Table

of Contents


What is psilocybin? .................................................................................................................... 3
Is it natural? ................................................................................................................................... 3
Is it the same thing as magic mushrooms? .................................................................................... 3
How does it work in the brain? ...................................................................................................... 3

Rationale and research using psilocybin ..................................................................................... 5
How they fit together .................................................................................................................... 5
Treatment-resistant depression (The Lancet) ............................................................................... 6
The Future and the Legal Status of Psilocybin ............................................................................... 6

The neuroscience of psilocybin ................................................................................................... 8
Cerebral Blood Flow ...................................................................................................................... 8
5-HT2A Receptor ........................................................................................................................... 8
Phospholipase A2 Pathway ............................................................................................................ 9
Phospholipase C Pathway .............................................................................................................. 9

International Research ............................................................................................................. 10
Spiritual Significance .................................................................................................................... 10
Palliative Care .............................................................................................................................. 11
Drug Addiction ............................................................................................................................. 11

Australian Research ................................................................................................................. 12
The Royal Australia and New Zealand College of Psychiatry: Then and Now .............................. 12
Obstacles ..................................................................................................................................... 13
Where to from here? ................................................................................................................... 13

Side-Effects and Safety ............................................................................................................. 14
Setting the Parameters for Safety ............................................................................................... 14
Mental Side-Effects ...................................................................................................................... 14
Physical Side-Effects .................................................................................................................... 15




Published online, 2017.
Created by Michael J. Kugel
The information contained within this e-Book does not constitute medical advice. It is an information
pamphlet, and as always, nobody should act upon this information without first consulting a medical doctor.
All content is my own work, with the exception of the front cover, which was a creation that I designed by
adding two Google Images together, and running them through an e-Book cover designing platform called
Canva.

1

What is psilocybin?



Many people think they know what psilocybin is, but still have lots to learn. Many others
probably have never heard the word before. Either way, this section of the book is here to
clear the air and give an introduction to the molecule that may help to end intractable
depression.

Is it natural?

Psilocybin is the active compound found within the magic mushroom species, or psilocybin-
containing mushrooms. It is a naturally occurring, nitrogenous molecule, and bears the
scientific title alkaloid for that reason. It can also be created in a laboratory, in specific and
exact repeatable amounts. For this reason, in research, it is more common for the synthetic
version of the molecule to be ingested.

Is it the same thing as magic mushrooms?

Psilocybin is the thing that makes magic mushrooms magic. However, it exists outside of
mushrooms. It can be created in a laboratory environment and this is easier and more
precise for research purposes. If researchers were to instead provide whole mushrooms to
their patients, it would be impossible to know the exact dose of psilocybin that a patient
had been given. Dosage is important information for doctors and researchers to gather. It
has been shown that 25mg of psilocybin, per kilogram of body weight, is a more effective
treatment than 10mg/kg (see The Lancet study below).

How does it work in the brain?

Psilocybin works by binding to serotonin receptors. For more detail about these receptors
and the biochemical pathways they activate, see the neuroscience section of this e-Book. In
simple terms, however, psilocybin once ingested is converted by the liver into psilocin.
Psilocin is the active form of psilocybin. Psilocin is chemically a close relative of serotonin.
The similarity in their chemical structures can be seen in the image below.

Serotonin is a hormone that is famously responsible for happiness. It is the hormone that is
credited for joggers high, or the pleasure of eating a good meal. A simple explanation of
depression is that it amounts to a depletion of serotonin, or malfunctioning of serotonergic
neurons. For this reason, most current anti-depressants work by preventing the breakdown
of serotonin in the brain.

A more sophisticated view of depression is that it is a multifaceted disorder caused by many
different elements, but ultimately it is characterized by the dark, repetitive thought patterns
of the affected person. Through certain neuronal mechanisms (see The neuroscience of
psilocybin and depression below), psilocybin can alter ones mental perception of what is
real. This intense experience has such a large effect that previously held opinions, even dark
and repetitious ones, are often seen by the patient as being old and no longer relevant.
With their new perspective of the world, the person drops the chains of their old thought
patterns and sees themselves in a new light with more meaning and wellbeing.









