2019/2020

Rui Pedro Leal Andrade

Terapêutica com psilocibina e depressão – uma revisão sistemática

Psilocybin-assisted therapy and depression – a systematic review

abril, 2020

Mestrado Integrado em Medicina

Área: Psiquiatria e Saúde Mental

Tipologia: Monografia

Trabalho efetuado sob a Orientação de:

Professor Doutor Miguel Bragança

Trabalho organizado de acordo com as normas da revista:

Journal of Psychopharmacology

Rui Pedro Leal Andrade

Terapêutica com psilocibina e

depressão – uma revisão sistemática

Psilocybin-assisted therapy and

depression – a systematic review

abril, 2020

If the doors of perception were cleansed every thing would appear to man as it is,

Infinite. For man has closed himself up,

till he sees all things thro’ narrow chinks of his cavern William Blake

1

Psilocybin-assisted therapy and depression: a systematic review

Corresponding Author: Rui P Andrade, Faculdade de Medicina da Universidade do Porto, Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal Email: ruiandrade43@gmail.com

Rui P Andrade a, Miguel Bragança b

a Faculty of Medicine of the University of Porto

b Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto, Portugal

2

Abstract Background: Psilocybin is a naturally occurring serotonin receptor agonist that can be, more commonly, found in the Psilocybe mushrooms. Consumed by indigenous cultures for millenia, Psilocybin, in the 1960s, was marketed in many countries under the trade name Indocybin, and was safely used as an adjunct to psychotherapy in the treatment of depression and anxiety, before its eventual ban. Recently, the safety and ease of practical use of psilocybin propelled its resurrection and positive preliminary reports on the safety and tolerability of psilocybin for multiples diseases, such as obsessive-compulsive disorder and addiction, have been published. Aims: The main objective of this review is to outline existing scientific information about the effects of Psilocybin-based therapy on patients diagnosed with depression. Methods: Using PubMed as the database, a research was conducted, based on the research words *Psilocybin and *Depression and targeting clinical trials. References of selected articles and review articles were also assessed. Results: A total of 4 articles met the inclusion criteria. 2 articles evaluate psilocybin effects in 32 patients with treatment-resistant depression. The remaining 2 articles evaluate psilocybin effects in 80 patients with cancer-related anxiety and depression. All articles showed that psilocybin produced immediate and substantial improvements in depression, that, ultimately, could sustain up to 6 months. Conclusion: Psilocybin-assisted therapy is a very appealing new possibility in the treatment of depression. However, due to the small populations of the existing trials, future studies are needed to prove this positive association and to fully understand Psilocybin´s mechanisms of action and effects.

Keywords: Psilocybin; Depression

3

Introduction

Psilocybin (4-phospholoxy-N,N-dimethyltryptamine) is a naturally occurring serotonin receptor

agonist that can be, more commonly, found in the Psilocybe genus of mushrooms (Carhart-Harris et al.,

2016). As an example of a classic psychedelic drug, it is inserted in the tryptamine class, with lysergic acid

diethylamide (LSD) and dimethyltryptamine (DMT), a psychoactive compound present in the sacramental

beverage ayahuasca.

Classic psychedelic consumption by humans seems to be ancient, as indigenous cultures in the

western hemisphere have used ayahuasca, psilocybin-containing mushrooms and mescaline-containing

cacti for millennia (Johnson et al., 2008; Johnson et al., 2019). These cultures attributed to these plants

and fungi a divine origin (Johnson et al., 2008) and consequently restricted their use to highly ritualized

and controlled sacramental, religious and healing contexts (Johnson et al., 2008; Johnson et al., 2019).

Despite its ancient use, western science was only introduced to psychedelics in 1897, when

Arthur Heffter isolated mescaline (Johnson et al., 2019; Nutt, 2019). However, the real breakthrough came

with the discovery of LSD and its psychedelic effects, by Albert Hofmann in 1943, which marks the

beginning of the clinical interest in psychedelic drugs (Johnson et al., 2019). Hoffman continued his

research and, later, discovered psilocybin, the active ingredient of the so-called “magic mushrooms”

(Nutt, 2016; Nutt, 2019).

Before its eventually ban, hundreds of papers were published on LSD and psilocybin (Nutt, 2019),

as psychedelics, became widely used by psychiatrists in research and clinical practice, (Carhart-Harris and

Goodwin, 2017) with promising results for end-of-life psychological distress and addiction (Johnson et al.,

2019). In 1960s, Psilocibin was marketed in many countries under the trade name Indocybin and was

safely used as an adjunct to psychotherapy in the treatment of depression and anxiety (Johnson et al.,

2018).

The recreative use of classic psychedelics was not uncommon among adolescents and young

adults in the 1960s (Johnson et al., 2019) and, because psychedelics mimicked some of the symptoms of

acute psychosis, an alarmist campaigning bugun, that negatively affected perceptions of psychedelics

(Carhart-Harris and Goodwin, 2017). In 1967, LSD was classified under Schedule I of the 1967 United

Nations convention on drugs (Schedule 1 drugs are defined as having no accepted medical use and

significant potential for harm and dependence) (Nutt, 2019), based on some very dubious research

findings of harm (Nutt, 2016). Other psychedelics, as psilocybin and mescaline, were also included, even

though the evidence of harm was minimal (Nutt, 2019).

The safety and ease of practical use of psilocybin propelled its resurrection and renewed interest

in psychedelics-based therapy, in a series of neuroimaging, psychological and psychopharmacological

studies alongside small clinical studies (Carhart-Harris and Goodwin, 2017; Nutt, 2016) and double-blind

placebo-controlled trials (Nutt, 2016). Now, there are positive preliminary reports on the safety and

tolerability of psilocybin for multiples diseases, such as obsessive-compulsive disorder, end-of-life

psychological distress, addiction and major depressive disorder (Carhart-Harris and Goodwin, 2017).

Depression is a common psychiatric illness, with a lifetime risk of 15-18% (Malhi and Mann, 2018).

This disease is associated with a low quality of life and poor prognosis (De Gregorio et al., 2018). In 2008,

the World Health Organization ranked major depression as the third cause of burden of disease worldwide

and projected that it will rank first by 2030 (Malhi and Mann, 2018).

The main objective, when treating a depressive episode, is the complete remission of depressive

symptoms, and this treatment varies between psychological therapy, pharmacotherapy, or both. With

adequate treatment, episodes last about three to six months, more than half of patients recover within

six months and nearly three quarters within a year. However, nearly 27% of patients do not recover and

develop a chronic depressive illness. Furthermore, comorbid anxiety has a key role in limiting recovery

and the proportion of people who recover decreases as years pass, dropping to approximately 60% at two

4

years, 40% at four years, and 30% at six years. Depression recurrence is very high, almost 80% of patients

experience at least one more episode in their lifetime and this risk increases with every episode (Malhi

and Mann, 2018).

With these recurrence numbers, it is important to look beyond the actual spectrum of treatment

to find new solutions. And Psilocybin, a classic psychedelic, that has shown promise in the treatment of

other psychiatrics illnesses, could be one of the answers. Therefore, the main objective of this review is

to present scientific evidence on the efficacy of Psilocybin-based therapy on patients diagnosed with

depression.

5

Materials and Methods

To analyze the possible role of Psilocybin based treatment in depression, Pubmed was queried

for all references until December 21, 2019. The search terms were “Psilocybin* AND Depression*”, and

filters restricting the results to clinical trials were applied. It yielded 15 articles. Posteriorly, in a first

selection phase, titles and abstracts of all articles were read and, in a second phase, the full articles were

assessed.

The criteria applied to select the articles were:

• Patients diagnosed with depression;

• Original results regarding outcome measures of depression.

6

Results

The initial search produced 145 articles. After he first phase selection, 15 articles were selected,

which posteriorly were selected in the second phase selection, resulting in four articles that were included

in this systematic review.

These four articles were organized into two different groups.

In one of the groups, two articles evaluate Psilocybin’s effects in patients with treatment-

resistant depression. Both were open-label feasibility trials, with a total of 32 patients and one loss to

follow-up. In these studies were included patients with major depression of a moderate to severe degree

(at least 17 on the 21-item Hamilton Depression Rating scale [HAM-D]), and no improvement despite two

adequate courses of antidepressant treatment of different pharmacological classes, lasting at least six

weeks within the current depressive episode (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016).

In the other group, two articles evaluate Psilocybin’s effects in patients with cancer-related

anxiety and depression. Both were randomized, double-blind, cross-over trials that followed a total of 80

patients with 11 lost to follow-up. In these, were included patients with a potentially life-threatening

cancer diagnosis and a diagnosis that included anxiety and/or mood symptoms, based on the Diagnostic

and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (Griffiths et al., 2016; Ross et al.,

2016).

Outcome measures

In the trials, outcome measures of depression were utilized to assess Psilocybin’s therapeutic

effects. As an example, the Beck Depression Inventory (BDI) was present in all four trials.

Additionally, different outcome measures, such as of anxiety and quality of life, were utilized by

each trial (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016).

More information about outcome measures and time of assessment are listed in Table 1.

Drug Sessions

In the Carhart-Harris et al. trials, patients received a low oral dose of psilocybin (10 mg) on the

first drug session and a high oral dose of psilocybin (25 mg) on the second drug session, separated by one

week. The low dose session was included, not to serve as control or as treatment session, but rather as a

safety session (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016).

In the Griffiths et al. trial, patients received either a high psilocybin dose (22 or 30 mg/70 kg) or

a low dose (1 or 3 mg/70 kg) on the first session and the opposite drug on the second session, separated

by five weeks. The low dose was included to serve as a placebo. The high dose was decreased from 30 to

22 mg/70 kg after two of the first three participants who received a high dose were discontinued from

the study, one from vomiting shortly after capsule administration and another for personal reasons.

