-stimulus parieto-occipital alpha power values, thus preventing a subsequent stimulus-induced decrease
in alpha power (Kometer, et al., 2013). Furthermore, psilocybin strongly decreased N170 potentials associated with the onset of
visual perceptual changes, including visual hallucinations (Kometer, et al., 2013). These effects were blocked by pretreatment
with the serotonin (5-HT) 2A antagonist ketanserin, indicating that activation of 5-HT2A receptors by psilocybin modulates
neurophysiological and phenomenological indices of visual processing (Kometer, et al., 2013).
Pokorny and coworkers (2017) showed that psilocybin significantly increased explicit and implicit emotional empathy
in healthy human subjects compared to placebo. The study also found that psilocybin did not significantly affect cognitive
empathy or moral behavior, thus suggesting that the effects of psilocybin on social cognition are specific to emotional empathy
and may not directly influence moral decision-making. The findings of this study highlight the potential therapeutic applications
of psilocybin in improving social skills and empathy.
Convergent and divergent thinking performance was found to be improved after a non-blind microdose of psychedelic
mushrooms, while fluid intelligence was unaffected (Prochazkova, et al., 2018). Better performance was found in a second
session when compared to the first session. According to the authors, these results provide quantitative support for the cognitive-
enhancing properties of microdosed psychedelics (Prochazkova, et al., 2018).
Barrett and coworkers (2018) reported that psilocybin exerted dose-dependent effects on several cognitive functions,
including psychomotor performance, working memory, episodic memory, associative learning, and visual perception. There was
no evidence of psychological impairment or delirium with psilocybin.
Another study (Mason, et al., 2021) found that there were no reports of adverse effects during a psilocybin trial.
However, some research participants reported mild and brief symptomatic syndromes, for example: changes in mood, perception
and thought processes. These effects were generally well tolerated and disappeared within a few hours after administration of
the substance.
Cavanna and coworkers (2022) found that low doses of psilocybin mushrooms can result in noticeable subjective effects.
EEG results showed altered theta rhythms, associated with memory and attention processes, but without evidence to support the
improvement of well-being, creativity and other cognitive functions. Additionally, according to the study (Cavanna, et al, 2022),
anticipation plays a role, to some extent, in some of the anecdotal benefits attributed to microdosing psilocybin mushrooms.

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Other studies (Mason, et al., 2021; Barrett, et al., 2018; Wittmann, et al., 2007) showed that psilocybin did not produce
cognitive enhancement, but affected memory, perception, and creative thinking performances in several neuropsychological
assessments, therefore suggesting that it is premature to consider that psilocybin contributes to cognitive enhancement.
4.4 LSD
Goldberger (1966) evaluated effects on cognitive performance of LSD, placebo, and social isolation. The loss of the
sense of time was more profound and the difficulties in concentrating more debilitating and widespread with LSD when
compared to placebo. On the other hand, eight hours of isolation did not produce significant group effects of impairment or
improvement.
Schmidt and coworkers (2018b) showed that LSD administration impaired inhibitory performance and reduced neuronal
activity in several regions, including the right middle temporal gyrus, superior/middle/inferior frontal gyrus, left anterior
cingulate and superior frontal cortex, and left postcentral gyrus and cerebellum. The study also found that parahippocampal
activation during response inhibition was differentially related to inhibitory performance after placebo and LSD administration.
Additionally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive
and visual imagery impairments (Schmidt, et al., 2018b).
Roseman and coworkers (2016) found that under the influence of LSD, the visual cortex behaves as if it is processing
spatially localized visual information. This result suggests that LSD induces changes in the visual system that mimic the
processing of visual stimuli even when there is no external visual input. In addition, activation in the left superior frontal gyrus
under LSD exposure was also found to be negatively related to LSD-induced cognitive impairments and visual perceptions
(Roseman, et al., 2016).
Hutten and coworkers (2020) observed few adverse effects during the use of low doses of LSD, such as confusion and
anxiety, fatigue and increased blood pressure and heart rate and body temperature. These effects were mild and transient.
Flashback phenomena were also reported in some participants after LSD administration (Ley, et al., 2023).
Results obtained by De Wit, et al., (2022) considered that, in the context of a controlled environment and in a limited
number of administrations, low (13 or 26 μg) and repeated doses of LSD are safe but produce no significant changes in mood or
cognition in healthy participants. In contrast, Hutten, and coworkers (2020) showed that low doses of LSD (5, 10 and 20 μg)
exerted selective and beneficial effects on mood and cognition in most observations. Also, positive effects included an
improvement in positive mood, friendliness, arousal, and a decrease in attention lapses.
Ley and coworkers (2023) found no evidence of qualitative differences in altered states of consciousness induced by
equally strong doses of LSD, mescaline, and psilocybin. The subjective experience did not significantly differ between the three
substances. The study supports dose finding for research and psychedelic-assisted therapy, indicating that LSD can be used in a
controlled and monitored setting for therapeutic purposes.
4.5 Ayahuasca and DMT
Two studies investigated the effects of ayahuasca in cognitive functions (Rocha, et al., 2021; Rossi, et al, 2023). Rocha
and coworkers (2021) aimed to assess the acute and prolonged effects of a single dose of ayahuasca on the recognition of
emotions in facial expressions in healthy volunteers. The trial included a facial recognition task performed before and after drug
intake, subjective effects assessment, tolerability measures, and measurement of brain-derived neurotrophic factor plasma levels
(BDNF). The results showed that ayahuasca did not significantly modify FERT results compared to placebo. No significant
effects were observed on cardiovascular measures and BDNF. The study also highlighted the time-dependent deterioration of

