Psilocybin's effects on the brain and implications for depression treatment

Katariina Sarajärvi

Psychology, bachelor's level 2020

Luleå University of Technology Department of Business Administration, Technology and Social Sciences

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Abstrakt

Mental ohälsa och särskilt depression är globala problem. Nya behandlingsalternativ behövs för de

som inte får hjälp av nuvarande behandlingar. Psilocybin är ett ämne som finns i så kallade magiska

svampar och har blivit en potentiell kandidat. Psilocybin påverkar hjärnan genom att inaktivera

vissa delar, vilket leder till förändringar i perception, medvetandet och antidepressiva responser

bland annat. Tidigare forskning har fokuserat på hur psilocybin påverkar hjärnan samt visat att även

kortvarig behandling med psilocybin kan framkalla en långvarig förbättring av hur man mår. Denna

analys inkluderar nio experiementella studier om psilocybins effekter på depressiva symtom.

Resultatet visar att psilocybin minskar depressiva symptom, även långvarigt. Endast kortvariga

milda bieffekter var rapporterade. Framtida forskning bör ha ett större antal av deltagare samt

fokusera på att identifiera idealgruppen för denna typ av behandling.

Nyckelord: psilocybin, psykedelisk terapi, depression

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Abstract

Mental illnesses, especially depression, are a global problem that require new treatment options to

those whose symptoms are resistant to the current ones. Psilocybin, which is a naturally occurring

drug in mushrooms, has become a potential candidate. It affects the brain by deactivating certain

areas, causing not only changes in perception and consciousness but antidepressive responses as

well, thereby improving well-being. Previous studies have looked at psilocybin and how it affects

the brain, and also shown that short trials with psilocybin can cause long-lasting improvement.

Here, I conducted an analysis including nine experimental articles that had studied psilocybin’s

effects on depressive symptoms. Results confirm that psilocybin does decrease depressive

symptoms, even long-lastingly, while only transient mild side effects being fairly common. Some

conclusions could also be drawn of which types of patients will benefit of psilocybin treatment most

likely. Future research with bigger sample sizes is needed, as well as more focus on identifying the

ideal settings and patients of psilocybin-assisted therapy.

Keywords: psilocybin, psychedelic-assisted therapy, depression

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Introduction

Psychedelic-assisted therapy is a potential candidate to add to the existing forms of treatment

against mental illnesses. As the current treatments are in some cases non-effective, and mental

health conditions are costly to the hospital and inpatient care, interest has grown in new areas of

treatment (Bush, 2020; Meikle et al., 2020). Although psychedelics are controversial and

implementing them in therapy would require both legal and attitudinal changes, they possibly hold

an effective way of treating people with problems that are resistant to the treatments that are

currently in use in health care.

Psilocybin is a naturally occurring psychedelic drug that structurally resembles serotonin,

and it is found in some mushroom species (Carhart-Harris et al., 2016), often called magic

mushrooms. Psilocybin’s effects usually became detectable in 30-60 minutes after dosing, peak

within two to three hours and fade within six hours (Carhart-Harris et al., 2016).

In moderate or large doses psychedelics induce changes in perception, mood, and

consciousness, possibly causing visual enhancement, visual disturbances, delusions, or real

hallucinations (Prochazkova et al., 2018). On the other hand, the primary effects at low doses are

enhanced cognitive flexibility, associative learning, cortical neural plasticity, and antidepressant

responses (Carhart-Harris et al., 2016). Improvements in well-being and optimism have also been

recorded (Carhart-Harris et al., 2014; 2016; Anderson et al., 2019), as well as reduce in anxious,

depressive, and obsessive-compulsive symptoms (Carhart-Harris et al, 2016). Low dosages are

thought to enhance cognition without the disruptive effects (Rifkin et al., 2020), but both full and

low doses have been hypothesized to have clinical benefits (Anderson et al., 2019).