 2

Rationale and research
using psilocybin


Depression is often linked to a persons perspective of themselves, or their place in the
world. They have a point of view, and it repeats itself incessantly within their minds.
Psilocybin brings about a strong response in people suffering from depression. It enables
them to see a new perspective and evaluate their life in terms of a deeper meaning.
Psilocybin is a way to treat intractable depression. It is not about just making someone feel
better temporarily. It is aimed at actually making a person revaluate themselves and their
relationships on a deep level.

How they fit together

The phenomenological experience engendered by a psilocybin trip is suited to the
treatment of depression. Depression is a rut of negative thinking, and psilocybin shakes the
rut away by giving an experience that is so powerful it cannot be digested unless a person
alters some old way of their thinking.

Also, the psilocybin molecule fits into a serotonin receptor in the brain which is not
surprising, given that psilocybin differs by only a few atoms from the serotonin molecule.
The serotonergic system has long been held out as the key to treating depression. While
current-day anti-depressants work primarily by altering the workings of the entire
serotonergic system, psilocybin targets specifically the 5-HT2a receptor this is a particular
subtype of a sub-group of serotonergic receptors. The fact that psilocybin has such high
specificity for its target, as compared to current anti-depressants, is a reason why psilocybin
has far fewer side-effects. It also strengthens the argument for using it, in some cases,
instead of current anti-depressants.

Treatment-resistant depression (The Lancet)

One trial conducted in England in 2016 (published in The Lancet) sought to find the impact
that psilocybin might have on the most difficult cases of treatment-resistant depression.

The study focused on 12 patients1. Half of the research subjects were male, half were
female. All the patients had been non-responsive to at least two other types of drugs that
are already legally available and widely used for treating depression. Since nothing had been
helping them, these patients had been stuck with their depression for an average time of
more than 17 years. These were not the easy nuts to crack.

All patients were given a low dose so as to make sure it was safe for them, and after that
they moved on to the high dose. In both dosing sessions, they were watched closely by
medical and psychiatric doctors. They were prepped before these sessions to make sure
they understood what they were in for, and to talk through any fears or expectations that
they had. This was not a recreational activity.

The results of this study were phenomenal. Seven of the twelve patients involved in the trial
were cured of their intractable depression. Technically, this means that their score on the
Beck Depression Index (BDI) was cut by at least 50%. That this was achieved at all is an
outstanding outcome. That it was achieved using only a single high-dose of a very non-toxic
drug, is astonishing. Furthermore, these patients remained in remission for at least 3-
months after the study had ended. This is a big deal in the treatment of intractable
depression. These results were published in the most prestigious medical research journal in
the world.

The Future and the Legal Status of Psilocybin

People on the cutting edge of psychotherapy are already attuned to this knowledge, as are
the governmental bodies that regulate medicines and clinical trials. Years ago, the U.S. Food
and Drug Administration (FDA) gave permission for phase 2 trials to be run with psilocybin.
These trials have since gathered some excellent results, which can be found here and here,
for example. Given these great results, it is likely that the FDA will approve further research
through phase 3 trials. These will be trials with similar methods, but bigger sample sizes.
They will run for approximately 4-years. If results continue to be sufficiently impressive, the

1
This is not a large sample size, but given the legal regulations governing research with psilocybin, it is all
that could be reasonably achieved by the Imperial College London at the time that the study was
conducted.
FDA will approve psilocybin at the end of the phase 3 trials. Therefore, its possible that
psilocybin will become a legally prescribable medication in the U.S. by 2023, or so.

In Australia, the Therapeutic Goods Administration (TGA) has recently been granted greater
scope by the Federal Government to expedite approval of drugs that have already been
approved by the U.S. FDA. Therefore, its possible that shortly after 2023, psilocybin may
also be a legally prescribable medication in Australia.

It is also possible, if only an ethics committee would approve it, that Australia could host
one of the research centres that could gather data for the FDA phase 3 studies. One reason
that ethics committees have denied applications to conduct research with psychedelic drugs
in the past is because of a lack of funding for such research. You can donate here to the
crowdfunding effort to ensure that sufficient funding is available for this research.




























 3

The neuroscience of
psilocybin


What exactly happens when a person ingests psilocybin, and how it translates into the
mystical experiences that are so reliably induced is not yet known. Despite this, much is
known about the basic pharmacological actions and neurological effects of psilocybin. There
are many factors from this research that make psilocybin an attractive treatment option for
depression.