Furthermore, the low dose was, also, decreased from 3 to 1 mg/70 kg after 12 participants (Griffiths et

al., 2016). These decisions are supported by data from a previous study in healthy participants that

suggested that rates of psychologically challenging experience were substantially greater at 30 than at 20

mg/kg and that significant psilocybin’s effects were present at 5 mg/70 kg (Griffiths et al., 2011), which

raised concern that 3 mg/70 kg might not serve as an inactive placebo (Griffiths et al., 2016).

In the Ross et al. trial, patients received either a 0.3 mg/kg dose of Psylocibin or a 250 mg dose

of niacin (used as a control) on the first session and the opposite drug on the second session, separated

by seven weeks (Ross et al., 2016).

In all trials, the drug sessions followed existing recommendations for administering moderate to

high doses of serotoninergic psychedelics (Johnson et al., 2008). Therefore, drug sessions were conducted

in an aesthethic living-room-like environment, where patients were invited to relax on a bed in a supine

7

or reclined position. Music was played in earphones and patients were encouraged to close their eyes. In

all sessions, patients were supervised by at least two staff members and medical (blood pressure and

heart rate) and psychiatric assessments were conducted at regular intervals to assess safety. When

psilocybin effects had subsided, subjective effects were assessed (Carhart-Harris et al., 2018; Carhart-

Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016).

Psychotherapy

The four trials had relatively different psychotherapy designs. In these trials, psychotherapy

sessions correspond to meetings between patients and psychiatrics or clinicals that followed all the

procedures from before to after the drug administration. Despite the differences in the design, all trials

follow the same three psychotherapy principles: Preparation, Acute and Peri-acute Support and

Integration.

Preparation corresponds to obtaining background information from the patient, reviewing their

intentions and purposes of participation in the trial and their treatment goals It’s important to build a

relationship of trust with the patient, providing information on what can be expected from Psilocybin

administration and how them should react to its effects, and answering to any questions or doubts.

Acute and peri-acute support corresponds to being physically and emotionally present for the

patient before, during and after drug sessions. During sessions, monitors were non-directive and

supportive, and they encouraged patients to direct their attention to their internal experience, allowing

them to experience a mostly uninterrupted inner experience.

Integration corresponds to the psychotherapy sessions after the drug administration. In these,

monitors should listen to the patient’s testimony about their experience. It’s important to add some

interpretation and potential meaning to the content of experience, as well as give advice regarding

maintaining positive changes in lifestyle (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016; Griffiths

et al., 2016; Ross et al., 2016).

More information about the number of psychotherapy and its distribution are presented in the

Table 2.

8

Discussion

The results in this systematic review demonstrate a positive association between Psilocybin

administration and reduction of depressive symptoms (Table 2).

In terms of Treatment-Resistant Depression trials, it was observed that two doses of Psilocybin

alongside psychological support significantly reduces depressive symptoms. All patients presented some

reduction in symptoms from baseline to one week after the second dose. These reductions sustained to

three (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016) and six months after the second dose

(Carhart-Harris et al., 2018).

It is worth noting that, in the 2016 trial, seven of the eight patients that met criteria for clinical

response one week after treatment, maintained response, and five of the seven that met criteria for

remission one week after treatment maintained remission, in the end of the three months follow-up

(Carhart-Harris et al., 2016). In the 2017 trial, six of the nine responders at five weeks after treatment,

maintained that criteria in the end of the six months follow-up (Carhart-Harris et al., 2018).

In terms of Cancer-Related Anxiety and Depression, it was also observed rapid and clinically

relevant effects of Psilocybin that sustained up to six months (Griffiths et al., 2016; Ross et al., 2016), and

that these effects are dose related (Griffiths et al., 2016). Both studies utilized a double-blind design and

resorted to active control compounds to address design-based confounds associated with the use of a

psychoactive drug. It’s important to address that the placebo effect is a major confound in the

development of novel antidepressant drugs, because it can produce antidepressant effects in 30 to 40%

of the patients (McCorvy et al., 2016). Therefore, the fact that each study used active control compounds,

low dose of Psilocybin (Griffiths et al., 2016) and niacin (Ross et al., 2016), it’s relevant, because minimizes

the potential outcome that effects are due to placebo rather than an active drug’s effect (McCorvy et al.,

2016; Nutt, 2019). Moreover, both studies utilized a crossover design, where patients received placebo

or the active psilocybin dose in the first administration and the opposite drug in the second. In both

studies, reduction in depressive symptoms was higher with the active Psilocybin dose than placebo before

crossover. Additionally, patients that received placebo first, exhibited marked reductions in depression

symptoms once they received the active Psilocybin doses (Griffiths et al., 2016; Ross et al., 2016).

It is worth noting that in the Griffiths et al. trial, 92 % of patients that received the high dose of

Psilocybin first met criteria for response at five weeks after administration and 79% maintained that

criteria at six months of follow-up (Griffiths et al., 2016). In the Ross et al. trial, 83% of patients that

received the Psilocybin dose first met criteria for response at seven weeks after administration and about

80 % maintained that criteria at, approximately, six and a half months after administration (Ross et al.,

2016).

These results are congruent to those observed in a double-blind, placebo-controlled trial of

patients with advanced-stage cancer and anxiety, realized by Grob et al. In this study, patients received

either a 0,2mg/kg dose of Psilocybin or a 250 mg dose of niacin, used as placebo, in the first administration

and the opposite drug in the second. One of the outcome measures applied was the BDI score, and it was

observed a decrease of almost 30% between the first session and one month after the second treatment

session and this decrease was sustained and became significant at six months follow-up (Grob et al.,

2011).

Beside anti-depressive effects, other possible effects of Psilocybin were assessed. In all studies,

outcome measures of anxiety were applied, and an anxiolytic effect was observed (Carhart-Harris et al.,

2018; Carhart-Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016). These results are encouraging

since anxiety is common in the context of depression and could manifest both as comorbidity and as a

predominant feature of major depressive disorder (Malhi and Mann, 2018).

Administration of high dose of Psilocybin also increased measures of quality of life (Griffiths et

al., 2016; Ross et al., 2016), life meaning, and optimism, changes that were also expressed in ratings by

9

community observers of participants attitudes and behaviors (Ross et al., 2016). An analysis realized by

Studero et al. had similar results, being observed sustained positive changes in personality, attitudes, and

values, in which the most often reported subjective changes were more self-understanding and tolerance

of others, less egocentricity, less materialistic and a renewed relationship to the environment, and more

appreciation of music and art (Studerus et al., 2011).

Regarding attitudes towards death, such as death anxiety or death transcendence, the results

were ambiguous (Griffiths et al., 2016; Ross et al., 2016).

The importance of the Psilocybin experience

The word Psychedelic is a neologism that combines the words psychē (“soul”) and dēloun (“to

reveal”), which can mean “mind-revealing” (Carhart-Harris and Goodwin, 2017). In fact, Psilocybin induces

an altered state of consciousness, characterized by alterations in perception, mood, volition, cognition

and self-experience (Kyzar et al., 2017), inducing a state of dreaminess, contemplativeness, and reduction

of attentiveness (Studerus et al., 2011). Psychedelics, such as Psilocybin can reduce the rigid thinking,

while promoting greater environmental sensitivity and emotional release (Carhart-Harris and Goodwin,

2017).

To assess the effects of psychedelics drugs, were created scores, such as the Altered States of

Consciousness (ASC) and the Hallucinogen Rating Scale (HRS).

Three of the Four trials used ASC to assess the effects of Psilocybin: one with the 5-dimension

ASC, (Oceanic boundlessness, dread of ego dissolution, visionary restructuralization, auditory alterations

and vigilance reduction), alongside HRS (Griffiths et al., 2016); and the remaining two with the 11-

dimension ASC ( experience of unity, spiritual experience, blissful state, insightfulness, disembodiment,

impaired cognition, anxiety, complex imagery, elementary imagery, audio/visual synesthesia and

meaning) (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016).

A psilocybin experience lasts approximately four to seven hours, and its normal effects vary

anywhere from one to twenty-four hours. The experience is divided in: on-set (beginning in the ingestion

and lasting 20 to 60 minutes); come-up (15 to 30 minutes); plateau (two to four hours); come down (one

to three hours); and after-effects (one to 24 hours, depending on the dose) (Geiger et al., 2018).

Therefore, in all trials, patients ranked their subjective experience once Psilocybin´s effects had subsided

to a negligible level (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016; Griffiths et al., 2016; Ross et

al., 2016).

It was observed a dose related subjective experience, with patients rating theirs significantly

higher after the high dose administration of Psilocybin (Carhart-Harris et al., 2018; Carhart-Harris et al.,

2016; Griffiths et al., 2016). Moreover, a strong relationship between experience of unity, spiritual

experience and blissful state was confirmed, and it was observed that these factors and insight can predict

better clinical outcomes after high dose administration (Carhart-Harris et al., 2016).

It´s impossible to address the psychological effects of psilocybin and not to mention the concept

of mystical experience.

In fact, reports of mystical experiences date back millennia (Barrett and Griffiths, 2018; Johnson

et al., 2019), have been described by theologians, psychologists, and philosophers (Johnson et al., 2019),

and have a wide range of apparent etiologies: meditation and prayer; sensory deprivation/isolation; music

listening by “deep listeners”; breathwork; and lastly ingestion of classic hallucinogens (Barrett and

Griffiths, 2018).

Mystical experiences are subjective and can be divided in diverse features, and some of them are

already in the previous scores, such as the sense of unity, that can be divided in introvertive – ego

dissolution; and extrovertive – unity despite the separation of all things. In addition, other dimensions

represent the mystical experience: sacredness – the holiness of what is experienced; noetic quality – the

10

feeling that the reality that’s experienced is more real than everyday reality, and represents the ultimate

reality; positive mood – a sense of joy, peace, tenderness, tranquility, awe and ecstasy; transcendence of

time and space - notions of time and space have no meaning; and, at last, ineffability – the experience is

difficult to put into words (Barrett and Griffiths, 2018; Johnson et al., 2019).