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ayahuasca alkaloids, particularly DMT. Some participants reported feeling visual effects, tranquility/relaxation, and well-being
(Rocha, et al., 2021).
Ayahuasca also reduced reaction times for emotion recognition and empathy, improving (faster) emotional processing
and inducing an anxiolytic effect (Rossi, et al., 2023). Results also suggest that the acute administration of ayahuasca can have
both positive and negative effects on neuropsychological performance. In general, ayahuasca was well-tolerated, with mainly
nausea, gastrointestinal discomfort, and vomiting reported as side effects, and produced typical psychedelic/hallucinogenic
effects (Rossi, et al., 2023; Rocha, et al., 2021).
Daumann and coworkers (2010) investigated the effects of DMT on cognitive measurements and neurobiological
activation. It was also demonstrated that the administration of DMT alone led to a decrease in the blood oxygenation level-
dependent (BOLD) response during the performance of an alerting task, particularly in extrastriate regions during visual alerting
and in the temporal regions during an auditory stimulus (Daumann, et al., 2010). However, the study did not specifically assess
outcomes for cognitive enhancement, so further research is needed to better understand the effects of ayahuasca on psychological
functions (Rocha, et al., 2021). Thus, it is not clear that DMT, present in ayahuasca, can improve cognition (Rocha, et al., 2021;
Daumann, et al., 2010).
4.6 Ketamine
One article (Lofwall, et al., 2006) showed that ketamine produces selective and brief pharmacological effects (dose-
dependent) on cognitive functions related to memory, attention, psychomotricity, and subjective experience. Although concrete
evidence that ketamine can produce cognitive-enhancing effects was not provided, no evidence was found that the drug produces
significant harm.
Daumann and coworkers (2010) also showed that the administration of S-ketamine led to increased cortical activation
in the left insula and in the precentral gyrus, responsible for motor, auditory and emotional activities.
4.7 Ibogaine
Forsyth and coworkers (2016) investigated the effects of ibogaine in healthy male volunteers that received a single 20
mg dose of ibogaine after 6 days pretreatment with double-blind paroxetine or placebo. The authors used a battery of
psychometric tests and subjective mood ratings performed before and 2h after ibogaine. Results showed that ibogaine did not
alter psychological evaluation and mood ratings.
4.8 Mescaline
Ley and coworkers (2023) found no evidence of qualitative differences in altered states of consciousness induced by
equally doses of mescaline, LSD, and psilocybin. The subjective effects of the three substances were found to be comparable at
psychoactive-equivalent doses. Furthermore, adverse effects were reported. Mescaline caused slightly more subacute adverse
effects (12-24 h) than LSD and psilocybin.
Another study (Halpern, et al., 2005) showed that people of Navajo ethnicity, who regularly ingested peyote in a
religious setting, did not exhibit significant cognitive impairments compared to those with minimal substance use.
5. Conclusion
Taken together the results from the present study indicate that although several pieces of evidence suggest that the use
of psychedelics may improve cognitive performance, there are still important limitations regarding the differences in the
procedures adopted, small sample sizes, and insufficient range of testing in healthy volunteers. These limitations make it

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challenging to capture the full spectrum of experiences people might have in natural settings or with varying dosages. Assessing
effects across multiple dosages and different stages of the psychedelic experience could provide a more comprehensive
understanding of their impacts. This could encompass variations in intensity, duration, and potential therapeutic or adverse effects
at different points of the experience. To conclude, the results from the present review suggest that, although there were no serious
adverse effects resulting from the use of the psychedelic drugs investigated, further studies on the use of psychedelics with the
aim of improving cognitive enhancement in healthy people are still warranted.
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