Cerebral Blood Flow

Cerebral blood flow has been shown to correlate to depression. In particular, patients who
have depression exhibited increased blood flow to certain portions of the brain. These
include the thalamus, the medial pre-frontal cortex and the posterior cingulate cortex.
Psilocybin has been shown in fMRI scans to decrease the flow of blood to these areas.

Psilocybin triggers a release of calcium within brain cells (see the Phospholipase C Pathway
below). Calcium is known to be a smooth-muscle vasodilator. This means it constricts the
blood vessels in certain areas of the body, including the brain. This is one mechanism by
which psilocybin induces a decrease in cerebral blood flow.

The phospholipase A2 pathway also promotes in a decrease in cerebral blood flow (see
Phospholipase A2 below).

5-HT2A Receptor

The mechanisms that allow this to occur have not yet been fully elucidated. But, what is
known is that psilocybin activates a serotonin receptor known as the 5-HT2A receptor. Once
activated, this receptor creates chemical chain reactions. One such chain reaction is known
as the phospholipase A2 pathway. The other is the phospholipase C pathway.

Phospholipase A2 Pathway

Psilocybin is preferential towards the phospholipase A2 pathway. In this reaction sequence,
firstly phospholipase A2 is activated, and it subsequently transforms lipid molecules from
the cell membrane into arachidonic acid a chemical that is important in the synthesis of
thromboxanes. Thromboxanes are released by platelets at a site of injury to clot the blood
and constrict the blood vessels. The decreased cerebral blood flow engendered by
psilocybin ingestion is in part due to the thromboxanes, and other relate molecules, that
stem from the phospholipase A2 pathway.

Phospholipase C Pathway

When phospholipase C is activated, it recruits calcium from a compartment in the cell called
the endoplasmic reticulum. Calcium exists in an electrically charged state within a cell, and
for this reason, when it floods out of the endoplasmic reticulum, the cell itself becomes
more electrically charged. As a result, the cell is more likely to fire it is now more sensitive
to changes in voltage.

Furthermore, the calcium also affects another protein called calmodulin. Calmodulin
prevents potassium from exiting the cell. Since potassium also has a positive electric charge
within a cell, the result is that the cell becomes even more likely to fire.

These could both be mechanisms by which psilocybin permits for perception of things not
normally perceived.












 4

International Research


There have been several studies supporting the potential role for psilocybin in palliative
care. Its strong mental effects have also been investigated for their potential in treating
tobacco addictions and alcoholism. Below exists a summary of many useful trials.

Spiritual Significance

The spiritual experience that psilocybin can engender has become the subject of research at
the prestigious Johns Hopkins University. According to this research, which relied about the
9-point Mysticism Scale, and the Pahnke-Richards Mystical Experience Questionnaire,
psilocybin can reliably make someone feel a sense of sacredness and a sense a oneness with
the world. Furthermore, after the drug-effects wear off, the spiritual/emotional effects
persevere. For 14-months after their psilocybin treatment, volunteers from the Johns
Hopkins trial, were still reporting being positively changed, behaviorally and attitudinally by
the drug-induced spiritual experience. Their friends and family were also surveyed, and also
noticed the sustained difference between the time before and after the psilocybin
experience. Perhaps most tellingly, 58% of the trial volunteers rated their experience as
being in the top 5 most meaningful experiences in their entire life.

The spiritual experience induced by psilocybin has been used by tribal cultures for millennia
in ritualistic settings. In fact, the Western World was introduced to psilocybin after an
amateur mycologist returned from Mexico in the late-1950s with a tale about a magic
mushroom species that the natives there were using for religious practices. Shortly after,
psilocybin was researched for its relationship to spiritual experiences by no less an authority
than Harvard University. Then, 25-years later, the people who took part in the Harvard trial
were contacted and surveyed. Nearly all of those who had taken psilocybin in the study still
attributed great meaning and significance to the experience they had that day, while those
in the control group barely mustered a remembrance of it.


Palliative Care

When it comes to patients with end-stage illness, the ability of psilocybin to produce
meaningful experiences in a non-toxic and reliable manner is of great importance. These
patients often struggle with end-of-life anxiety, characterized by a loss of personal meaning
and connection to self and other. One double-blind placebo controlled pilot study exploring
the use of psilocybin treatment for patients with end-of-life anxiety found that anxiety was
significantly diminished in all 12 patients, 3-months post-treatment. 8 of the 12 patients had
significant reductions in depressive symptomology at 6-months post-treatment. This study
was performed by the University of California, Los Angeles in 2011.