Psilocybin seems to deactivate certain areas in the brain, as opposed to activating them

(Nutt, 2017), by at least decreasing blood flow and venous oxygenation (Carhart-Harris et al.,

2012). As psilocybin resembles serotonin, it modulates serotonergic neurotransmission in the limbic

system and hubs related to it in the prefrontal cortex (Grimm, Kraehenmann, Preller, Seifritz &

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Vollenweider, 2018), which is thought to be the reason why psychedelics have antidepressive

effects (Grimm et al., 2018). More specifically, psilocybin seems to decrease activity in the

amygdala, the thalamus, the anterior and posterior cingulate cortex, the medial prefrontal cortex,

and the striatum (Carhart-Harris et al., 2012; Kraehenmann et al., 2015). These structures do not

have specific, restricted functions – they can be thought to hold the brain and the human

consciousness together (Carhart-Harris et al., 2014).

Although the neural basis for depression has not quite been mapped, a variety of brain

regions and circuits have been studied (Pandya, Altinay, Malone & Anand, 2012). Areas that have

been identified are the amygdala, the dorsal and medial prefrontal cortex, the dorsal and ventral

anterior cingulate cortex, the orbital frontal cortex and the insula (Bower, 1992; Drevets et al.,

1992; Pandya, Altinay, Malone & Anand, 2012). Many of these areas happen to be areas that

psilocybin affects. The amygdala has been implicated to have a role in the pathophysiology of

depression, and how excessive blood flow is in the amygdala can indicate the severity of the

disorder (Bower, 1992). The amygdala is also known to be sensitive to emotional stimuli (Janak &

Tye, 2015; Sergerie et al., 2008) and hyper-sensitive to negative emotional stimuli (Drevets et al.,

1992; Ma, 2015). The previously mentioned serotonergic system has a major role in processing

emotional stimuli (Laursen et al., 2016), and affecting serotonergic transmission has previously

been proven to shift emotional biases from negative to positive (Kraehenmann et al., 2016; Grimm

et al., 2018).

Functional connectivity measures have shown that psilocybin affects the default mode

network (Carhart-Harris et al., 2013). The default mode network, also called default network or

default state network, includes a variety of brain regions and gets activated during internally

focused tasks (Buckner, Andrews-Hanna & Schacter, 2008; Andrews-Hanna, Reidler, Sepulcre,

Poulin & Buckner, 2010), such as autobiographical memory retrieval, theory of mind, thinking

about the past or the future, others or ourselves (Buckner et al., 2008; Andrews-Hanna et al., 2010).

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Its dysfunction has been related to several disorders, most often depression, autism, dementia, and

schizophrenia (Broyd et al., 2009; Thomas, Malcolm & Lastra, 2017). Rumination is one of the

most characterizing symptoms of depression, and functional brain imaging studies have found that

the default mode network is involved in ruminative processes (Hamilton, Farmer, Fogelman &

Gotlib, 2015; Zhou et al., 2020). The network seems to be located in the anterior and posterior

midline, posterior cingulate cortex, the lateral parietal cortex, the inferior parietal lobules, the lateral

temporal cortex, the prefrontal cortex, the medial prefrontal cortex, and the medial temporal lobe

(Buckner et al., 2008; Thomas et al., 2017).

Much like a lot of other things in psychology, the therapeutic mechanisms of psychedelic

treatments are not well-understood, but there is evidence of that they work when treating mood

disorders (Carhart-Harris et al., 2017; Ruban & Kołodziej, 2018; Kelly et al., 2019). In several

previous studies patients have tolerated psilocybin well (Carhart-Harris et al., 2016; Carhart-Harris

et al., 2018; Rucker, Iliff & Nutt, 2018) and longitudinal studies have shown that the positive

effects of psilocybin can last up to six months (Grob et al., 2011; Carhart-Harris et al., 2018). Not

only this, but because changes in the default mode network characterize mood disorders (Mulders et

al., 2015; Kaiser et al. 2015) affecting it can trigger responses to therapy (Thomas et al., 2017;

Ruban & Kołodziej, 2018). Psychedelics also promote neural plasticity and cognitive flexibility

(Carhart-Harris et al., 2016; Kelly et al., 2019), something that is very needed when treating

disorders that are characterized by fixated thought patterns, like depression and anxiety.

The theoretic background supports the idea of using psilocybin in therapy. Psilocybin seems

to target a lot of brain areas that are relevant to depression and/or depressive symptoms, and many

of its caused effects are useful in therapy in general.

