BIOLOGICAL BASIS OF BEHAVIOR
Psychology 321
Spring, 2005 HGH 225
Dr. John M. Morgan MWF, 8am to 9:00
Chemistry of Psilocybin and Synaptic Transmitters Involved
By: Hannah Rich
Psilocybin is a type of hallucinogenic mushroom that is
ingested by eating the raw fungi. The mushroom can also be made
into a tea and drunk. In some of the later studies done on
psilocybin, the drug was synthetically produced and then either
inhaled or injected by an IV. The drug enters the blood stream
and can cross the blood brain barrier because of it relative
metabolic similarity to serotonin (Fuller 1985). This means that
since psilocybin is chemical resemblance to the neurotransmitter
serotonin, psilocybin can trick the protein channels embedded in
the membrane of the blood vessel and pass through as if it were
serotonin and not a drug. Psilocybin (4phosphodimethyltryptamine
or N, N dimethyltryptamine (DMT)) is a naturally occurring
indoleamine hallucinogen and is metabolized to psilocin after
ingestion (Umbricht, Koller, Vollenweider, Schmid, 2001).
Psilocin is the active chemical in the plant and it is what
causes hallucinations and other behavioral changes in the
individual taking the substance. It is stated that psilocybin is
used in research because it is short-acting, naturally occurring
and draws less attention then other well-know hallucinogens
(Strassman 1996). There are not many studies done with human
subjects so the majority of data has been collected with animals
(rats in particular). In many articles the effects, both
neurological and behavioral are likened to the effects of the
hallucinogen LSD.
The hallucinogen psilocybin is considered to be a monoamine
related substance that is mediated by the effects of activity by
serotonergic systems in the central nervous system (Grilly
1998). When talking about the serotonergic systems that are
affected by the drug Psilocybin the research is focusing on the
central systems and not the periphery nerve networks. The drug
is considered to be part of the indolealkylamine group and is
classified in the chemical class of tryptamines. A number of
indolealkylamines that are hallucinogenic can be divided into
three basic groups, tryptamine derivatives, beta-carbolines, and
lysergic acid derivatives (Glennon 1985, Nichols and Glennon
1984). Psilocybin is tryptamine derived. The indole nucleus of
serotonin is commonly found in the chemical class of tryptamines
(Abraham, Aldridge, Gogia 1996). Psilocybin in one of the best
studied tryptamine derivatives and is related to other
indolealkylamines that are derived from various plants (Nichols
and Glennon 1996).
Psilocybin and other indolealkylamines chemically resemble
the neurotransmitter serotonin (Kalat 2004, Glennon 1985).
Hallucinogenic agents such as psilocybin have a serotonin
receptor affinity which means that psilocybin has a tendency to
bind to a particular type of receptor, which in this case are
serotonin receptors (Glennon 1985). In experiments done by
Glennon (1985) it was found that indolealkylamine analogues
(psilocybin) were found to interact with the serotonin receptors
in a competitive manner which gives rise to the hypothesis that
psilocybin has a preference for a specific serotonergic
receptor. The tendency for indoleamine hallucinogens such as
psilocybin to bind to the serotonin receptors is also highly
correlated with their hallucinogenic potency in humans (Umbricht
et al 2001, Abraham et al 1996).
Psilocybin is a serotonin agonist, which means that the
drug mimics or increases the effects of the neurotransmitter
serotonin (Kalat 2004, Kruk and Pycock, 1979). Psilocybin is a
direct agonist because it mimics the action of serotonin on
tissue receptors (Fuller 1985). This direct agonist of serotonin
decreases the rate of serotonin synthesis and turnover in the
brain (Fuller 1985).
According to Kalat, psilocybin and similar drugs stimulate
the serotonin type 2 receptors (5HT2A) at inappropriate times
and for longer than usual durations (Kalat 2004, Vollenweider
1999). Other sources state that psilocybin is a mixed 5HT2A and
5HT1A receptor agonist (Vollenweider, Vontobel, Hell, Leenders,
1999). Some researches say that since the actions and properties
of the receptors are still not completely known it is accepted
that drugs such as psilocybin affect both receptors but with
different affinities. Vollenweider and colleges state that the
serotonin agonist psilocybin binds with high affinity at 5HT2A
receptors and to a lesser extent at 5HT1A receptors (1999).
Another article contradicts that statement and says that
psilocybin has nearly equal affinity for both receptor sites
(Strassman 1996).
New data also indicates that psilocybin may also influence
dopamine systems. Experiments done by Vollenweider and colleges
raised the possibility of that symptoms of psilocybin may be
secondary responses to increased dopaminergic transmission,
presumably through a serotonin dopamine interaction
(Vollenweider et al 1999). It is stated that psilocybin has no
direct affinity for dopamine receptors but when the 5HT2A
receptors are located on dopaminergic neurons within the
striatum and nucleus accumbens an exchange might take place
between serotonin and dopamine resulting in a serotonin mediated
psilocybin induced dopamine release (Vollenweider et al 1999).
It is thought according to these concepts that psilocybin may
increase dopamine release through 5HT receptor activation; this
is through activation of both 5HT1A and 5HT2A receptors
(Vollenweider et al 1999). Although this is just a hypothesis
the possibility of the relationship can not be ruled out.
Presynaptic serotonergic receptors, according to Kruk and
Pycock (1979), are thought to exist on the serotonergic cell
bodies and dendrites in the raphe nuclei. The raphe nuclei and
the reticular formation (which controls the altering of
consciousness) are found within the medulla which contains
nuclei for several cranial nerves (Kruk and Pycock 1979, Kalat
2004). The raphe nuclei are thought to contain clusters of
serotonergic neurons and send axons to the forebrain, increasing
or decreasing the brain's readiness to respond to stimuli
(Jacobs 1985, Kalat 2004).
The distribution of 5HT receptors in the CNS forms a
network with the cell bodies of the major 5HT neurons residing
in the midline raphe nuclei. The densest aggregation of
serotonergic cell bodies is found in the dorsal and median raphe
nuclei (Jacobs 1985). Axons then ascend into the basal ganglia,
hypothalamus, thalamus, hippocampus, limbic forebrain and areas
of the cerebral cortex (Kruk and Pycock 1979). These axons
project to virtually all portions of the central nervous system
(Jacobs 1985). The functions of 5HT receptors are varied and
include the control of mood and behavior, motor activity,
feeding and the control of hunger, thermoregulation, sleep, and
certain hallucinatory states (Kruk and Pycock 1979).