Subsequent studies with bigger sample sizes found that between 70-80% of patients with
end-of-live anxiety were significantly helped in terms of mood, outlook and depressive
symptoms, even 6-months after their psilocybin treatment. These studies were performed
at the New York University as well as Johns Hopkins University, and the results were
published in late-2016.


Drug Addiction

Several more recent trials have investigated the ability of psilocybin to induce sustained
changes in personality and behaviour (Johnson et. al., 2014; Bogenschutz et. al., 2015).
These trials both focused on abstinence from addiction as the primary outcome measure.
Both used similar models of pre-treatment and post-treatment psychological support, as
well as co-therapist teams providing support to a patient who, when under the influence of
psilocybin, simply lays upon a bed or couch, with eyeshades on and listening to pre-
selected, calming music. In the first trial, 15 tobacco addicts who had previously failed their
attempts to quit smoking at least 6 times, were given psilocybin-treatment. Patients were
not blind to the treatment, they knew the were receiving psilocybin, not placebo. Prior to
treatment, addicts used an average of 19 cigarettes per day, but 6-months following
treatment, 12 of the 15 (80%) of patients had maintained their abstinence.

In another trial focusing on psilocybin-treatment and addiction, 10 alcoholic patients were
given the standard psilocybin-treatment. This study was also open-label by design, thus
subjects knew that they were receiving psilocybin. There was a statistically significant
promotion of abstinence in these subjects, though not as pronounced as in tobacco addicts.
One limitation of both studies is the fact that patients knew that they were receiving
psilocybin, and this may have introduced expectancy bias into the results. Taken with the
data body as a whole, however, it is not surprising that psilocybin could promote long-term
changes in behaviour, and break habitual behaviour patterns, especially those that are
emotionally fuelled.





 5

Australian Research


Despite the growing base of research from sources around the world, sadly Australia lags in
this frontier of psychiatric medicine. This wasnt always so, however. When psilocybin was
discovered by the Western World in the mid-20th century, Australias professional
psychiatric bodies highly encouraged further research into its potential uses. This section is
a tour of what Australias psychiatric profession has been saying for the past half-century, in
terms of psilocybin and related compounds. It is also a look forward to more a more fruitful
era of psilocybin-based research in Australias short-term future.

The Royal Australia and New Zealand College of Psychiatry: Then and Now

Here in Australia, back in 1972, the Royal Australia and New Zealand College of Psychiatry
concluded publically that there is, a distinctive place for the use of these substances
[hallucinogenic drugs] in the treatment of neurosis, particularly intractable anxiety
neurosis. Their attitude toward psilocybin, and other psychedelic substances, was
commonplace around the world of psychiatry at the time. The substances had been recently
discovered, and the social stigma that exists today was not yet born. Pharmaceutical
companies as well as research institutions such as universities were heavily invested in
investigating the effects of psilocybin and the psychedelics, and some even made it to
market.

In 1968, the Medical Journal of Australia published an article by the Royal Australasian
College of Psychiatrists, which argued that there is, undoubtedly scope for the legitimate
use of the hallucinogenic drugs, both in research and in psychotherapy. Nothing has
changed in terms of the good fit of psychedelics for particular uses in psychotherapy. The
only things that have changed are the law surrounding psychedelic drugs, as well as social
attitudes towards them. Thus we now deprive ourselves of drugs weve known for decades
to be very useful.

Even after the initial hype about the psychedelics, there were calls within Australia, at a
professional level for the Royal Australia and New Zealand College of Psychiatry to institute
a, committee for the investigation of psychedelic therapies. The question still remains:
why is it, after so long, that we still are yet to act on the advice given by the organizations
that represent the medical and psychiatric professions in Australia?

Obstacles

One quite specific reason why research has not been started in Australia, despite the recent
resurgence of such research around the world, is that ethics committees in Australia, who
govern whether certain types of research can or cant be done, are politically motivated.
According to one recent paper published in the Australian and New Zealand Journal of
Psychiatry, ethics committees have been very conservative in their responses despite
demonstrated safety and promising results in clinical trials overseas.

It is necessary for political leaders to take a stand on this issue. Senator Richard Di Natale,
leader of the Greens Party, and medical doctor by trade, said that, I'm really open for the
conversation and I'm keen to get Parliament talking about this. While this has not yet
happened, it is necessary for the wellbeing of many people in Australia that it does happen,
on the double.