To assess this type of experience, the Mysticism scale (Griffiths et al., 2016) and the Mystical

Experience Questionnaire (Griffiths et al., 2016; Ross et al., 2016) were used.

As it was observed previously in healthy patients (Griffiths et al., 2008; Griffiths et al., 2011;

Griffiths et al., 2006), Psilocybin can, dose-dependently, induce a highly meaningful mystical experience

(Griffiths et al., 2016; Ross et al., 2016), with patients rating their experience as the singular or top five

most spiritually significant, or the singular or top five most personally meaningful experience of their

entire lives (Ross et al., 2016). These mystical experiences are, not only, associated with positive cognitive,

affective, spiritual, and behavioral effects that can sustain in time (Griffiths et al., 2016; Ross et al., 2016),

but also, can predict positive alteration in BDI, HADS and Spielberger’s State Anxiety Inventory (STAI-S)

scores (Ross et al., 2016).

Adverse Effects

As with all medications, there are risks inherent in the administration of psilocybin. However,

psilocybin possesses remarkably low physiological toxicity and is not associated with end organ damage,

carcinogenicity, teratogenicity, lasting neuropsychological deficits or overdose (Bogenschutz and Ross,

2018).

In consistency with the previous research (Bogenschutz and Ross, 2018; Geiger et al., 2018), the

most common medical adverse effects were transient nausea and headache.

As it was known (Geiger et al., 2018), Psychedelics administration provokes tachycardia and

increased diastolic and systolic blood pressure, therefore, patients diagnosed with major cardiovascular

diseases were excluded from trials (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016; Griffiths et al.,

2016; Ross et al., 2016).

When it comes to the psychiatric adverse effects, the most common was transient anxiety, with

rare cases of paranoia (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016; Griffiths et al., 2016; Ross

et al., 2016). One patient became uncommunicative during the peak of his experience and, despite the

facts that this normalized after the acute drug effects had abated and that he considered his experience

“blissfull”, the patient decided not to complete the trial. Another patient reported a distressfull vision of

his father attempting to physically harm him when he was a child, and this was associated with a transient

worsening of symptoms (Carhart-Harris et al., 2018).

The acute psychiatric effects of psilocybin administration, that translates into a positive or

negative experience, are influenced by set (personality and expectations of the individual), setting

(environmental conditions and context of use) and dose (Bogenschutz and Ross, 2018).

In all trials, the commonly called “bad trips” were absent (Carhart-Harris et al., 2018; Carhart-

Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016). These severe adverse psychological experiences,

that include symptoms of anxiety, panic, dysphoria, depersonalization, paranoid ideation, fear that the

experience will never end, and fear of losing one’s mind, tend to occur in poorly prepared individuals, who

have psychological risk factors, such as severe mental illness or recent trauma, and use the substance in

an uncontrolled setting (Bogenschutz and Ross, 2018; Johnson et al., 2019).The fact that all participants

attend preparatory sessions and were accompanied by professional during administration session that

were realized in a supportive setting prevented these experiences from happening.

Serious adverse effects such as psychotic-like positive symptoms, hallucinogen persisting

perception disorder were also absent (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016; Griffiths et

al., 2016; Ross et al., 2016). These are known, albeit rare, adverse effects caused by Psychedelic

11

administration in patients with predisposition (Bogenschutz and Ross, 2018; Geiger et al., 2018) and,

because of this, patients current or previously diagnosed or with immediate family member diagnosed

with psychotic disorder were excluded. (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016; Griffiths et

al., 2016; Ross et al., 2016)

More information about the adverse effects observed in the trials are presented in the Table 3.

Pharmacology

Psilocybin is a prodrug and, upon ingestion rapid dephosphorylates into psilocin (4-hydroxy-

dimethyltryptamine), its active ingredient (Geiger et al., 2018; Lee and Roth, 2012). When orally

administrated, psilocybin is almost entirely transformed into psilocin during first-pass liver metabolism.

However, when the administration is intravenous, it requires a conversion of psilocybin to psilocin in the

kidneys, a process that may be less efficient (Tófoli and de Araujo, 2016). The elimination half-life of

psilocin is approximately three hours in healthy adults, depending on individual characteristics and route

of administration (Bogenschutz and Ross, 2018).

Psilocybin is a relatively safe drug, its intravenous median lethal dose (LD50) has been

determined to be above 250 mg/kg and its lethal dose in humans has been estimated at approximately

1000 times an effective dose (Johnson et al., 2018), by comparison, cocaine lethal dose is about 15,

ketamine about 38 and fluoxetine about 100 times an effective dose (Rucker et al., 2016).

Psilocin has a complex pharmacology with affinity for multiple neurotransmitter receptors. It has

high affinity for serotonin receptors -1D, -2B, -2C, -5, -6 and -7 (5-HT1D,2B,2C,5,6,7) and moderate affinity

for serotonin receptors -1A, - 1B, and -2A (5-HT1A,1B,2A). It also has activity at histamine-1, alpha-2A and

-2B, and dopamine-3 receptors. Additionally, inhibits the sodium-dependent serotonin transporter

(Geiger et al., 2018). Nevertheless, it has long been appreciated that Psilocybin, as a classic psychedelic,

display more affinity for 5-HT2A receptors. In fact, in 5-HT2A knockout mice, classical hallucinogens, as

psilocybin, are devoid of activity and it was demonstrated that the psychedelic actions of psilocybin in

humans are abolished by pretreatment with relatively selective 5-HT2A antagonists (Lee and Roth, 2012).

From a molecular standpoint, available evidence suggests that psychedelics, by activating 5-HT2A

receptors located on cortical pyramidal neurons, increase the expression of brain-derived neurotrophic

factor (BDNF) (Vollenweider and Kometer, 2010).

Many other psychotropic drugs, including antidepressant and atypical antipsychotic mediate

their actions in part by interactions with the 5HT2A receptor (Howland, 2016).

Neural Mechanisms of Action

Despite all the knowledge about its pharmacology, the neuronal mechanisms responsible for the

psychedelic actions of psilocybin remain controversial. 5-HT2A receptors were found both on internal

pyramidal neurons and on GABA-ergic interneurons. Therefore, these findings have implied that Psilocin

actions might be due to a mixture of actions on both excitatory (e.g., pyramidal) and inhibitory (e.g.,

GABA-ergic interneuronal) neuronal circuits which means that psilocybin could induce their effects via

augmenting either excitatory or inhibitory neuronal activity (Lee and Roth, 2012).

In 2014, Petri et al. observed stable functional connections support cycles only present in the

psychedelic state, especially an increased integration between cortical regions. The authors found that

Psilocybin disrupts the normal of the brain, but not establishes random associations. Instead, the

Psilocybin experience is associated with a more intercommunicative mode of brain function, with the

emergence of strong, topologically long-range functional connections, absent in a normal state (Petri et

al., 2014).

In the 2018 Carhart-Harris trial, patients completed pre-treatment and one-day post-treatment

functional magnetic resonance imaging (fMRI), measuring cerebral blood flow (CBF) and blood oxygen-

12

level dependent (BOLD) resting-state functional connectivity (RSFC), to evaluate changes in brain function

before and after psilocybin treatment (Carhart-Harris et al., 2018; Carhart-Harris et al., 2017).

Previously, Carhart-Harris observed, during the Psilocybin experience in healthy patients,

decreases in CBF and BOLD signals in the anterior cingulate cortex/medial prefrontal cortex, in which, the

magnitude of CBF decreases correlated positively with the intensity of the Psilocybin’s subjective effects,

and also, significantly decreases in the positive coupling of two key structural hubs, the medial prefrontal

cortex and the posterior cingulate cortex, and the default-mode network (DMN) which it’s associated.

Therefore, it is worth to mention that activity in and connectivity with the medial prefrontal cortex are

elevated in depression and normalized after treatment (Carhart-Harris et al., 2012).

When analyzing changes in resting-state brain blood flow and functional connectivity one day

after Psilocybin treatment, Carhart-Harris et al. observed decreases in CBF bilaterally in the temporal

lobes and in the amygdala that, in this case, correlates with reductions in depressive mood. Regarding the

DMN, instead of a decrease, an increase in the DMN integrity was observed. Specific increases in RSFC

that were present between the ventromedial prefrontal cortex and bilateral inferior-lateral parietal cortex

nodes of the DMN, predict treatment response at five weeks, with responders showing significantly

increases. Furthermore, a decreased in RSFC between the bilateral parahippocampus and prefrontal

cortex was observed, and this was also predictive of treatment response at five weeks. Additionally, acute

mystical experience during the high-dose psilocybin session was predictive of the bilateral

parahippocampus RSFC changes (Carhart-Harris et al., 2017).

With these evidences (Carhart-Harris et al., 2012; Carhart-Harris et al., 2017), Carhart-Harris et

al. proposed that Psilocybin acts through a “reset” mechanism, in which acute modular disintegration,

acute decreases in DMN integrity, enables a subsequent re-integration and resumption of normal

functioning, post-acutely increases in DMN integrity, accompanied by improvements in mood (Carhart-

Harris et al., 2017). It is important to note that Berman et al. have demonstrated that, in depressed

patients, greater amount of brain is active in the DMN condition, being this overengagement a cause, or

a manifestation, of the self-deprecatory rumination experience by these patients (Berman et al., 2011).

Therefore, a decrease in DMN integrity could represent a disruption of depressive processes, giving the

patients a sense of a reality free of depression that they could aspire, and possibly allowing the brain to

“reset” into a new, free of depression, state (Nutt, 2019). Nevertheless, further investigation is needed to

properly test this “reset” model.

