2019/2020
Rui Pedro Leal Andrade
Terapêutica com psilocibina e depressão – uma revisão sistemática
Psilocybin-assisted therapy and depression
– a systematic review
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
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
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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: [email protected]
Rui P Andrade
a, Miguel Bragança
ba
Faculty of Medicine of the University of Porto
b
Department of Clinical Neurosciences and Mental Health, Faculty of
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AbstractBackground: 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.
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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), aspsychedelics, 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
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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.
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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;
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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
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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 (Harris et al., 2018; Carhart-Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016)
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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.
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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
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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
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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 (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
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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)
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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
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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
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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
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
18
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20
Appendix
Figure 1: Flowchart of included articles.
Table 1: Outcome measures applied in the trials. Table 2: Results
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
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 DrugSessions 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 DrugSessions
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
26
Treatment-resistant DepressionStudy 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%)
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
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