The aim for this paper was to research psilocybin’s effects on the brain and whether or not it

can be used in therapy to help clients who suffer with depression. Psilocybin’s effects on the brain

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have been talked through in this introduction. I also hypothesized that psilocybin can be useful in

therapy with patients who have depressive symptoms, and that will be discussed from now on.

Method

Literature searches and selection

A search of experimental articles was first conducted using a filtered search in PubMed

(https://www.ncbi.nlm.nih.gov/pubmed/) using psilocybin and depression as keywords. A filter

called “Clinical trials” was used, so that no meta-analyses or literature reviews showed up in the

search. This search resulted in ten studies.

Out of this search, studies that measured depressive symptoms or mood ratings prior and

post psilocybin treatment could be included. A second criteria was that the studies had to

hypothesize about psilocybin affecting depressive symptoms or mood or in some way indicate

psilocybin’s usefulness or effects in therapy. These criteria eliminated one study.

In total, these searches and inclusion criteria yielded a sample of nine studies from seven

different publications (see Appendix A).

Study design

Background information of the studies and their participants can be found in Appendix B. Out of

the participants, 44.5% (n=100) were women and the mean age of all was 44.45 (SD=9.96). Seven

of the studies administrated both a low- and a high-dose trial of psilocybin (10mg and 25mg), one

study only a high dose trial (0.3mg/kg), and two studies only a moderate-dose trial (0.16mg/kg and

0.2mg/kg). The three studies that only did one trial of psilocybin did a second trial with placebo.

The general study design was that after screening, the participants got to meet with study

staff to review their purpose and intention of participation, tell about their personal history as well

as go through the basics of the treatment sessions. An additional goal of this was to establish trust

and comfort between the patient and the staff. The treatment trials were carried out at the research

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facilities. The rooms were decorated in order to provide a comfortable environment for the

participants. The monitors took a nondirective and supportive role, the participants got informed

that they’ll be able to discuss their experiences afterwards. After the session, the participants got to

either go home with someone close to them or stay the night at the research unit. Questionnairies

and inventories got done at different times depending on the study, but always at least before the

sessions and after the sessions.

Analysis

The data analysis was done by comparing the studies and checking for same questionnairies and

inventories. These were then summarized to make it easy to get an overview of several studies at

once (see Table 1, Appendix B). Inventories that are commonly used in measuring depressive

symptoms and/or overall wellbeing were included. Results that were not relevant to the hypothesis

of this paper did not get analyzed in order to keep the analysis simple and limited. This excluded

inventories that are used for anxiety, State-Trait Anxiety Inventory (STAI-T) being an exception as

it was used in the majority of the studies. Measurements that were done in between the trials are

included in results but not in the Table 2 (see Appendix C). Shortly, the results presented in this

analysis do not include everything from the reviewed studies and it is therefore advised to see the

studies listed in Appendix A for detailed results.

Results

All of the studies got significant results in lowering depressive symptoms whenever their measuring

took place. The symptom measures were reported at one week, three weeks, five weeks, three

months and/or six months depending on the study. Table 2 shows mean clinical ratings that were

measured right before the trial and after all of them.

Results in brain imaging showed that psilocybin decreased cerebral blood flow in the left

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Heschl’s gyrus, the left precentral gyrus, the left planum temporale, the left superior temporale, the

left superior temporal gyrus, right and left amygdala, the right supramarginal gyrus and the right

parietal operculum (Kraehenmann et al., 2015; Carhart-Harris et al., 2017). Reduction in the

amygdala’s blood flow was significantly connected to the decrease of depressive symptoms

(Carhart-Harris et al., 2017), and amygdala reactivity change was significantly correlated with

positive mood (Kraehenmann et al., 2015). Increases in the subgenual anterior cingulate cortex’s

resting-state functional connectivity (RSFC) were recorded, as well as increases in the ventromedial

prefrontal cortex’s (vmPFC) RSFC, but these did not correlate with reductions in depressive

symptoms (Carhart-Harris et al., 2017) – however, increase in the vmPFC RSFC did predict

treatment response at five weeks, and so did increased parahippocampal RSFC within the lateral

and medial prefrontal cortex (Carhart-Harris et al., 2017).