Using the same population, Roseman et al. hypothesized that amygdala responses to emotional

faces would be altered post-treatment with psilocybin. They observed an increased amygdala response

to emotional faces one day after treatment and, that these increases in amygdala responses to fearful

versus neutral faces were related to a successful clinical outcome one week after treatment (Roseman et

al., 2018). These findings are in contrast to observations of decreased amygdala responses after treatment

with conventional antidepressants, particularly Serotonin Selective Reuptake Inhibitors (SSRIs) (Ma,

2015), representing a fundamental difference in these treatments’ therapeutic actions. Psilocybin,

contrary to SSRIs, has the ability to allow patients to confront and work through negative emotions, being

proposed that Psilocybin assisted therapy treats depression by reviving emotional responsiveness

(Roseman et al., 2018). Unfortunately, these observations are, also, in contrast to previous observations

of unspecific decreases in right amygdala responses to negative and neutral stimuli after Psilocybin

administration (Kraehenmann et al., 2015). Therefore, further investigation is required to test the real

relation between amygdala responses to emotional faces and psilocybin administration.

Studies Limitations

All four studies have limitations that prevent us from doing definitive inferences about the

Psilocybin’s therapeutic efficacy.

Both Carhart-Harris et al trials are small-scale, open label trials, with no control group, thus the

results can potentially be inflated. Most patients in both trials are self-referred, which mean, that they

13

actively sought this specific treatment and, the extremely positive results can be influenced by an

expectancy bias (Carhart-Harris et al., 2018; Carhart-Harris et al., 2016). In the 2018 trial, eight patients

were added to the previous 12, however, 20 continues to represent a small population, and these eight

patients were all male, limiting the extrapolation to the general population (Carhart-Harris et al., 2018).

In the remaining trials (Griffiths et al., 2016; Ross et al., 2016), despite the increase in patients, the populations remain relatively small. Additionally, patients in the Griffiths et al. trial are predominantly highly educated white people (Griffiths et al., 2016) and, in the Ross et al. trial are predominantly white females (Ross et al., 2016), which, in both studies, limits the generalization. The fact that both have a crossover design, enables assessment of acute and sustained Psilocybin’s effects in all patients, however, it prevents double-blind assessment of the active dose Psilocybin’s efficacy based on across group comparisons after crossover (Griffiths et al., 2016; Ross et al., 2016). Despite the blinding procedures, it is important to take into account the unique psilocybin’s subjective effects and the persisting challenging to adequately obscure them. This issue was addressed in the Ross et al. trial, in which, at the end of each dosing session, staff team present in the session recorded their guesses as to whether the participant received the psilocybin or the active placebo, and guessed correctly in 97 % of the participants (Ross et al., 2016).

Another limitation, noted in the Griffiths et al. trial, is the utilization of participants-rated

Persisting Effects Questionnaire and Community Observer Questionnaire, that hasn’t been independently

validated, to assess changes in attitudes and mood (Griffiths et al., 2016).

14

Limitations

This systematic review has its own limitations.

First, only one search engine, PUBMED, was used. Therefore, it is possible that relevant articles

are not included in this review, articles that could have bring new results and essential knowledge to the

scarce existing information on the subject.

Second, being a systematic review, it has its inherent limitations. A meta-analysis would allow us

extract more precise information and to reach more solid conclusions. Nevertheless, this review offers a

complete description of the present knowledge related to the Psilocybin and its utilization in Depression.

Third, the patients present in the trials represent, by themselves, a limitation. In the Carhart-

Harris et al. trials, patients were diagnosed with major depression of a moderate to severe degree.

Meanwhile, in the remaining two trials, patients were diagnosed with cancer-related depression and

anxiety, which despite being very common, it is not often very severe, (Carhart-Harris and Goodwin, 2017)

representing a difference to the Carhart-Harris et al.’s patients. Specifying, in the Griffiths et al. trial, only

69% of the patients presented depressed mood (Griffiths et al., 2016) and, in the Ross, et al. trial, only

28% of the patients were diagnosed with chronic adjustment disorder with anxiety and depressed mood

(Ross et al., 2016). In both trials, the outcome measures of depression were assessed in all patients and

not specifically in patients diagnosed with depression, with BDI measures at baseline being significantly

lower (Griffiths et al., 2016; Ross et al., 2016). Therefore, the real values of these outcomes and their

evolution, after the Psilocybin administration, are absent, which lead us to approach the results with

caution.

15

Conclusion

In conclusion, due to its low toxicity, favorable side effect profile, and immediate and sustained

anti-depressant effects with little exposure, Psilocybin presents itself as a promising and revolutionary

therapeutic for depression. However, the research is still in its infancy, the information is scarse and the

clinical trials have considerable limitations. Therefore, further research is required to achieve more robust

and conclusive information related to various subjects of the Psilocybin-assisted therapy.

Psychological support is essential to the Psilocybin-assisted therapy. Th antidepressant effects

are limited when psychedelics are administered without psychological support and this administration

could even worse a patient’s condition (Carhart-Harris and Goodwin, 2017). In the other hand, Ross et al.

and Griffiths et al trials were important to address the concerns of Psilocybin-assisted therapy being just

a psychotherapy placebo (Nutt, 2019), demonstrating that placebo administration with psychological

support had worse results than Psilocybin administration with psychological support. Therefore,

considering its importance, it is necessary to define the real extent of the psychological support.

Evaluating the psychological support magnitude would, not only, allow us to minimize this work of

therapy, which is time expansive, but also to better comprehend the Psilocybin effects and its most

efficient dosage and how to maximize the personal mystical drug experience.

Another step in the research would be de comparison between Psilocybin’s efficacy with an

established treatment, such as ketamine, due to their similarities in efficacy with a single dose and effects

during administration. However, Psilocybin’s distinctive effects and experience could represent an

obstacle to the blinding process.

It is also important, and looking back to the different population in the articles here reviewed,

which patients should be chosen to the clinical development of Psilocybin for depression. Carhart-Harris

believes that Psilocybin will be most effective if administrated prior to the treatment-resistant stages of

depression. In contrast, Goodwin defends patients diagnosed with treatment-resistant depression as the

most needed of this novel treatment (Carhart-Harris and Goodwin, 2017).

Recently, both the European Medicines Agency and the Food and Drug Administration approved

a multicenter multi-country trial of psilocybin, started in 2019. In this trial, treatment-resistant depression

patients were randomized and received one of three doses: 1, 10, and 25 mg given once (Nutt, 2019). This

multi dose trial in important to address the questions regarding the Psilocybin’s dose efficacy, using the 1

mg arm as an approximation to an inert placebo and analyzing the differences between the 10 mg dose

that usually produces perceptual distortion and the 25 mg dose that has the ability to produce a more

profound and complete psychedelic experience (Carhart-Harris and Goodwin, 2017).

If the trial reports positive results, then both regulators are willing to approve psilocybin as a

medicine (Nutt, 2019).

It impossible to address Psilocybin and not mention the growing concept of microdosing. This

corresponds to the practice of repeatedly consume very-low, sub-hallucinogenic doses of psychedelics,

most commonly, for performance enhancement purposes, such as to increase energy, creativity and

concentration (Hutten et al., 2019). This is a new, poorly investigated, area that needs further research to

comprehend, not only, its mechanisms of actions, but also its relevant use.

16

List of Abbreviations

LSD: Lysergic acid diethylamide

DMT: Dimethyltryptamine

WHO:

HAM-D: Hamilton Depression Rating scale

DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

BDI: Beck Depression Inventory

ASC: Altered States of Consciousness scale

HRS: Hallucinogen Rating Scale

STAI-S: Spielberger’s State Anxiety Inventory score

LD50: Median lethal dose

5-HT1A, 1B, 1D, 2A, 2B, 2C, 5, 6, 7: serotonin receptors -1A, -1B, -1D, -2A, -2B, -2C, -5, -6, -7

BDNF: Brain-derived neurotrophic factor

fMRI: Functional magnetic resonance imaging

CBF: cerebral blood flow

BOLD: blood oxygen-level dependent

RSFC: resting-state functional connectivity

DMN: Default-mode network

SSRIs: Serotonin Selective Reuptake Inhibitors

17

Funding

The authors did not receive any specific grant from funding agencies in the public, commercial,

or no-for-profit sectors.

Acknowledgements

Not applicable.

Conflict of Interests

The authors declared no potential conflicts of interest in relation to the subject of this article.

18

References

Barrett FS and Griffiths RR (2018) Classic Hallucinogens and Mystical Experiences: Phenomenology and Neural Correlates. Curr Top Behav Neurosci 36: 393-430.

Berman MG, Peltier S, Nee DE, et al. (2011) Depression, rumination and the default network. Soc Cogn Affect Neurosci 6(5): 548-555.

Bogenschutz MP and Ross S (2018) Therapeutic Applications of Classic Hallucinogens. Curr Top Behav Neurosci 36: 361-391.

Carhart-Harris RL, Bolstridge M, Day CMJ, et al. (2018) Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl) 235(2): 399-408.

Carhart-Harris RL, Bolstridge M, Rucker J, et al. (2016) Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry 3(7): 619-627.

Carhart-Harris RL, Erritzoe D, Williams T, et al. (2012) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A 109(6): 2138-2143.

Carhart-Harris RL and Goodwin GM (2017) The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology 42(11): 2105-2113.

Carhart-Harris RL, Roseman L, Bolstridge M, et al. (2017) Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep 7(1): 13187.

De Gregorio D, Enns JP, Nuñez NA, et al. (2018) d-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders. Prog Brain Res 242: 69-96.

Geiger HA, Wurst MG and Daniels RN (2018) DARK Classics in Chemical Neuroscience: Psilocybin. ACS Chem Neurosci 9(10): 2438-2447.

Griffiths R, Richards W, Johnson M, et al. (2008) Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol 22(6): 621-632.

Griffiths RR, Johnson MW, Carducci MA, et al. (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 30(12): 1181-1197.

Griffiths RR, Johnson MW, Richards WA, et al. (2011) Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology (Berl) 218(4): 649-665.

Griffiths RR, Richards WA, McCann U, et al. (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl) 187(3): 268-283; discussion 284-292.