According to Leysen (1985), the serotonin 5HT1 and 5HT2
sites represent two distinct types of binding sites, each with
different drug binding properties and distinct distribution in
the brain. As of 1985 only the 5HT2 sites had been demonstrated
to be in control of multiple roles. All of these roles were
considered to be serotonin induced, some of the roles included:
behavioral excitation in rodents, impaired blood circulation,
provoked inflammation, and the perception of subjective feelings
(Leysen 1985).
It has been found that some serotonergic autoreceptors are
located on the serotonin containing neurons in the dorsal raphe
nucleus, to be more specific the autoreceptors are found at the
presynaptic nerve endings (Moret 1985). The cell bodies of these
autoreceptor serotonergic neurons are located in the raphe
nuclei and project into various brain regions such as the
cortex, hippocampus, hypothalamus and the corpus striatum (Moret
1985). These serotonergic autoreceptors remain completely
available to agonists that are added into surrounding fluid.
This is because endogenous transmitters do not appear to reach
concentrations high enough to activate the receptors (Moret
1985). Endogenous serotonin refers to the serotonin that is
innate to the individual. It is the serotonin that the body
makes to carry out its functions. Other substances, like for
instance psilocybin, need to be inserted into the body and then
the serotonin receptors require these chemically similar
molecules to fit into the receptors to activate the neuron. Many
of the serotonergic neurons are thought to be endogenously
active because they display a slow, regular firing rate without
a connection to any presynaptic cell (Jacobs 1985).
Since the serotonergic neurons in the raphe nuclei comprise
a group of cells that share many characteristics including
responses to various stimuli, drugs or physiological variables,
the group of serotonergic neurons is called a system. This
serotonergic system works together to produce integrated
functional effects that are also global in nature (Jacobs 1985).
This serotonergic system is a major site for the action of
hallucinogenic drugs (Jacobs 1985). It is thought to be the site
for the phenomena of hallucinations. This system refers to the
central serotonergic system and not the peripheral system.
According to Jacobs (1985), serotonergic neurons comprise
the site at which many drugs, including hallucinogens, exert a
significant portion of their action. Jacobs states that these
neurons therefore constitute an essential interface between such
drugs and their physiological and behavioral effects (1985).
Research on the hallucinogenic drug psilocybin has
encountered many setbacks including the limited number of human
research participants and the difficulty of administering
hallucinogenic drugs to humans. The research on serotonin has
been very extensive in the last twenty years but researchers
still do not know what the specific functions of the different
receptors are. In researching psilocybin the research available
seemed quite outdated but the journal articles provided more
recent discoveries. The research on psilocybin, as well as for
other hallucinogens, is far from complete and there are many
more discoveries to be made in the neurophyscopharmacology of
hallucinogenic drugs.
References
Abraham, H.D., Aldridge, A.M., and Gogia, M.B. (1996). The
psychopharmacology of hallucinogens. Neurophyscopharmacology.
14, 285.
Fuller, R.W. (1985). Drugs altering serotonin synthesis and
metabolism. In Neuropharmacology of Serotonin (ed. A.R. Green)
p.1. Oxford University Press, Oxford.
Glennon, R.A. (1985). Involvement of serotonin in the
action of hallucinogenic agents. In Neuropharmacology of
Serotonin (ed. A.R. Green) p.253. Oxford University Press,
Oxford.
Grilly, D.M. (1998). Drugs and Human Behavior. Allyn and
Bacon, Boston.
Jacobs, B.L. (1985). An overview of brain serotonergic unit
activity and its relevance to the Neuropharmacology of
serotonin. In Neuropharmacology of Serotonin (ed. A.R. Green)
p.196. Oxford University Press, Oxford.
Kalat, J.W. (2004). Biological Psychology. Wadsworth,
United States.
Kruk, Z.L., Pycock, C.J. (1979). Neurotransmitters and
Drugs. p.94-104. University Park Press, Baltimore.
Leysen, J.E. (1985). Characterization of serotonin receptor
binding sites. In Neuropharmacology of Serotonin (ed. A.R.
Green) p.79. Oxford University Press, Oxford.
Moret, C. (1985). Pharmacology of the serotonin
autoreceptor. In Neuropharmacology of Serotonin (ed. A.R. Green)
p.21. Oxford University Press, Oxford.
Nichols, D.E., and Glennon, R.A. (1984). Medicinal
chemistry and structure activity relationships of hallucinogens.
In Hallucinogens: Neurochemical, Behavioral, and Clinical
Perspectives (ed. B.L. Jacobs) p.95. Raven Press, New York.
Strassman, R.J. (1996). Human psychopharmacology of N, N-
dimethyltryptamine. Behavioral Brain Research. 73, 121.
Umbricht, D., Koller, R., Vollenweider, F.X., and Schmid,
L. (2001). Mismatch negativity predicts psychotic experiences
induced by nmda receptor antagonist in healthy volunteers.
Journal of Psychiatry. v.32.
Vollenweider, F.X., Vontobel, P., Hell, D., and Leenders,
K.L. (1999). 5-HT modulation of dopamine release in basal
ganglia in psilocybin-induced psychosis in man.
Neurophyscopharmacology. v.20.
Part of the Neuron Affected, Inhibitory or Excitatory Potential
Changes and Ion Channels Affected by Psilocybin By: Michelle
Richards
Psilocybin belongs to the classification of drugs called
hallucinogens. Hallucinogens typically act by stimulating
serotonin receptors at different times or for longer durations
than serotonin itself would (Kalat 2004). When psilocybin enters
the brain, the enzyme alkaline breaks down one of its phosphate
groups through hydrolysis. It then becomes psilocin, an even
stronger hallucinogen (Psilocybin 2003). It is particularly
potent due to the position of its hydroxyl group (Jacobs 1984).
Psilocin is a postsynaptic serotonin receptor agonist. In other
words, its similar structure allows it to mimic serotonin,
fitting into some types of serotonin receptors and producing the
same effect as endogenous serotonin (Merriam Webster 2003).