Where to from here?

The current crowdfunding effort, along with the continued drive in international research is
making psilocybin research in Australia an ever-more attainable outcome. The leaders in the
world for psilocybin-based research are based in North America. The Heffter Research
Institute (HRI) is dedicated to the highest quality of scientific research and investigation.
Partnerships are pending between research groups in Sydney and Melbourne, to join forces
with the HRI. In such a plan, Australia would host a study centre and collect data for the
phase 3 trials required by the U.S. FDA. The likelihood is that we will be researching the
psychotherapeutic applications of psilocybin, particularly in the treatment of depression, in
Australia, by 2020. Once the phase 3 studies are complete and all data has been analyzed by
the FDA, it should be approximately 2023. From there, it will be a short-term process to
have psilocybin-assisted psychotherapy for the treatment of intractable depression
expedited for approval by the TGA in Australia. Therefore, this is a medium-term goal,
achievable within a 7-year time frame.

It will help the cause if this eBook is spread around. The knowledge that this book contains
is valuable information, and is unknown to the vast majority of the general public. It would
also help if people would donate to the crowdfunding of this research, since it is otherwise
difficult to find the funds to pay for such research.

Psilocybin is a great potential medicine for curing intractable depression, and there is no
valid argument against performing further research with it in Australia, as soon as possible.


 6

Side-Effects and Safety


Psilocybin is a drug with powerful potential in the treatment of depression. Being powerful,
it also has potential to do harm. Within a medical context, parameters are put in place that
limit the potential for damage. In fact, in over 500 administrations of psilocybin to human
research subjects, there has not been a single serious adverse effect. Nonetheless, there are
a number of mild-moderate side-effects that need mention, and a range of safety
considerations, particularly for those who would be tempted to attempt a DIY psilocybin
treatment.

Setting the Parameters for Safety

Psilocybin is almost always ingested in the context of a safe and comfortable environment,
during research. Usually, a hospital room will be furnished with homely furniture and art.
The patient will lay down, with eye-shades on, and in the presence of male and female
psychotherapists. They are often hooked up to various medical devices to keep track of their
heart rate, and a doctor is on call in case a serious adverse event takes place. Furthermore,
for weeks before a psilocybin session, patients talk through their expectations and are given
a lot of information about what they can expect. After they have their psilocybin dose, and
the powerful experience that comes with it, the patients stay in contact with their
psychotherapists to talk it over and make sense of it in a constructive way. With all these
safety parameters put in place, it is unlikely that a person will lash out irrationally or have
intense panic attacks.

Mental Side-Effects

The most common mental side-effects of psilocybin are anxiety and confusion. It may seem
odd to treat depression with a drug that causes anxiety as a side-effect. But it does make
sense when taking the context into consideration.

Psilocybin can cause anxiety temporarily, because it is a strong psycho-active compound.
This means that when it starts to hit, a person feels themselves increasingly losing control of
all their regular perceptions of the world. This is not so much a change in visual perception
as it is a change in mental perception. A patient will not likely see unicorns flying through
the air, or hallucinations of that nature. Instead, a patient will begin to have deep insights,
or the sense of deep insights, and they will have them in a powerful and profound way, in
rapid succession. This sensation can be an overwhelming one. As such, anxiety can come
about because the drug induces such a change in conscious awareness.

Anxiety caused by the onset of the mental effects of psilocybin is not a long-lasting
experience. If it is not experienced as the drug sets in, it may be encountered later on, as
the drug reaches its peak effects, or anywhere in between. The anxiety will not continue
once the drug effects wear off, which usually takes no longer than 6-7 hours. In the
presence of trained psychotherapists, anxiety is usually contained to a mild-moderate level,
and only lasts a few minutes.

Physical Side-Effects

Most commonly observed physical side-effects of psilocybin are mild-moderate and include
things like nausea, headache, pupil dilation and hypertension. For this reason, those with
heart problems have not been accepted into the research trials conducted to date. The
hypertensive tendency that psilocybin can occasion is normally short-lived, and wears off
after the drug effects subside. In healthy volunteers, this temporarily elevated blood-
pressure is not a major concern. The headache caused by psilocybin will be short-lived, but
has been known to last for up to three days. Psilocybin is a very safe substance, with very
low toxicity even compared with common daily drugs like caffeine.