Grob CS, Danforth AL, Chopra GS, et al. (2011) Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer. Archives of General Psychiatry 68(1): 71-78.

Howland RH (2016) Antidepressant, Antipsychotic, and Hallucinogen Drugs for the Treatment of Psychiatric Disorders: A Convergence at the Serotonin-2A Receptor. J Psychosoc Nurs Ment Health Serv 54(7): 21-24.

Hutten N, Mason NL, Dolder PC, et al. (2019) Motives and Side-Effects of Microdosing With Psychedelics Among Users. Int J Neuropsychopharmacol 22(7): 426-434.

Johnson M, Richards W and Griffiths R (2008) Human hallucinogen research: guidelines for safety. J Psychopharmacol 22(6): 603-620.

Johnson MW, Griffiths RR, Hendricks PS, et al. (2018) The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology 142: 143-166.

Johnson MW, Hendricks PS, Barrett FS, et al. (2019) Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacol Ther 197: 83-102.

Kraehenmann R, Preller KH, Scheidegger M, et al. (2015) Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biol Psychiatry 78(8): 572-581.

Kyzar EJ, Nichols CD, Gainetdinov RR, et al. (2017) Psychedelic Drugs in Biomedicine. Trends Pharmacol Sci 38(11): 992-1005.

Lee HM and Roth BL (2012) Hallucinogen actions on human brain revealed. Proc Natl Acad Sci U S A 109(6): 1820-1821.

19

Ma Y (2015) Neuropsychological mechanism underlying antidepressant effect: a systematic meta-analysis. Mol Psychiatry 20(3): 311-319.

Malhi GS and Mann JJ (2018) Depression. Lancet 392(10161): 2299-2312. McCorvy JD, Olsen RH and Roth BL (2016) Psilocybin for depression and anxiety associated with life-

threatening illnesses. J Psychopharmacol 30(12): 1209-1210. Nutt D (2016) Psilocybin for anxiety and depression in cancer care? Lessons from the past and prospects

for the future. J Psychopharmacol 30(12): 1163-1164.

Nutt D (2019) Psychedelic drugs-a new era inpsychiatry?. Dialogues Clin Neurosci 21(2): 139-147. Petri G, Expert P, Turkheimer F, et al. (2014) Homological scaffolds of brain functional networks. J R Soc

Interface 11(101): 20140873. Roseman L, Demetriou L, Wall MB, et al. (2018) Increased amygdala responses to emotional faces after

psilocybin for treatment-resistant depression. Neuropharmacology 142: 263-269. Ross S, Bossis A, Guss J, et al. (2016) Rapid and sustained symptom reduction following psilocybin

treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol 30(12): 1165-1180.

Rucker JJ, Jelen LA, Flynn S, et al. (2016) Psychedelics in the treatment of unipolar mood disorders: a systematic review. J Psychopharmacol 30(12): 1220-1229.

Studerus E, Kometer M, Hasler F, et al. (2011) Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol 25(11): 1434-1452.

Tófoli LF and de Araujo DB (2016) Treating Addiction: Perspectives from EEG and Imaging Studies on Psychedelics. Int Rev Neurobiol 129: 157-185.

Vollenweider FX and Kometer M (2010) The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 11(9): 642-651.

20

Appendix

Figure 1: Flowchart of included articles.

Table 1: Outcome measures applied in the trials.

Table 2: Results

Table 3: Adverse Effects.

21

Figure 1. Flowchart of included articles.

Studies identified through Pubmed searching

(n=15)

Studies included in this systematic review

(n=4)

Studies after title and abstract reading

(n=7)

Articles excluded after full text

reading

(n=3)

Studies excluded after title and

abstract reading

(n=8)

22

Table 1. Outcome Measures applied in the trials. QIDS – Quick Inventory of Depressive Symptoms; BDI – Beck Inventory Depression; STAI-T – Spielberger’s Trait Anxiety Inventory; SHAPS – Snaith-Hamilton Pleasure Scale; HAM-D – Hamilton Depression Rating Scale; MARDS – Montgomery-Asberg Depression Rating Scale; GAF – Global Assessment of Functioning; HAM-A – Hamilton Anxiety Rating Scale; HADS-D, -A and -T Hospital Anxiety and Depression Scale, separate measure of Depression, Anxiety and total score, respectively; STAI-S – Spielberger’s State Anxiety Inventory; POMS – Profile of Mood States; BSI – Brief Symptom Inventory; MQOL – Mcgil Quality of Life Questionnaire, overall quality of life (total score) and meaningful existence (subscale); LOT-R – Life Orientation Test-Revised; LAP-R – Life Attitude Profile-Revised, Death Acceptance and Coherence dimensions; DTS – Death Transcendence Scale; DEM – Demoralization scale; HAI – Hopelessness Assessment and Illness scale; DAS – Death Anxiety Scale; WHO-Bref – World Health Organization Quality of Life scale, brief version; FACIT-SWB – Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being.

Study Outcome Measures Timing of Assessment

Treatment-resistant Depression

Carhart-Harris et al. (2016)

Primary Outcome Measures

QIDS

Baseline; 1-,2-,3- and 5-weeks and 3- months follow-up

Secondary Outcome Measures

BDI Baseline; 1-week and 3-months follow-up STAI-T

SHAPS

HAM-D Baseline; 1-week follow-up

MARDS

GAF

Carhart-Harris et al. (2018)

Primary Outcome Measures

QIDS

Baseline; 1-,2-,3- and 5-weeks and 3- and 6-months follow-up

Secondary Outcome Measures

BDI Baseline; 1-week and 3-and 6-months follow-up STAI-T

SHAPS Baseline; 1-week and 3-months follow-up

HAM-D Baseline; 1-week follow-up

GAF

Cancer-related Anxiety and Depression

Griffiths et al. (2016)

Primary Outcome Measures

HAM-D Baseline; 5 weeks after first session 1; 5 weeks and 6 months after second session

HAM-A

Secondary Outcome Measures

BDI

HADS-D, -A and Total

STAI-S and -T

POMS

BSI

MQOL

LOT-R

LAP-R

DTS

Purpose in Life

Ross et al. (2016)

Primary Outcome Measures

HADS-A, -D and Total Baseline; 1 day prior and 1 day after first session; 2 and 6 weeks after first dose; 1 day prior and 1 day after second session; 6 and 26 weeks after second session.

BDI

STAI-S and -T

Secondary Outcome Measures

DEM Baseline; 2 weeks after first dose and 26 weeks after second session

HAI

DAS

DTS

WHO-Bref

FACIT-SWB

23

Study Design Population Drug Sessions

Psychotherapy Sessions

Results Limitations

Treatment-resistant Depression

Carhart-Harris et al. (2016)

Open-label, single-arm pilot study; 3 m follow-up

9 severe or very severe depression; 3 moderate depression N=12 6Female Mean age=42,6

2 psilocybin doses, 7 days apart; 1st10 mg 2nd25 mg

4 sessions: 1 before 1st drug dose; During drug session; 2 sessions after 2nd drug dose (1 day and 1 wk follow-up)

All patients showed some decrease in depressive symptoms, with maximum effects at 2 wk follow-up. At 1 wk follow-up, response ratea was 67% and remission rateb was 58%. At 3 m, response ratea was 58% and remission rateb was 42%. (BDI: Baseline 33,7; 1 wk: 8,7; 3 m: 15,2)

Open-label design; No control group; Small population.

Carhart-Harris et al. (2018)

Open-label, single-arm pilot study; 6 m follow-up

18 severe or very severe depression; 2 moderate depression N=20 6Female Mean age=44,1

2 psilocybin doses, 7 days apart: 1st10 mg: 2nd25 mg

4 sessions: 1 before 1st drug dose; During drug session; 2 sessions after 2nd drug dose (1 day and 1 wk follow-up)

All patients showed some decrease in depressive symptoms; maximum effects at 5-week follow-up. At 5-week, response ratea was 45% and remission rateb was 20%. Results remained positive at 3- and 6-months follow-up. (BDI: Baseline: 34,5; 1 wk: 11,8; 3 m: 19,2; 6 m: 19,5)

Open-label design; No control group; Small population; Predominantly male patients.

24

Study Design Population Drug Sessions

Psychotherapy Sessions

Results Limitations

Cancer-related Anxiety and Depression

Griffiths et al. (2016)

Randomized, double-blind, cross-over trial; 6 m follow-up

11 CAD with Anxiety; 11 CAD with Mixed Anxiety and Depressive Mood; 5 Dysthymic Disorder; 5 GAD; 14 MDD; 4 GAD and MDD; 1 GAD and dysthymic disorder. N=51 25Female Mean age=56,3

2 psilocybin doses, 5 wk apart: 1st low dose (1 or 3 mg/70kg) or high dose (22 or 30 mg/70kg); 2nd opposite dose.

8 sessions minimum: 2 or more before 1stdrug session; During 1stdrug dose; 2 or more between doses; During 2nddrug dose; 2 or more after.

Decrease in depressive symptoms was higher with high-dose Psilocybin and sustained to the 6-monts follow-up. HD1st patients had better results, overall. HD1st responsec and remission ratesd, 5 wk after 1st dose, were, respectively, 92% and 60% (vs 32% and 16% in ld1st) and 79% and 71% at 6-m follow-up (vs 77% and 59% in ld1st) (BDI HD1st: Baseline: 17,7 5 wk after 1stdose: 7,00 5 wk after 2nd

dose: 5,80 6 m follow-up: 6,17)

Small Population; Crossover Design; Limited blinding; Questionnaire no independent validated.