Specifically, psilocin activates the 5HT2A and 5HT1A receptors.
Stimulation of 5HT1 receptors is associated with an inhibitory
response while stimulation of the 5HT2 receptors is associated
with an excitatory response. Soma of the serotonergic neurons
are located in the midline raphe nuclei of the pons and in the
medulla oblongata. Axons extend to the basal ganglia,
hypothalamus, limbic forebrain, parts of the cerebral cortex,
and to the spinal cord (Kruk and Pycock 1979). Functions
believed to be moderated by serotonin include sleep, mood,
arousal, control of motor activity, hunger, thermoregulation,
and some neuroendocrine control mechanisms in the hypothalamus.
(Powell 2004, Kruk and Pycock 1979).
One theory states that effects caused by psilocin result from
stimulation of receptors in the raphe nuclei. According to this
theory, the raphe system has two main functions. One is related
to stimulation of motor neurons when a person is awake. The
other is to suppress sensory systems during the waking state
(Powell 2004). When psilocin binds to the 5HT2A receptors, it
inhibits the uptake of serotonin, thereby decreasing inhibitory
serotonin activity. This results in an increase of alertness and
arousal. Another theory asserts that the important activity of
psilocin takes place at the proximal dendrites of level V
pyramidal cells, as this is the area of the brain with the
highest concentration of 5HT2A receptors. In support of this
theory, this is the only area of the brain where directly
applies serotonin excites cells. The receptors do not activate
pyramidal cells directly but through action potential. This is
demonstrated by the fact that drugs that stop the action
potential prevent the 5HT2A induced excitation. While action
potential is required for such excitation, stimulation of the
5HT2A receptors does not result in increased action potential.
The excitation mechanism can also be blocked by presynaptic
inhibitors, showing that activity in the presynaptic 5HT2A
receptors that connect with pyramidal cells is also crucial
(Connely 2004). According to Marek and Aghajanian 1998, page
1123, "An enhancement of asynchronous evoked [excitatory
postsynaptic potentials] via 5HT2A receptors provides a possible
synaptic mechanism for the hallucinogenic effects of these
drugs."
Psilocybin is an indoleamine, in the same chemical group with
serotonin and tryptamine. According to the 2003 Merriam Webster
Medical Dictionary, an indoleamine is "any of various indole
derivatives that contain an amine group." Typically,
indoleamines have an affinity for dopamine receptors. A classic
example is LSD, whose chemical structure is very similar to
psilocybin. Psilocybin does not. Yet, a research team in
Switzerland conducting a series of experiments with psilocybin
noticed that pretreatment with a dopamine antagonist reduces
some symptoms of psilocybin psychosis (Vollenweider 1998). So,
some effects of psilocybin may not result from direct
stimulation of serotonin receptors, but instead in response to
dopaminergic transmission. To explore the relationship between
psilocybin and dopamine, the team conducted a study using
positron emission tomography and a selective radioligand to
measure dopamine receptor activity in the striatal neurons of
subjects before and after they had received a dose of
psilocybin. The radioligand attempts to bind to the same
receptors in the striatal neurons as endogenous dopamine.
Measures before and after administration of psilocybin showed a
decrease in the binding potential of the radioligand. This
suggests that the receptors were occupied by an increased
concentration of endogenous dopamine (Vollenweider 1998). It is
still unclear how psilocybin stimulates a release of dopamine.
This is especially complicated by the fact that other 5HT2
antagonists have been shown to increase striatal dopamine
release, but stimulation of the receptors has not. However,
5HT1A agonists sometimes increase dopamine release, so it may be
a result of the combined stimulation (Vollenweider 1998).
Stimulation of 5HT2A receptors is connected with stimulation of
phospholipase C, an enzyme that hydrolyzes lecithin. When the
enzyme is stimulated, it hydrolyzes phosphatidylinositol. The
resulting compounds are inositol and diacylglycerol. Inositol
regulates the release of calcium and diacylglycerol aids in
activation of protein kinase C (Rabin, Regina, and Doat 2001).
It has been suggested that this connection to the production of
calcium may increase the potential for asynchronous synaptic
transmission (Connely 2004). Most synaptic transmission is
synchronous, meaning that when the action potential reaches the
presynaptic terminal, the influx of calcium ions leads to the
release of many synaptic transmitters. In asynchronous
transmission, there is a low level release of transmitters for
up to a second after synchronous release (Connely 2004).
Asynchronous release is sustained by residual calcium ions
remaining in the terminal after the initial influx (Marek and
Aghajanian 1998). Marek and Aghajanian found that psilocybin
promotes the asynchronous release of glutamate onto layer V
pyramidal cells and increases regional cerebral glucose
metabolism (Marek and Aghajanian 1998). When hallucinogens are
present at pyramidal cells, asynchronous transmission increases
from a rare occurrence that is practically unrecordable to a
common occurrence that is highly recordable. Synchronous
transmission in pyramidal cells can be blocked by replacing the
calcium ions in the synapse with strontium ions. Asynchronous
transmission cannot be blocked this way, and when a pyramidal
cell is under the influence of a hallucinogen the excitatory
potentials it receives also cannot be blocked. This may be due
to the increased calcium release that takes place in connection
with stimulation of 5HT2A receptors (Connely 2004).
Stimulation of serotonin receptors has varying effects on action
potential. Studies using rat brains showed that stimulation of
5HT2A receptors induces inhibitory postsynaptic potentials in
layer II pyramidal cells by exciting GABAergic interneurons
while the majority of potentials produced in layer V pyramidal
cells are excitatory postsynaptic potentials. Findings also
indicate that stimulation of these receptors primarily increases
frequency rather than amplitude of excitatory postsynaptic
currents. Apical dendrites of the pyramidal cells are much more
sensitive than basilar dendrites to such stimulation.
Psilocybin is also called 4 phospho DMT and another name for
psilocin is 4 hydroxy N, N dimethyltryptamine. Psilocybin is
part of a group of ring substituted N,N Dialkyl derivatives.