No study reported serious aversive effects. Elevated blood pressures, both systolic and

diastolic were recorded in three studies in some of the participants (Grob et al., 2011; Griffiths et

al., 2016 Ross et al., 2016). Transient nausea, vomiting, headache, physical discomfort,

psychological discomfort, confusion, and anxiety were quite common (Grob et al., 2011; Carhart-

Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016). These were most often categorized as

mild, sometimes moderate and even rarely severe. Three participants had transient paranoia

(Carhart-Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016), but no hospitalization was

needed. No cases of prolonged changes in perception or prolonged psychosis were reported.

One study’s results were that pre-treatment speech can indicate treatment success (Carrillo

et al., 2018). Those who responded most to the treatment were also those who at baseline interviews

used fewer emotional words (Carrillo et al., 2018). Experiences of unity, spiritual experiences,

mystical experiences, blissful states and experiences of insight during the trials were also significant

indicators of response to treatment (Griffiths et al., 2016; Carhart-Harris et al., 2018), as well as

acute peak experiences under psilocybin (Carhart-Harris et al., 2017).

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Discussion

The aim for this paper was to research psilocybin’s effects on the brain and whether or not it can be

used in therapy to help clients with depression.

In the light of this analysis, psilocybin affects the brain by deactivating several brain areas

and by damping down brain activity. There is plenty of evidence of psilocybin’s positive effects on

depression, and most importantly, no lasting or severe negative consequences of psilocybin trials

were reported in the studies included in this paper.

The complexity of the human brain makes it hard to say with confidence how and why

psilocybin’s, or other drugs’ for that matter, effects can be therapeutic. It isn’t fully clear either

which brain areas depression affects and how. Although several areas have been identified through

plenty of studies, those studies do often also include areas that other studies do not, and sometimes

the findings are contradictory (Carhart-Harris et al., 2017). Kraehenmann et al. (2015) and Carhart-

Harris et al. (2017) reported in their studies several brain areas that psilocybin affected. These were

in line with previous findings. Decreased blood flow in the amygdala correlated with reduction of

depressive symptoms (Carhart-Harris et al., 2017), as indicated by previous studies. More

interestingly, increases in parahippocampal or vmPFC RSFC did not correlate with a decrease of

depressive symptoms, but could at the same time correlate with treatment response (Carhart-Harris

et al., 2017). That could mean that those areas are not relevant to the maintenance of depressive

symptoms but do play a role when it comes to therapeutic change.

All of the studies included in this analysis got significant results in lowering depressive

symptoms. The greatest feature of psilocybin is that it works immediately. Within 30-60 minutes

after dosing its effects are noticeable (Carhart-Harris et al., 2016), and they seem to be long-lasting

as well, as reduction in depressive symptoms got recorded at six months (Grob et al., 2011; Carhart-

Harris et al., 2018). Considering that in these studies the participants got psilocybin two times at

most, that is fascinating. The side effects have tended to be mild and transient. Compared to a lot of

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the current medications, that is a remarkable advantage.

The studies in this analysis reported improvement of well-being on all of the patients. It was

though noted that certain characteristics of the trip indicated greater response to treatment. These

usually were out-of-this-world or very peaceful and giving experiences. Acute peaks during the trip

were also indicators of greater response (Carhart-Harris et al., 2017). How and why this is,

remained unexplained. Carrillo et al. (2018) hypothesized that speech can also be an indicator of

response, and their results were that those who at baseline interviews used least emotionally

charged language also improved the most during the study (Carrillo et al., 2018). A possible

explanation to this is that those patients had greatest room for improvement (Carrillo et al., 2018). It

is to be expected that some people react to a certain treatment better than others, so it’s good that

there starts to be evidence of ideal patients for psilocybin. That should guide further research.

A limitation of all analyses of this type is publication bias, the fact that they are based on

research that gets published. This means that neither unpublished studies nor studies that are still in

progress get analyzed. This can make the analysis skew. The studies in this analysis all used very

similar procedures in their trials, which indicates heterogeneity. At the same time, clinical trials are

very regulated, and a lot of standards have to be followed. The similar procedures also help to

analyze whether or not just this approach can be applicable, which it seems to be. Considering how

rarely clinical trials on drugs get to be done the sample size of nine studies is moderate.