Ross et al. (2016)

Randomized, double.blind, placebo-controlled, crossover trial;

18 CAD with Anxiety; 8 CAD with Mixed Anxiety and Depressive Mood; 5 GAD.

2 drug doses, 7 wk apart:

10 sessions minimum:

Prior to the crossover (at 7 wk after 1st

dose), reduction of depressive symptoms was greater in the P-1st-P. The reduction of symptoms remained significant until the 26 wk post-2nd dose follow-up. 7 wk after 1st

dose P-1st-P had 83%

Small Population; Crossover Design;

25

Approximately 6 m follw-up

N=29 18Female Mean age=56,28

1st

Psilocybin (0,3mg/kg) or Niacin 250 mg) 2nd

Opposite Drug

3 sessions before 1stdose; During 1stdose; 3 sessions between doses; During 2nddose; 3 sessions after 2nddose.

response ratesa (14% in N-1st-P). At 6,5 m follow-up, after both groups had received Psilocybin, response ratesa were approximately 60 % in the N-1st--P and 80% in the P-1st-P. (BDI P-1st-P: Approximately 15 at baseline, 5 at 1 wk and 6 at 7 wk after 1st dose).

Limited blinding;

Table 2 Results. N=Total of Participants in the study. wk: week(s); m: month(es). BDI: Beck Depression Inventory; CAD: Chronic Adjustment Disorder; GAD: Generalized Anxiety Disorder; MDD: Major Depressive Disorder. HD1st: patients that received high dose of Psilocybin in the 1st drug session. ld1st: patients that received low dose of Psilocybin in the 1st drug session. P-1st-P: patients that received Psilocybin in the first drug session. N-1st-P: patients that received Niacin in the first drug session. a – Response rate corresponds to a 50% reduction in BDI score relative to Baseline; b – Remission rate corresponds to a score of ≤ 9 on the BDI. c – Response rate corresponds to a ≥ reduction in the HAMD relative to Baseline; d – Remission rate corresponds to a ≥ reduction in the HAMD relative to Baseline and a score ≤7.

26

Treatment-resistant Depression

Study Adverse Effects

Carhart-Harris et al. (2016)

Medical Transient Nausea (n=4)

Transient Headache (n=4)

Psychiatric

Transient Anxiety (n=12)

Transient Confusion or Thought Disorder (n=9)

Mild and transient Paranoia (n=1)

Carhart-Harris et al. (2018)

Medical

Transient Headache (n=8)

Transient Nausea (n=5)

Psychiatric

Transient Anxiety (n=15)

Transient Paranoia (n=3)

Distressful Vision (n=1)

Becoming Uncommunicative during the peak of experience (n=1)

Cancer-related Anxiety and Depression

Study Drug Sessions Adverse Effects

Griffiths et al. (2016)

High-dose Psilocybin

Medical Physical discomfort (any type) (21%)

Nausea or Vomiting (15%)

Psychiatric

Psychological discomfort (any type) (32%)

Anxiety (26%)

Transient Paranoia (2%)

Low-dose Psilocybin

Medical

Physical discomfort (any type) (8%)

Psychiatric Anxiety (15%)

Psychological discomfort (any type) (12%)

Ross et al. (2016)

Psilocybin dose

Medical Headaches/migraine (28%)

Nausea (14%)

Psychiatric Transient Anxiety (17%)

Transient Paranoid Ideation (3%)

Transient Thought Disorder (3%) Table 3 – Adverse Effects

27

Agradecimentos

Ao professor Miguel Bragança, por todo o apoio, tempo e trabalho despendidos na realização

desta revisão.

À minha mãe, pelo exemplo de resiliência que é, pelo esforço hercúleo que tem realizado ao

longo da sua vida para poder dar aos filhos aquilo que nunca teve e por todos os dias, independentemente

de o mundo à sua volta estar a ruir, ter um sorriso e um abraço para me dar.

Ao meu irmão, por ser tudo aquilo que se espera de um irmão mais velho, um exemplo, um amigo

nos momentos alegres e um porto de abrigo nos tempos conturbados, e por me ter dado a alegria de

poder ser tio: a ti Francisca.

À Magda e Raquel, por serem as irmãs que nunca tive.

A toda a minha família que me educou e me tornou na pessoa que hoje sou.

Aos meus amigos, aos de sempre e aos de agora, mas sobretudo àqueles que sempre me vão

acompanhar. Aos meus amigos de infância, por aprendermos, errarmos, crescermos juntos. Ao eterno

GAAB, pelo melhor ano da minha vida. Aos meus amigos que hoje são mestres de Medicina, àqueles que

um dia um serão como eu e àquele que se mudou para Engenharia. Ao meu restrito Royal Straight Flush

e às minhas duas Lil Sis, por me ampararem quando caí e por me segurarem quando me levantava

demasiado, tornando-se mais que família.

Por último, porque, ironicamente fica mais difícil transpor para palavras aquilo que queremos

dizer àqueles que mais o merecem, à Cat. Por ser a minha eterna luz ao fundo do túnel, por todas as

críticas construtivas e não construtivas, por ser aquela palavra amiga e de reconforto sempre presente,

por me fazer crescer e me tornar finalmente num homem, mas, acima de tudo, por ser a minha

condicional e eterna companheira.

28

Anexos

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 1/16

Submit Paper

Please read the guidelines belowbefore visiting the submission site!

Submission Site

Manuscript Submission Guidelines:

1. Article types2. Editorial Policies

2.1 Peer review policy2.2 Authorship2.3 Acknowledgments2.4 Funding2.5 Declaration of conflicting interests2.6 Research ethics and patient consent2.7 Clinical Trials2.8 Preclinical studies using animals2.9 Reporting Guidelines2.10 Conflict Resolution2.11 Research Data

3. Publishing Policies3.1 Publication Ethics3.2 Contributor's publishing agreement3.3 Open Access and author archiving3.4 Permissions

4. Preparing your manuscript 4.1 Word processing formats4.2 Artwork, figures and other graphics

Journal of Psychopharmacology

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 2/16

4.3 Supplemental material4.4 Journal layout4.5 Reference style4.6 English language editing services

5. Submitting your manuscript5.1 How to submit your manuscript5.2 Title, keywords and abstracts5.3 Corresponding author contact details5.4 ORCID

6. On acceptance and publication6.1 SAGE Production6.2 Access to your published article6.3 Online First publication

7. Further Information

This Journal is a member of the Committee on Publication EthicsThis Journal recommends that authors follow the Uniform Requirements for ManuscriptsSubmitted to Biomedical Journals formulated by the International Committee of MedicalJournal Editors (ICMJE)

There are no fees payable to submit or publish in this journal.

Please read the guidelines below then visit the Journal’s submission sitehttps://mc.manuscriptcentral.com/jop to upload your manuscript. Please note thatmanuscripts not conforming to these guidelines may be returned.

Only manuscripts of sufficient quality that meet the aims and scope of Journal ofPsychopharmacology will be reviewed.

As part of the submission process you will be required to warrant that you aresubmitting your original work, that you have the rights in the work, and that youhave obtained and can supply all necessary permissions for the reproduction ofany copyright works not owned by you, that you are submitting the work for firstpublication in the Journal and that it is not being considered for publicationelsewhere and has not already been published elsewhere. Please see ourguidelines on prior publication and note that Journal of Psychopharmacology mayaccept submissions of papers that have been posted on pre-print servers; pleasealert the Editorial Office when submitting (contact details are at the end of theseguidelines) and include the DOI for the preprint in the designated field in themanuscript submission system. Authors should not post an updated version oftheir paper on the preprint server while it is being peer reviewed for possiblepublication in the journal. If the article is accepted for publication, the author may

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 3/16

re-use their work according to the journal's author archiving policy.

Back to top

1. Article types

Journal of Psychopharmacology is a peer-reviewed journal which welcomes the followingarticle types for publication:

Original Papers:Research Reports, describing new experimental findings; both fullpapers and short reports requiring rapid dissemination.

The journal is more flexible in terms of the length of the article. Therefore there areno word limits for any type of article.

Review Articles: The Editors wish to encourage the following types of review, butrequest that authors contact them (j.psychopharm@imperial.ac.uk) in advance:

1. General reviews: providing a synthesis of an area of psychopharmacology;2. Perspectives: brief overviews, which are 4-6 printed pages in length including

references, that address important new areas of general interest3. Critiques: focused and provocative reviews that are followed by a number of

invited commentaries, with a concluding reply from the main author

Null Results in Brief are original reports of null results of important a priori hypothesestested with sufficient statistical power. Supplementary Material is generally not to be usedto provide additional details about study methods or results.

Please indicate in your cover letter that your submission is for the Null Results in Briefcategory. Relatively rigid criteria are applied during the evaluation. The submittedmanuscript should fulfill the following criteria:

1. The manuscript should add to current knowledge and be useful to futureinvestigators making decisions regarding future research directions, replicationand/or inclusion in meta-analysis.

2. Only brief methodological details should be provided, although these should besufficient to allow readers to evaluate the results. Detailed study methodologydescribed elsewhere (e.g., in prior publications) may be referenced.

3. The authors should clearly specify hypotheses that demonstrate a clear rationalefor the data being presented. Priority will be given to articles that address well-defined biological /cognitive pathways.

4. The statistical power should be sufficient to enable the null results to beinterpretable, and should be at least equal to or greater than that in priorempirical publications.

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 4/16

5. Authors are encouraged to combine as much null data as possible into a singlepublication. Authors are also encouraged to incorporate null data into studiesreporting positive findings for pathway markers.

Brief abstract (100 words)800 words of text8 or fewer references2 figures and/or tables

Letters to the Editors: Readers' letters should address issues raised by publishedarticles or should report significant new findings that merit rapid dissemination. Thedecision to publish is made by the Editors, in order to ensure a timely appearance inprint. All letters are reviewed by the Editors (and, in some cases, the Editorial Board);letters under consideration for publication may be sent for peer review to the authorsand/or reviewers of the original paper for a response, but the decision to publish isultimately made by the Editors. Authors of letters that are rejected for publication may stillbe asked permission for their work to be shared with the authors of the original paper forthe purpose of fostering academic discourse and idea sharing.Authors may refuse this request.