Member of this group of chemical compounds have an alkyl
substituent on the aromatic nucleus. Serotonin is unable to
cross the blood brain barrier due to its ring hydroxyl group
(Osborne 1982). The difference in psilocybin's hydroxyl group
allows it to penetrate the blood brain barrier. This is why
ingesting psilocybin results in activation of cerebral serotonin
receptors, while systemically injecting serotonin does not.
Psilocybin is the phosphate esther of psilocin. Differences in
psilocin's structure make it somewhat more potent than
psilocybin (Jacobs 1984).
The neurological effects of psilocybin are not yet fully
understood. Many research projects are currently underway. In
one recent study, researchers discovered increased plasma
concentrations of adrenocorticotropic hormone and cortisol
during peak effects of psilocybin. This suggests that 5HT2A
receptor stimulation activates the hypothalamo pituitary adrenal
axis (Hasler, Grimberg, and Vollenweider 2003). Another recent
study suggests that psilocybin induces visual distortions via
5HT2A receptor activation (Carter, et. al. 2004). Although it is
clear that most effects of psilocybin are caused by stimulation
of the 5HT2A receptor site, the relationship between the
activation, the resulting biochemical changes, and perceived
effects on those who experience hallucinations from psilocybin
are for the most part unknown.
References
Carter, Olivia L., Pettigrew, John D., Burr, David C., Alais,
David, Hasler, Felix and Vollenweider, Franz X. (2004)
Psilocybin impairs high-level but not low-level motion
perception. NeuroReport, Volume 15, Number 12. 26 August 2004.
(pp 1947-1951) Lippincott Williams & Wilkins.
Connely, Bill. (2004) Neuropharmacology of Hallucinogens: A
brief introduction.
http://www.erowid.org/psychoactives/pharmacology/pharmacology_ar
ticle1.shtml
Hasler, F., Grimberg, M.A. Benz, and Vollenweider, F.X. (2003)
Effects of 2A Receptor Challenge by Psilocybin on Cognitive
Performance and Neuroendocrine Measures in Healthy Humans: A
serotonin model of psychosis. European Neuropsychopharmacology,
Volume 13, Supplement 4. October 2003. (p S450)
Jacobs, Barry L. (1984) Hallucinogens: Neurochemical,
Behavioral, and Clinical Perspectives. New York, New York: Raven
Press.
Kalat, James W. (2004) Biological Psychology, 8th ed. Canada:
Wadsworth.
Kruk, Zygmunt L. and Pycock, Christopher J. (1979)
Neurotransmitters and Drugs. Baltimore, Maryland: University
Park Press.
Marek, Gerard J. and Aghajanian, George K. (1998) The
Electrophysiology of Prefrontal Serotonin Systems: Therapeutic
Implications for Mood and Psychosis. Biological Psychiatry. (pp
1118-1127) From the Department of Psychiatry and Department of
Pharmacology, Yale School of Medicine, Connecticut Mental Health
Center, New Haven, Connecticut.
Merriam-Webster Medical Dictionary online at MedlinePlus.
Updated 04 February 2003.
http://www.nlm.nih.gov/medlineplus/mplusdictionary.html
Bethesda, Maryland: U.S. National Library of Medicine.
Newman, P.P., M.D. (1980) Neurophysiology. Jamaica, N.Y.:
Spectrum Publications.
Osborne, Neville N. (1982) Biology of Serotonergic Transmission.
New York: John Wiley & Sons, Ltd.
Powell, Simon G. (2004) The Psilocybin Solution: Prelude to a
Paradigm Shift.
Psilocybin: Reciprocal Net Common Molecule. (2003) Reciprocal
Net Site Network.
http://www.reciprocalnet.org/recipnet/showsample.jsp?sampleId=27
344568
Rabin, Richard A., Regina, Meridith, and Doat, Mirielle J.C. 5-
HT2A Receptor-stimulated Phosphoinositide Hydrolysis in the
Stimulus Effects of Hallucinogens. (2001) Pharmacology,
Biochemistry and Behavior. Volume 72, 2002. (pp 29-37)
Department of Pharmacology and Toxicology, School of Medicine
and Biomedical Sciences, State University of New York at
Buffalo, Buffalo, NY.
Vollenweider, Franz X, M.D., Vontobel, Peter, PhD., Hell,
Daniel, M.D., and Leenders, Klaus, M.D. (1998) 5HT Modulation of
Dopamine Release in Basal Ganglia in Psilocybin Induced
Psychosis in Man: A PET Study with [11C]raclopride.
Neuropsychopharmacology 1999, Volume 20, Number 5. (pp 424-431)
New York, New York: Elsevier Science Inc.
PHYSIOLOGICAL (WHOLE BODY) CHANGES and
PRIMARY BEHAVIOR CHANGES
SHAWNEE O. THAYER
Physiological (Whole Body) Changes
Psilocybin, the active psychotomimetic, hallucinogenic
chemical found in the psilocybe genus of mushrooms, is absorbed
through the mouth and stomach and is a monoamine-related
substance (Levitt 1975, Grilly, 1998). This means that
psilocybin's biochemical effects are mediated by changes in the
activity of serotonin, dopamine, and norepinephrine in the
central nervous system (made up of the brain and the spinal
cord) primarily by way of 5HT2a receptors (Grilly 1998, Hasler
2003). Monoamine-related drugs share a basic similarity in
molecular structure with monoamine neurotransmitters serotonin,
dopamine, and norepinephrine. Psilocybin produces bodily
changes which are mostly sympathomimetic. This means that
psilocybin mimics the effects of stimulating postganglionic
adrenergic sympathetic nerves (online medical). The effects of
this sympathetic nervous system arousal may consist of pupillary
dilation, increases in blood pressure and heart rate,
exaggeration of deep tendon reflexes, tremor, nausea,
piloerection (hair erection), and increased body temperature
(Grilly 1998).
Psilocybin creates distinct psychological (hallucinogenic,
entheogenic) changes in humans. Because of the mind-altering
properties of the drug, much research on psilocybin is devoted
to understanding its physiological effects on brain chemistry.
A recent study tested prefrontal activation during a
cognitive challenge and the neurometabolic effects of four
different drugs on 113 regions of interest of the brain
(Gouzoulis 1999). The four substances tested were psilocybin,
d-methamphetamine (METH), methylenedioxyethylamphetamine (MDE),
and a placebo in healthy volunteers. No significant differences
of global cerebral metabolism were found in the four groups.