Further research in double-blind randomized control trials is needed. Future studies should

aim to have a higher number of participants in order to heighten the generalizability. As the field

advances the focus should shift to identifying the ideal patients to this treatment type. Currently, the

majority of studies have been conducted in Europe or north America, so there is an apparent need of

trials in other continents later on. Hopefully it will become easier in the near future to do studies on

psilocybin, as it seems to have a great potential in treating depression, and there is an apparent need

of new methods.

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Appendix A

A list of the studies included in the analysis

Carhart-Harris, R.L., Bolstridge, M., Rucker, J., Day, C.M.J., Erritzoe, D., Kaelen, M., Bloomfield,

M., Rickard, J.A., Forbes, B., Feilding, A., Taylor, D., Pilling, S., Curran, V.H. & Nutt, D.J.

(2016). Psilocybin with psychological support for treatment-resistant depression: an open

label feasibility study. Lancet Psychiatry, 3, 619-627. doi:10.1016/52215-0366(16)30065-7

Carhart-Harris, R.L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J.N., Wall, M.B.,

Tanner, M., Kaelen, M., McGonigle, J., Murphy, K., Leech, R., Curran, H.V. & Nutt, D.J.

(2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms.

Scientific Reports, 7(1), 1-11. doi:10.1038/s41598-017-13282-7

Carhart-Harris, R.L., Bolstridge, M., Day, C.M.J., Rucker, J., Watts, R., Erritzoe, D.E., Kaelen, M.,

Giribaldi, B., Bloomfield, M., Pilling, S., Rickard, J.A., Forbes, B., Feilding, A., Taylor, D.,

Curran, H.V. & Nutt, D.J. (2018). Psilocybin with psychological support for treatment

resistant depression: six-month follow-up. Psychopharmagolocy, 235, 399-408.

doi:10.1007/s00213-017-4771-x

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19

Appendix B

Background information of the studies and participants

Table 1 Background information of the studies and participants

Study Country Number of participants

Number of women/men (%)

Age M (SD)

Carhart-Harris et al. (2016)

the United Kingdom

12 50/50 42.67 (10.165)

Carhart-Harris et al. (2017)

the United Kingdom

19 21/79 42.8 (10.3)

Carhart-Harris et al. (2018)

the United Kingdom

20 30/70 44.05 (11.024)

Carrillo et al. (2018)

the United Kingdom

17ª 29/71 44.59 (10.97)

Griffiths et al. (2016)

the USA 51 49/51 56.3 (9.99)

Grob et al. (2011)

the USA 12 92/8 ᵇ

Kraehenmann et al. (2015)

Switzerland 25 36/64 24.2 (3.42)

Roseman et al. (2018)

the United Kingdom

19 32/68 44.7 (10.9)

Ross et al. (2016) the USA 29 62/38 56.28 (12.93)

Note. ªOnly the experimental group included ᵇRanged from 36 to 58

20

Appendix C

Mean clinical ratings before and after the psilocybin trials

Table 2 Mean clinical ratings before and after the psilocybin trials

Study BDI GAF HAM-D

MADRS SHAPS STAI-T QIDS

Carhart-Harris et al. (2016)

33.7 to 15.2**

50.3 to 77.7**

21.4 to 7.4**

31.0 to 9.7**

7.5 to 2.8**

70.1 to 54.8**

19.2 to 10.0**

Carhart-Harris et al. (2017)

16.9 to 10.9***

Carhart-Harris et al. (2018)

34.5 to 19.5***

48.9 to 74.2***

24.1 to 9.3***

6.6 to 3.3**

68.6 to 53.8***

Carrillo et al. (2018)

ª

Griffiths et al. (2016)

18.1 to 7.1***

22.58 to

6.59***

47.6 to 36.1**

Grob et al. (2011)

16 to 7*

38 to 40

Kraehenmann et al. (2015)

12 to 35

Roseman et al. (2018)

ᵇ c

Ross et al. (2016)

16 to 7,5*

49 to 35*

Note. BDI=Beck Depression Inventory. GAF=Global Assessment of Functioning. HAM-D=Hamilton Depression Rating scale. MADRS=Montgomery-Åsberg Depression Rating Scale. SHAPS=Snaith-Hamilton Pleasure Scale. STAI-T=State-Trait Anxiety Inventory. QIDS=Quick Inventory of Depressive Symptoms. ª ≥ 50% reduction ᵇ Change 10.2 ± 5.3 c Change 23.8 ± 15.2