Case Reports will only be considered if they make a major impact on the field andgenerally need to reflect findings from more than a single case. Please submit your workin the Short Report section.

The journal no longer accepts Book Reviews. The British Association forPsychopharmacology (BAP) publishes book reviews in their newsletter.

Please contact Prof Brian E. Leonard, Emeritus Professor of Pharmacology, NationalUniversity of Ireland, Galway (email:belucg@iol.ie).

Neuroscience-based Nomenclature (NbN) for Journal of Psychopharmacology

A few years ago on the Journal of Psychopharmacology Prof Nutt published an editorialon the need for a new nomenclature in psychopharmacology.[Nutt DJ. (2009)beyond_psychoanaleptics_-_can_we_improve_antidepressant_drug_nomenclature.pdf? J Psychopharmacol. 23(4):343-5.Erratum in: J Psychopharmacol. 23(7):861].

This sparked interest from the ECNP who set up a working group with several otherinternational psychopharmacology organisations e.g. ACNP CINP, and after 5 years ofregular meetings, a new nomenclature has been develop and posted as a freeeducational App.

The next stage is to begin the challenging process of using the new nomenclature inscientific journals and the Journal of Psychopharmacology is one of about 10 who have

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 5/16

j y p gyagreed to try to do this. The details are in an editorial published in 2016 [Nutt DJ, Blier P.(2016) neuroscience-based_nomenclature_nbn_for_journal_of_psychopharmacology.pdf. J Psychopharmacol.30(5):413-5]

So when you write your papers for the Journal of Psychopharmacology please try to usethe attached glossary to explain what drugs you used and how they work.

Back to top

2. Editorial policies

2.1 Peer review policy

The journal's policy is to obtain a minimum of three independent reviews ofeach article. It operates a single blind reviewing policy in which the reviewers’names are concealed .

Referees will be encouraged to provide substantive, constructive reviews thatprovide suggestions for improving the work and distinguish betweenmandatory and non-mandatory recommendations. All manuscripts acceptedfor publication are subject to editing for presentation, style and grammar. Anymajor redrafting is agreed with the author but the Editor's decision on the textis final.

All our referees are highly valued and each year a thanks to all reviewers ispublished on the Journal's homepage. A Thanks to All 2016 Reviewers canbe found here.

2.2 Authorship

Papers should only be submitted for consideration once consent is given byall contributing authors. Those submitting papers should carefully check thatall those whose work contributed to the paper are acknowledged ascontributing authors.

The list of authors should include all those who can legitimately claimauthorship. This is all those who:

1. Made a substantial contribution to the concept and design, acquisitionof data or analysis and interpretation of data,

2. Drafted the article or revised it critically for important intellectual content,3 Approved the version to be published

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 6/16

3. Approved the version to be published.

Authors should meet the conditions of all of the points above. Each authorshould have participated sufficiently in the work to take public responsibilityfor appropriate portions of the content.When a large, multicentre group has conducted the work, the group shouldidentify the individuals who accept direct responsibility for the manuscript.These individuals should fully meet the criteria for authorship.

Acquisition of funding, collection of data, or general supervision of theresearch group alone does not constitute authorship, although all contributorswho do not meet the criteria for authorship should be listed in theAcknowledgments section. Please refer to the International Committee ofMedical Journal Editors (ICMJE) authorship guidelines for more informationon authorship.

2.3 Acknowledgements

All contributors who do not meet the criteria for authorship should be listed inan Acknowledgements section. Examples of those who might beacknowledged include a person who provided purely technical help, or adepartment chair who provided only general support.

2.3.1 Writing Assistance

Individuals who provided writing assistance, e.g. from a specialistcommunications company or individual, do not qualify as authors and soshould be included in the Acknowledgements section. Authors must discloseany writing assistance – including the individual’s name, company and levelof input – and identify the entity that paid for this assistance.

It is not necessary to disclose use of language polishing services.

Please supply any personal acknowledgements separately to the main text tofacilitate anonymous peer review.

2.4 Funding

The Journal of Psychopharmacology requires all authors to acknowledgetheir funding in a consistent fashion under a separate heading. Please visitthe Funding Acknowledgements page on the SAGE Journal Author Gatewayto confirm the format of the acknowledgment text in the event of funding, orstate: “This research received no specific grant from any funding agency inthe public, commercial, or not-for-profit sectors.”

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 7/16

2.5 Declaration of conflicting interests

It is the policy of Journal of Psychopharmacology to require a declaration ofconflicting interests from all authors enabling a statement to be carried withinthe paginated pages of all published articles.

Please ensure that a ‘Declaration of Conflicting Interests’ statement isincluded at the end of your manuscript, after any Acknowledgements andprior to the references. If no conflict exists, please state that “The Author(s)declare(s) that there is no conflict of interest.”

For guidance on conflict of interest statements, please see the ICMJErecommendations here.

2.6 Research ethics and patient consent

Medical research involving human subjects must be conducted according tothe World Medical Association Declaration of Helsinki.

Submitted manuscripts should conform to the ICMJE Recommendations forthe Conduct, Reporting, Editing, and Publication of Scholarly Work in MedicalJournals, and all papers reporting animal and/or human studies must state inthe methods section that the relevant Ethics Committee or InstitutionalReview Board provided (or waived) approval. Please ensure that you haveprovided the full name and institution of the review committee, in addition tothe approval number.

For research articles, authors are also required to state in the methodssection whether participants provided informed consent and whether theconsent was written or verbal.

Information on informed consent to report individual cases or case seriesshould be included in the manuscript text. A statement is required regardingwhether written informed consent for patient information and images to bepublished was provided by the patient(s) or a legally authorizedrepresentative. Please do not submit the patient’s actual written informedconsent with your article, as this in itself breaches the patient’s confidentiality.The Journal requests that you confirm to us, in writing, that you have obtainedwritten informed consent but the written consent itself should be held by theauthors/investigators themselves, for example in a patient’s hospital record.The confirmatory letter may be uploaded with your submission as a separatefile.

Please also refer to the ICMJE Recommendations for the Protection of

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 8/16

Please also refer to the ICMJE Recommendations for the Protection ofResearch Participants

All research involving animals submitted for publication must be approved byan ethics committee with oversight of the facility in which the studies wereconducted. The journal has adopted the Consensus Author Guidelines onAnimal Ethics and Welfare for Veterinary Journals published by theInternational Association of Veterinary Editors.

2.7 Clinical trials

The Journal of Psychopharmacology conforms to the ICMJE requirement thatclinical trials are registered in a WHO-approved public trials registry at orbefore the time of first patient enrolment as a condition of consideration forpublication. The trial registry name and URL, and registration number mustbe included at the end of the abstract.

2.8 Preclinical studies using animals

Manuscripts describing experiments that have used animals must includestatements to confirm that the work was:

Approved by the competent authority responsible for ensuringcompliance with the regulations governing the use of animals inscientific experiments (e.g., Animals (Scientific Procedures) Act 1986(UK), as updated in 2010; Directive 2010/63/EU (rest of Europe)Awarded ethical approval by an official body (e.g. an Animal Welfareand Ethical Review Body, in the UK).

The use of noxious or stressful stimuli must be justified according to:

the objectives of the experimentthe likely benefits arising from the workthe validity of the procedure in the context of the research objectives:e.g., ., that the type(s) of stress that were used are relevant fortranslation of the findings to humans

Experiments in which animals experience a moderate or severe noxiousstimulus, or stress (e.g. electric shocks, immobilization, prolonged bouts ofswimming), will require special justification, particularly in respect of the type,duration and intensity of the stimulus. Authors should include a statement toconfirm (and, ideally, provide evidence) that the use of a less severeprocedure would compromise the objectives of the experiment. In thiscontext, authors must consider the cumulative harm to animals that have

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 9/16

experienced more than one form of noxious stimulus and/or stress.

Studies aimed at producing an animal ‘model’ of a psychiatric disorder (or‘disorder-like’ behaviour) in humans should also include a statement to justifythe extent to which the experimental procedure produces a validated animalanalogue of the human condition, bearing in mind the diagnostic criteriaspecified in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5®)

When reaching a decision on the suitability of the manuscript for publicationin this journal, editors and referees will take into account the harm to theanimals versus the potential benefits of the study. Authors should notassume that local ethical approval of the study, or evidence that a procedurehas been used for many years, will suffice as confirmation that either theethical and welfare aspects of the procedure or its contextual validity qualifyfor publication in this journal.

2.9 Reporting guidelines

The relevant EQUATOR Network reporting guidelines should be followeddepending on the type of study. For example, all randomized controlled trialssubmitted for publication should include a completed Consolidated Standardsof Reporting Trials (CONSORT) flow chart as a cited figure, and a completedCONSORT checklist as a supplementary file.

Manuscripts describing preclinical studies that have used animals mustcomply with the ARRIVE guidelines for reporting the design of, and protocolsfor, experiments that use animals [see https://www.nc3rs.org.uk/arrive-guidelines]

To ensure that preclinical experiments are ARRIVE compliant, authors arestrongly encouraged to consult the PREPARE guidelines (Planning Researchand Experimental Procedures on Animals: Recommendations forExcellence), when planning their experiments.

Other resources can be found at NLM’s Research Reporting Guidelines andInitiatives

2.10 Conflict Resolution

When there is a need for conflict resolution between the Editor and any otherparty involved in the review or publication of JoP, conflict resolution will beoverseen first by the Journal Sub-Committee. If this fails, the BAP Councilshall act as final authorityin the matter. It would be expected to seek the

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 10/16

shall act as final authorityin the matter. It would be expected to seek theadvice of the BAP Governance Panel in any such circumstances. Full detailsof this policy can be found in the British Association for Psychopharmacology(BAP) Journal Sub-committee: Terms of Reference August 2016 .

2.11 Research Data

SAGE acknowledges the importance of research data availability as anintegral part of the research and verification process for academic journalarticles.