Neurometabolic effects were found to include a significant
increase of regional glucose activity in the right anterior
cingulate of the brain, the right frontal operculum, and an
increase in activity of the right inferior temporal region. A
significant decrease in metabolism was found in the right
thalamus, the left precentral region and a decrease in activity
was found in the left thalamus. Overall there was a general
hypermetabolism of the prefrontal region of the right hemisphere
and hypometabolism in subcortical regions. During the cognitive
challenge activation of the middle prefrontal cortex was
eliminated and activation of Broca's area (right frontal
operculum) was reduced.
In a study conducted by A.M. Quetin, electrolyte levels,
liver toxicity tests and blood sugar levels were shown to be
unaffected by psilocybin (Passie 2002). White blood cells
temporarily decreased in number between the second and forth
hour after ingestion.
A study directed by F. Hasler studied the dose-dependent
physiological effects of psilocybin in healthy volunteers
(Hasler 2003). Four doses were administered to the
participants: a placebo (PL), 45 ('very low dose' VLD) mg/kg
body weight, 115 ('low dose' LD) mg/kg body weight, 215 ('medium
dose' MD) mg/kg body weight, and 315 ('high dose' HD) mg/kg body
weight. No significant elevation in blood pressure was noted,
although in the HD condition a short-lasting moderate rise in
blood pressure did occur one hour into the experiment. It was
concluded that no cardiovascular complications should be
expected from ingestion of psilocybin in healthy humans without
pre-existing medical conditions. A significant increase of the
levels of analyzed hormones thyroid-stimulating hormone (TSH),
prolactin (PRL), cortisol (CORT), and adrenocorticotropic
hormone (ACTH) were found during the peak effect (105 minutes)
of HD psilocybin, and by 300 minutes all hormones were back to
baseline. HD psilocybin also led to a short-term statistically
significant but clinically irrelevant increase on two liver
enzymes: gamma glutamyltransferase (GGT), and aspartate
aminotransferase (ASAT). These levels never rose out of normal
physiological range.
A study by F. Vollenweider looked at the effects of
psilocybin on brain activation patterns of healthy individuals
and the similarities its effects has to the effects of naturally
occurring psychosis on brain activation patterns (Vollenweider
2001). The 'psychotomimetic' effects of psilocybin are produced
through the excessive 5HT2A receptor activation. There is a
activation of the prefrontal cortex and overlapping changes in
cortical, straital, and thalamic regions of the brain.
Psilocybin disrupts the thalamo-cortical gate of external and
internal information to the cortex. This gating deficit is
thought to result in sensory overload with excessive processing
of external and internal stimuli, which leads to the person's
inability to screen out, filter, or gate these stimuli. This
can lead to cognitive fragmentation or breakdown of cognitive
integrity, and difficulty in distinguishing self from non-self.
Information was found to support but not conclusively prove this
effect of psilocybin on the brain.
Overall physiological effects are pupillary dilation,
slight increase in blood pressure and an increase in heart rate,
exaggeration of deep tendon reflexes, tremor, nausea, hair
erection, and increased body temperature. These changes are
largely due to sympathetic nervous system arousal (Grilly 1998).
There is stimulation of 5HT (5HT2, 5HT1) receptorswhich leads to
an increase in straital dopamine effects which are thought to
contribute to the psychomimetic effects of psilocybin
(Vollenweider 1999). Hypermetabolism was noted in distinct
frontal cortical areas of the right hemisphere, although during
a frontal activation task (specific cognitive demand) the
ability to increase metabolism in these areas was impaired,
contributing to the participants decreased reaction time and
inability to concentrate or focus on the task (Gouzoulis 1999).
Psilocybin-induced metabolic hyperfrontality and metabolic
alterations in the left temporal lobe, the occipital cortex, and
basal ganglia relate to hallucinations and ego disintegration
(Vollenweider 1997). Psilocybin disturbs cortico-striato-
thalamic pathways (Vollenweider 2001). The disruption of
thalamo-cortical gating of external and internal sensory
information to the cortex is thought to result in an overload of
stimulus information (internal and external). The result is
cognitive fragmentation (loss of identity, ego confusion).
Psilocybin exhibits low toxicity and is not found to be
hazardous to the somatic health of health participants (Hasler
2004, Passie 2002).
Primary Behavior Changes
The primary behavior changes experienced by ingestion of
psilocybin are largely psychological in nature. There are
individual changes in psycholo(patho)logical core dimentions,
mood, and attention (Hasler 2004). These changes are also
subjective, varying from person to person. Psilocybin also
causes hallucinations, which is why it is referred to as
psychotomimetic, although the type of hallucinations and
distortion of reality induced by psilocybin does not actually
mimic the type of psychosis found in schizophrenic and manic
humans (Grilly 1998).
A recent study tested the dose-dependent physiological and
psychological effects of psilocybin (Hasler 2004). Doses were
administered adjusted to the participant's body weight. The
subjects were given either the placebo (PL), 45 mg/kg ("very low
dose" VLD), 115 mg/kg ("low dose" LD), 215 mg/kg ("medium dose"
MD), or 315 mg/kg ("high dose" HD). Psychological changes were
measured by the "Altered States of Consciousness Rating Scale"
(5D-ASC), the "Frankfurt Attention Inventory" (FAIR), and the
"Adjective Mood Rating Scale" (AMRS). Psilocybin dose-
dependently induced alterations of affect, ego-functions,
perception and attention in all subjects. Doses of MD and HD
psilocybin led to a loosening of ego boundaries (derealization,
depersonalization phenomena associated with positive emotional
states such as heightened mood to euphoria, also includes
anxious ego dissolution associated with dysphoric mood states
caused by ego-disintegration and loss of self-control). MD, HD
psilocybin also caused pronounced changes in perception
(elementary hallucinations, synesthesia ("soundseeing" or
"colorhearing", etc.), changed meaning of percept, facilitated
recollection, and facilitated imagination). One participant (HD
psilocybin) experienced pronounced anxiety caused by the
disturbance of ego functioning, while all other participants
reported a loosening of boundaries between self and environment
which was accompanied by insight and experienced by the
participant as "unifying with a higher reality". Only MD and HD
psilocybin led to intervals of geometric and complex visual
hallucinations. VLD, LD psilocybin induced illusions
(intensification or distortion of visual perception).