The Journal of Psychopharmacology requests all authors submitting anyprimary data used in their research articles alongside their article submissionsto be published in the online version of the journal, or provide detailedinformation in their articles on how the data can be obtained. This informationshould include links to third-party data repositories or detailed contactinformation for third-party data sources. Data available only on an author-maintained website will need to be loaded onto either the journal’s platform ora third-party platform to ensure continuing accessibility. Examples of datatypes include but are not limited to: statistical data files, replication code, textfiles, audio files, images, videos, appendices, and additional charts andgraphs necessary to understand the original research. The editor(s) mayconsider limited embargoes on proprietary data. The editor(s) can also grantexceptions for data that cannot legally or ethically be released. All datasubmitted should comply with Institutional or Ethical Review Boardrequirements and applicable government regulations. For further information,please contact the editorial office at j.psychopharm@imperial.ac.uk.

See also Section 4.3. on supplemental material.

Back to top

3. Publishing policies

3.1 Publication ethics

SAGE is committed to upholding the integrity of the academic record. Weencourage authors to refer to the Committee on Publication Ethics’International Standards for Authors and view the Publication Ethics page onthe SAGE Author Gateway

3.1.1 Plagiarism

The Journal of Psychopharmacology and SAGE take issues of copyrightinfringement plagiarism or other breaches of best practice in publication very

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 11/16

infringement, plagiarism or other breaches of best practice in publication veryseriously. We seek to protect the rights of our authors and we alwaysinvestigate claims of plagiarism or misuse of published articles. Equally, weseek to protect the reputation of the journal against malpractice. Submittedarticles may be checked with duplication-checking software. Where an article,for example, is found to have plagiarised other work or included third-partycopyright material without permission or with insufficient acknowledgement,or where the authorship of the article is contested, we reserve the right totake action including, but not limited to: publishing an erratum or corrigendum(correction); retracting the article; taking up the matter with the head ofdepartment or dean of the author's institution and/or relevant academicbodies or societies; or taking appropriate legal action.

3.2 Contributor's publishing agreement

Before publication, SAGE requires the author as the rights holder to sign aJournal Contributor’s Publishing Agreement. SAGE’s Journal Contributor’sPublishing Agreement is an exclusive licence agreement which means thatthe author retains copyright in the work but grants SAGE the sole andexclusive right and licence to publish for the full legal term of copyright.Exceptions may exist where an assignment of copyright is required orpreferred by a proprietor other than SAGE. In this case copyright in the workwill be assigned from the author to the society. For more information pleasevisit our Frequently Asked Questions on the SAGE Journal Author Gateway.

3.3 Open Access and author archiving

The Journal of Psychopharmacology offers optional open access publishingvia the SAGE Choice programme. For more information please visit theSAGE Choice website. For information on funding body compliance, anddepositing your article in repositories, please visit SAGE Publishing Policieson our Journal Author Gateway.

3.4 Permissions

Authors are responsible for obtaining permission from copyright holders forreproducing any illustrations, tables, figures or lengthy quotations previouslypublished elsewhere. For further information including guidance on fairdealing for criticism and review, please visit our Frequently Asked Questionson the SAGE Journal Author Gateway

Back to top

4. Preparing your manuscript

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 12/16

p g y p

4.1 Word processing formats

Preferred formats for the text and tables of your manuscript are Word DOC,RTF, XLS. LaTeX files are also accepted. The text should be double-spacedthroughout and with a minimum of 3cm for left and right hand margins and5cm at head and foot. Text should be standard 10 or 12 point. Word andLaTex templates are available on the Manuscript Submission Guidelines pageof our Author Gateway.

4.2 Artwork, figures and other graphics

For guidance on the preparation of illustrations, pictures and graphs inelectronic format, please visit SAGE’s Manuscript Submission Guidelines

Figures supplied in colour will appear in colour online regardless of whetheror not these illustrations are reproduced in colour in the printed version. Forspecifically requested colour reproduction in print, you will receive informationregarding the costs from SAGE after receipt of your accepted article.

4.3 Supplemental material

This journal is able to host additional materials online (e.g. datasets,podcasts, videos, images etc.) alongside the full-text of the article. These willbe subjected to peer-review alongside the article. For more informationplease refer to our guidelines on submitting supplemental files, which can befound within our Manuscript Submission Guidelines.

4.4 Journal layout

The Journal of Psychopharmacology conforms to the SAGE house style. Click here to review guidelines on SAGE UK House Style.

4.5 Reference style

The Journal of Psychopharmacology adheres to the SAGE Harvard referencestyle. Click here to review the guidelines on SAGE Harvard to ensure yourmanuscript conforms to this reference style.

If you use EndNote to manage references, you can download the SAGEHarvard output file here

4.6 English language editing services

Authors seeking assistance with English language editing, translation, or

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 13/16

figure and manuscript formatting to fit the journal’s specifications shouldconsider using SAGE Language Services. Visit SAGE Language Services onour Journal Author Gateway for further information.

Back to top

5. Submitting your manuscript

5.1 How to submit your manuscript

The Journal of Psychopharmacology is hosted on SAGE Track, a web basedonline submission and peer review system powered by ScholarOne™Manuscripts. Visit http://mc.manuscriptcentral.com/jop to login and submityour article online.

IMPORTANT: Please check whether you already have an account in thesystem before trying to create a new one. If you have reviewed or authoredfor the journal in the past year it is likely that you will have had an accountcreated. For further guidance on submitting your manuscript online pleasevisit ScholarOne Online Help

5.2 Title, keywords and abstracts

Please supply a title, short title, an abstract and keywords to accompany yourarticle. The title, keywords and abstract are key to ensuring readers find yourarticle online through online search engines such as Google. Please refer tothe information and guidance on how best to title your article, write yourabstract and select your keywords by visiting the SAGE Journal AuthorGateway for guidelines on How to Help Readers Find Your Article Online

Please include an abstract (semistructured summary), incorporating thefollowing headings: (Background, Aims, Methods, Results/Outcomes,Conclusions/Interpretation, and Declaration of interest/Funding), notexceeding 250 words. The abstract is a crucial part of the paper and authorsare urged to devote some care to ensuring that all the important findings areincluded within the word limit. Our electronic submission system will ask youto copy and paste this section at the “Submit Abstract” stage.

5.3 Corresponding author contact details

ou will be asked to provide contact details and academic affiliations for all co-authors via the submission system and identify who is to be thecorresponding author. These details must match what appears on yourmanuscript. The affiliation listed in the manuscript should be the institution

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 14/16

where the research was conducted. If an author has moved to a newinstitution since completing the research, the new affiliation can be included ina manuscript note at the end of the paper. At this stage please ensure youhave included all the required statements and declarations and uploaded anyadditional supplementary files (including reporting guidelines where relevant).

5.4 ORCID

As part of our commitment to ensuring an ethical, transparent and fair peerreview process SAGE is a supporting member of ORCID, the OpenResearcher and Contributor ID. ORCID provides a unique and persistentdigital identifier that distinguishes researchers from every other researcher,even those who share the same name, and, through integration in keyresearch workflows such as manuscript and grant submission, supportsautomated linkages between researchers and their professional activities,ensuring that their work is recognized.

The collection of ORCID iDs from corresponding authors is now part of thesubmission process of this journal. If you already have an ORCID iD you willbe asked to associate that to your submission during the online submissionprocess. We also strongly encourage all co-authors to link their ORCID ID totheir accounts in our online peer review platforms. It takes seconds to do:click the link when prompted, sign into your ORCID account and our systemsare automatically updated. Your ORCID iD will become part of your acceptedpublication’s metadata, making your work attributable to you and only you.Your ORCID iD is published with your article so that fellow researchersreading your work can link to your ORCID profile and from there link to yourother publications.

If you do not already have an ORCID iD please follow this link to create oneor visit our ORCID homepage to learn more.

Back to top

6. On acceptance and publication

6.1 SAGE Production

Your SAGE Production Editor will keep you informed as to your article’sprogress throughout the production process. Proofs will be made available tothe corresponding author via our editing portal SAGE Edit or by email, andcorrections should be made directly or notified to us promptly. Authors arereminded to check their proofs carefully to confirm that all author information,i l di ffili ti d t t d t il t d

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 15/16

including names, affiliations, sequence and contact details are correct, andthat Funding and Conflict of Interest statements, if any, are accurate. Pleasenote that if there are any changes to the author list at this stage all authorswill be required to complete and sign a form authorising the change..

6.2 Access to your published article

SAGE provides authors with online access to their final article.

6.3 Online First publication

Online First allows final revision articles (completed articles in queue forassignment to an upcoming issue) to be published online prior to theirinclusion in a final journal issue which significantly reduces the lead timebetween submission and publication. For more information please visit ourOnline First Fact Sheet

Back to top

7. Further Information

Any correspondence, queries or additional requests for information on the manuscriptsubmission process should be sent to the Journal of Psychopharmacology editorial officeas follows:

Dr Pallab SethEditorial ManagerJournal of Psychopharmacology Editorial officeNeuropsychopharmacology UnitImperial College LondonBurlington-Danes BuildingHammersmith HospitalDu Cane RdLondon, W12 0NNj.psychopharm@imperial.ac.ukp.seth@imperial.ac.uk

Back to top

Include an abstract (semistructured summary), incorporating the following headings:(Background, Aims, Methods, Results/Outcomes, Conclusions/Interpretation, andDeclaration of interest/Funding), not exceeding 250 words. The abstract is a crucial partof the paper and authors are urged to devote some care to ensuring that all the importantfindings are included within the word limit. Our electronic submission system will ask you

4/4/2020 Manuscript Submission Guidelines: Journal of Psychopharmacology: SAGE Journals

https://journals.sagepub.com/author-instructions/JOP#Top 16/16

to copy and paste this section at the “Submit Abstract” stage.

More about this journal

Description Aims and Scope Editorial Board

Abstracting/Indexing