Psilocybin altered or amplified acoustic perception. General
inactivation (inactivation, drowsiness, tiredness), introversion
and dreaminess were robust in all subjects. Following HD
psilocybin, "dreaminess" was still present 24 hours after all
other effects had worn off. VLD and LD of psilocybin led to
mental states in which normal waking consciousness was
intermittently pervaded by short-lived drug states, the
"insightfulness" of higher doses of psilocybin being absent.
The subjects were administered different doses on subsequent
days, and they were unable to clearly state in retrospect which
day they had received which dose, suggesting that all doses of
psilocybin share subjective "qualities".
Another study tested the effects of psilocybin on D2-
dopamine receptors in healthy volunteers (Vollenweider 1999).
It concluded that psilocybin produces a psychotic syndrome that
included difficulties in reality appraisal and thinking,
disturbances of sensory perception and emotion, and impairment
of ego-functioning (loss of ego-boundaries). During the peak
period of psilocybin affects the participants' experienced
auditory and visual disturbances (illusions to complex scenery
hallucinations). Derealization and loosening of ego-boundaries
was experienced, and participants reported feelings of
heightened mood, euphoria, and feelings of grandiosity, and
three participants reacted with anxiety. Participants
experienced difficulties in concentrating and attention. The
content of thinking was often influenced by derealization, and
was accelerated or slowed down.
Overall behavior changes induced by psilocybin are
largely psychological in nature. They include affective
changes, disturbances in thinking, illusions, elementary and
complex hallucinations, and alterations in ego-functioning
(Vollenweider 1999). Also noted are changes in attention
(Hasler 2004). Due to set (the mental stability and
psychoemotional state of the person) and setting (the
environment), and the highly subjective nature of psilocybins
effects, a person's experience can be pleasant, or delightful,
and include a deep sense of connection with others and a general
sense of connection with nature and the universe, or can lead to
deep-seated emotional conflicts, and result in temporary
disconnection from reality (Perrine 1996).
References
Gouzoulis Mayfrank E, Schreckenberger M, Sabri O, Arning C,
Thelen B, Spitzer M, Kovar K, Hermle L, Bull U, Sass H
(1999): Neurometabolic effects of psilocybin, 3,4-
methylenedioxyethylamphetamine (MDE) and d-methamphetamine
in healthy volunteers; a double-blind, placebo controlled
PET study with [18F]FDG. Neuropschopharmacology 20:565-581
Grilly, David M. Drugs and Human Behavior. (1998) 3rd ed;
Allyn and Bacon, Boston
Hasler F, Grimberg U, Benz M A, Huber T, Vollenweider F (2004):
Acute psychological and physiological effects of psilocybin
in healthy humans: a double blind placebo controlled dose-
effect study. Psychopharmacology 172:145-156
Levitt, Robert A. (1975). Psychopharmacology: a biological
approach. Hemisphere Publishing Corporation, NW
Washington DC
Passie T, Seifert J, Schneider U, Emrick H (2002): The
Pharmacology of psilocybin. Addiction Biology
7:357-364
Perrine, Daniel M. (1996). The Chemistry of Mind-Altering
Drugs: history, pharmacology, and cultural context.
American Chemical Society, Wash DC
Vollenweider F, Leenders K, Scharfetter C, Maguire P,
Stadlemann O, Angst J (1997): Positron emission tomography
and florodeoxyglucose studies of metabolic hyperfrontality
and psychopathology in the psilocybin model of psychosis.
Neuropsychopharmacology 16:357-372
Vollenweider F, Vontobel P, Hell D, Leenders K (1999) 5-HT
modulation of dopamine release in basal ganglia in
psilocybin induced psychosis in man: a PET study with
["C]raclopride. Neuropsychopharmacology 20:424-433
Vollenweider F, Geyer M (2001): A systems model of altered
consciousness: integrating natural and drug-induced
psychosis. Brain Research Bulletin 56:495-507
Side Effect Behavior Changes and Effects Reported by Users of
the drug Psilocybin
By: Holly Young
There have been many experiments and personal testimonies
documenting the side effect behavior changes and effects
reported by users of the drug Psilocybin from ancient history
until more modern times. For instance, the Aztecs believed that
they were capable of moving back and forth between the earthly
and supernatural realms (Schwartz 1988). This travel between
realms was often associated with hallucinatory trances guided by
their god for the entheogens-the Prince of Flowers. The Aztecs
called this ritual "the flowery dream;" this was induced by
sacred mushrooms (Erowid). The trend towards experimenting with
Psilocybin to determine its effects on the body started in the
early 1960's with prominent psychologists like Timothy Leary and
Albert Hofmann taking Psilocybin themselves and reporting their
experiences (Levitt 1975: 270). Later, there were more
controlled double-blind studies performed with groups of
subjects where the drug is administered and neither the subjects
nor the experimenter know which group is receiving the drug and
which group is receiving the placebo. It is much easier in these
types of experiments to control for extraneous variables and to
find a good operational measure for the subjects' reactions to
Psilocybin. However, since the experiences reported by most
users of Psilocybin are within a narrow radius of variation, it
is possible to utilize individual's personal experiences of
Psilocybin as long as they are comparable to the experiences
reported by the majority of the Psilocybin users in other
experiments.
In general, both psilocybin and psilocybin produce yawning,
inability to concentrate, restlessness, increased heart rate,
and hallucinations (visual and auditory). These symptoms may
appear 30 to 60 minutes after the mushroom is eaten and can last
about four hours (Kuhn 1998). According to one online source,
there is a effect-time curve documenting the general reaction to
Psilocybin (see Appendix 1). The total duration of the reaction
is about 4-7 hours when the Psilocybin is ingested orally, but
the experience is divided into four stages: Onset, lasting from
15-60 minutes, Coming Up, lasting from 15-30 minutes, Plateau,
lasting from 2-4 hours, and Coming Down, lasting from 1-3 hours
(Schwartz 1988). In addition to these four general stages, there
are three different levels of effects. The mildest are the
Threshold Effects (from .25 gm to .75 gms of Psilcybe), which
are characterized by a slight cold feeling, mild gas or nausea,
nervous-feeling, pupil dilation, mild visual changes including
lights seeming brighter, and noticing movement at the periphery
of vision, giddiness, more emotional sensitivity, and other
effects related to a change in neurochemistry (Erowid, Schwartz
1988).
The next level, termed Medium Effects (from .75 gm to 2.5
gms of Psilocybe) are characterized by a cold feeling,
gastrointestinal discomfort, pupil-dilation, open-eye visual
effects, such as auras around lights, and rainbowing around
lighting, noticing movement around the visual periphery,
increased or decreased ability to focus, closed eye visuals with
an increased ability to visualize creatively spontaneous
detailed images, feelings of time-dilation, feelings of
belonging and connection, increased emotional sensitivity,
realizations of past feelings, realizations about how to live,
gain a new perspective on current lifestyle and behavior,
feelings of wonder, spirit, joy, sadness, despair, religious
awakening, contentment and possibly latent psychological
crisises come out (Erowid, Schwartz 1988). The most intense
level, termed the High Dose Effects (from 2.5 gms to 10 gms of
Psilocybin), include all of the Medium effects, usually with a
significantly more uncomfortable Coming Up, including pronounced
nausea, sometimes significant cognitive discomfort associated
with feelings of fear, and characterized by elaborate closed eye
visualizations, religious revelation, spiritual awakening, near
death experiences, loss of self, talking to seemingly external,
autonomous entities, extreme emotional responses, repressed
memories coming to life, latent psychological crises coming to
the surface, an increase in artistic sense and intense feelings
of wonder, connection, joy, fear. High Dose Effects could also
include extreme time-dilation (Erowid, Schwartz 1988).
One psychologist, Robert S. Gable, a professor of
psychology at Claremont Graduate School in Claremont,
California, wrote about his own personal experience with
Psilocybin. When he was at graduate school in the 1960's, he
took 4 mg of Psilocybin one day and reported his experience as
seeing "kaleidoscopic neon-glowing webs undulating in an inky
irridescent plasma" (Gable 1993: 43). He also wrote observer's
impressions of him being 'agitated,' at the same time as he
himself reports being involved in "kinesthetic exploration" for
the fun of it, like a child would (Gable 1993: 43). He
philosophied that a better, deeper symbolic medium would be a
kinesthetic language. After describing this experience to
Abraham Maslow, Maslow described it as a "peak experience"
(Gable 1993: 44). A peak experience, according to Maslow, is a
nonreligious, quasi-mystical, and/or mystical experience (Guiley
1991: 438). Peak experiences are sudden feelings of intense
happiness and well-being, and possibly the awareness of
"ultimate truth" and the unity of all things (1991: 438).
Accompanying these experiences is a heightened sense of control
over the body and emotions, and a wider sense of awareness, as
though one was standing upon a mountaintop (1991: 438). The
experience fills the individual with wonder and awe. He feels at
one with the world and is pleased with it; he or she has seen
the ultimate truth or the essence of all things (1991:438). This
definition of a peak experience fits most generally the
description study participants give after having injested
Psilocybin.
Another couple of interesting, interrelated experiments
have to do with participants who hear audible voices at high
doses of psilocybin by Horace Beach and Terrence McKenna. states
that a third of participants who used psilocybin mushrooms
reported a perceived voice (Beach 1997). This study claims that
"mushrooms can catalyze an auditory dialogue between the one who
ingests them and a voice of unknown origin" (Beach 1997). The
sample in the Beach study consisted of 128 participants, ninty-
nine males and twenty-nine females ranging in age from 18 to 75
(M = 40.72, SD = 12.86) (Beach 1997). Of the total questionnaire
responses, 35.9% (n =46) of the participants reported having
head a voice(s) with psilocybin use, while 64% (n+ 82) of the
participants stated that they had not heard a voice (Beach
1997). The group that reported having heard a voice(s) with
psilocybin use, on average, took the mushroom more times, took a
larger amount of dried grams of mushrooms per use, and took the
mushroom more often in darkness that the No group (the group
that reported hearing no voices (1997). The Yes group also used
psilocybin and then tried to evoke a voice(s) more times that
the No group did (1997). Also the Yes group reported taking
psilocybin more often while alone than the NO group; as
suggested by T. McKenna, by being alone talking is elminated as
a distraction (McKenna 1991, 1993). The second statistically
significant difference between the groups was the finding that
the Yes group endorsed having heard a voice(s) when using drugs
other than psilocybin significantly more often than did the No
group. (Beach 1997). The
participants rarely reported having heard more than a single
voice during an experience (1997). Additionally, the voice
experience could not be maintained for long periods of time
(more than 19 minutes) (1997). Though evidently a subtle
phenomenon, the voice(s) is reported most of the time as "clear-
sounding and sensible;" the voices also sounded old, male, and
"low-pitched, slow paced and of low volume" (1997). In a little
less than half of reported experiences, participants stated that
t voices expressed emotion; compassion, anger, love, calm,
humor, fear and sadness (1997). Under half of the reported
experiences, participants said that voice came from outside of
their heads; and a majority of participants also stated that the
voice(s) was not familiar when they first heard it with
psilocybin (1997). Also, in just under half of reported
experiences, participants said that the voice spoke in first
person (1997). An interesting finding of this study is that in
over 45% of participants' total experiences with a voice(s) and
psilocybin, sounds other than voices were present, such as "high
pitch, high tone, humming, buzzing, whirring, ringing, rustling,
rushing, water, howling, vibrations, whooshing, crinkling,
insect-like, drumming, whirling-circular" (1997). These reports
are similar to observations made by T. McKenna and D McKenna
(1993), and Weil (1980). Beach concludes that "the Logos may
superimpose itself on and utilize the formless white-noise of
internal or external stimuli to create a voice(s), and then,
entering the individual's faculty of audition, speaks"; "meaning
(or form) is superimposed on the formless" (1997).
In another experiment titled, "The effects of THC and
Psilocybin on Paranormal Phenomena," by R. Wezelman et al., the
researchers wanted to explore the effect of Psilocybin on ESP in
the Ganzfeld. Here (other) subjects who were experienced with
the use of halucinoids took a standard dose of Psilocybin in
Mexican mushrooms about half an hour before the session
(Wezelman 1997). Because of the exploratory nature, this part of
the experiment was not set up as a within subject design and
hence did not allow for valid evaluation of the effect of
Psilocybin. Also the experimenters introduced a new feature in
the procedure, namely rather than testing one person at a time
they tested two simultaneously (Wezelman 1997). This was done
to enhance the feelings of cohesion in the group and was part of
a series of measures taken to prevent potential bad trips.
During each session the experimenter could, if the situation
would demand this, contact the psychiatric department of the
nearby hospital. Fortunately, we never had to use this option.
Only 12 subjects participated only once (tripping) in this study
so it is impossible to compare their performances with and
without Psilocybin (1997). Although this comparison suggests
that the use of Psilocybin has a dramatic effect on the psi
scores, the alternative explanation is that the group of
selected subjects used (namely subjects with trip experience) is
a very special group with different personality characteristics
and that they would have scored in the same was when they had
been in a normal state of consciousness. In a
confirmatory study, twenty subjects participated twice in this
study (1997). They all had some experience with using mushrooms
and they were generally recruited from friends of the
experimentors or from friends from the Institute where the
experiments took place. Preceding one of the two sessions a
standard dose Mexican Mushrooms were prepared and taken by the
subject. After about 30 minutes the subject was introduced into
the Ganzfeld procedure which lasted about 45 minutes (1997).
During this time a 'sender' was looking a few times at a
randomly chosen video clip in another part of the building. At
the end of the 45 minutes the subject had to do the judging,
i.e. to select one out of 4 possible video clips as being the
target for the session that was just finished (1997). After
having entered this choice into the computer the 'sender' came
downstairs and told which one of the 4 clips was the actual
target (1997). After this the subject was left alone for about
another hour with music of his/her choice in order to get over
the most intense part of the trip. Subjects stayed at the
institute until they felt comfortable enough to return home. The
results were quite disappointing because the over-all scoring
rate in the tripping condition was exactly what could be
expected by chance. I.e. the tripping subjects did select the
correct target only once in every 4 sessions. In the control
condition the subjects did even worse but the difference was not
statistically significant. When discussing these findings
with some of the subjects it was mentioned that they had not
felt at ease during the experiment. This was to be expected
because the experiment was much more formal than the pilot
study. One felt basically alone. It was noted that in that
context experienced trippers probably would suppress negative
feelings that were coming up. Half of the target clips were
rather negative, for instance a fragment of a crashing airplane.
The remaining clips were positive, for instance the beautiful
images of a horse breaking free from a group of horses. When
breaking down the results for the two categories the researchers
found that results that at first sight looked disappointing were
actually quite fascinating. It turns out that for positive clips
the effect of psilocybin is positive with a scoring rate close
to the one found in the pilot study (1997). However, this effect
is completely annihilated by the effect of psilocybin in
sessions with negative clips as targets. There they saw that the
subjects seem to 'avoid' to get impressions about the negative
clips when tripping. It seems as if they try to avoid to drift
into a bad trip. The effect is completely the opposite when the
subjects are in their 'normal' state of consciousness. The
latter could be explained by the evolutionary value of getting
psi-impressions of negative events. Even though a single
experiment with a limited number of subjects can never give rise
to strong conclusions because the statistical power is too low,
the findings reported here seem to suggest that: Psi performance
is affected by the use of psychoactive drugs and that Psilocybin
increases scoring rates if the material is positive but it might
decrease scoring rates when the material is negative (1997).
This conclusion could be dependent on the context. If the
context is very pleasant and subjects feel they can allow
themselves to experience negative feelings, also negative clips
might show a positive rather than a negative effect. Although it
is common to confine experimental research reports to the
'numbers' we would like to add two qualitative observations. In
the second part of the study the judges were explicitly required
to be in a normal state. It turned out that this judging effect
then disappeared. Similarly, we found that in spite of the high
scoring rate in the pilot phase of the Psilocybin study the
impressions of the subjects were not clearly associated with the
target. In fact, tripping persons do report so many images that
there are correspondences with each target in the target-set and
choosing from them becomes quite difficult (1997). When asked,
the subjects said they 'felt in their stomach' which target was
the real target. Both observations suggest that further research
should focus on the effect of the drugs not only in the phase
where the impressions are supposed to 'come in' but also in the
judging phase where the final choice has to be made.
References
Beach, Horace. (1997). Listening for the Logos: a study of
reports of audible voices at high doses of psilocybin.
Newsletter of the Multidisciplinary Association for
Psychedelic Studies (MAPS) Volume 7 Number 1 pp. 12-17.
Guiley, Rosemary Ellen. Harper's Encyclopedia of Mystical and
Paranormal Experience.
New York: HarperCollins, 1991 438-439
Kuhn, C., Swartzwelder, S. and Wilson, W. (1998). Buzzed. The
Straight Facts About The Most Used And Abused Drugs From
Alcohol To Ecstasy. New York: W.W. Norton and Company.
Levitt, R.A. (1975). Psychopharmacology: a biological approach.
Washington, D.C.: Hemisphere Publishing Corporation.
McKenna, T. (1991). The archaic revival. San Francisco: Harper
San Francisco.
McKenna, T., & McKenna, D. (1999). The invisible landscape:
Mind, hallucinogens, and the I Ching. San Francisco: Harper
San Francisco.
Schwartz, Richart H. and Smith, Deborah. Hallucinogenic
Mushrooms.
Clinical Pediatrics 27. 70-73 (1988).
The Vault of Erowid: Sacred mushrooms. Retrieved from
www.erowid.org/plants/mushrooms. (21 February 2005).
Weil, A. (1980). The marriage of the sun and moon: A quest for
unity in consciousness. Boston: Houghton Mifflin Company.
Wezelman, R. & Bierman, D.J. (1997). Process Oriented Ganzfeld
Research in Amsterdam: The effects of THC and Psilocybin on
paranormal phenomena. Retrieved from
http://m0134.fmg.uva.nl/publications/2000/psychotropic_GF.p
df (28 February 2005).
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