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Sobriety diminishes, discriminates, and says no;

Pharmacological Constituents of drunkenness expands, unites, and says yes no account


of the universe in its totality can be final which leaves these
Mescaline & Salvinorin A other forms of consciousness quite disregarded
Preliminary Analysis --William James--
Anthropologists Carolyn Boyd and Philip Dering identified tw o hallucinogenic
plants in 4,000-year-old cave paintings near Pecos River, Texas: Images of
spiny ovals attached to staffs closely resemble the seed pods of jimson weed,
Derek T. Rostock and the disk-shaped crow ns of the peyote cactus are represented by dots and
deer impaled by arrows.
Psychology 472-01
University of Idaho
Spring 2003
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Peyote Cactus San Pedro Cactus


Lophophora williamsii: Trichocereus pachanoi
Relatively small and Andes: evidence of
spineless use in Peru over 3000
Deserts of Me xico and years ago
S.W. United States Mescaline highly
Crowns sliced off and dried concentrated in skin,
to form hard brown discs which is peeled, dried
known as mescal buttons and made into a
Buttons chewed and powder
swallowed for
hallucinogenic properties Natives boil slices of
stem and drink the
liquid

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San Pedro Varieties Antiquity Of The Divine Cactus


Centuries old (3000 years among Aztec) use throughout
Trichocereus present day S.W. United States and N. Me xico
peruvianus cactus Indigenous consumption believed to be connected with
religious rituals: releases spirit and power is absorbed by user
Other varieties of Peyote believed to be a om nipotent medic ine
Hernandez of the court o f King Philip II of Spain first reported
hallucinogens from information about strange herbs and medicines: collected
same family 1200 plants and first recorde d visions and mental
changes resulting from c onsum ption
Spanish Catholic priests circa 1600s asked confession from
native American converts of their pe yote use: believed plant
conjured demons

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Antiquity Antiquity
First explored scientifically by German chemist Arthur Aldous Huxley publishes The Doors Of Perception
Heffter who isolated alkaloids from mescal buttons: in 1954: integrated the psychedelic experience
self-experimentation for the sake of science into mainstream culture; enormous advocate of
American psychologist Heinrich Kluver detailed the drug which he viewed as infinite in its
mescaline phenomenology in 1928: published book significance
entitled Mescaline which contained experiential data of Native American Church (1918): Preservation of
the effects: proposed that the drug be used as a peyote rituals instituted through intertribal
research tool for uncovering the depths and
unconscious dynamics of the human psyche organization to allow members to legally ingest
1930s anthropologist Weston La Barre writes thesis on
peyote for religious purposes: one-quarter of a
peyote, noting that the essential goal of the native million members today.
American Indian is to obtain visions for prophecy, Apart from the above use, peyote is a Schedule 1
curing, and inner strength controlled substance that is illegal in all 50 states.

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Rituals Psychoactive Constancy

Sacramental use not considered abuse Alkaloid mescaline: unprecedented


presence: longevity, stability, and
Native participants surround fire: engage in psychoactive potential over immense
trance-like state, intensified by a pulsating periods of time.
drumbeat or chanting Scientists recently unearthed and performed
Experience of achieving a vision through chemical analysis on 1000 year-old, peyote
buttons strung around the necklace of a
direct communication with spirits skeletal corpse discovered in a Mexican
Tranquility burial cave, determining that the chemical
constituents of the plant contained
psychoactive viability.
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"Entheogen" Defined Hallucinogen


Literally means generating the divine within:
strictest sense refers to a psychoactive plant or Chemically and pharmacologically
chemical substance taken to occasion spiritual heterogeneous group of substances
or mystical experience
Looser definition: non-addictive artificial and that have in common the potency to
natural substances that induce alterations of cause in the user a distortion of
consciousness similar to those documented for
ritual ingestion of traditional shamanic inebriants perception and a mental state
Entheogen replaces the judgment-laden resembling psychosis
misnomer hallucinogen, and the culturally
freighted term psychedelic
250 plant species produce controlled substances:
hundreds more elicit psychoactive effect
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Mescaline Comparative
Classification: Hallucinogen Structural Resemblance

Entheogenic Plant Source: Peyote:


Phenylalkylamine
Phenethylamine derivative
Mescaline: categorical prototype
both qualitatively and quantitatively of
hallucinogenic substances

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Nearest Mescaline Structural


Similarity: Catecholamine NTs Mescaline Molecule

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Active Compounds of
Mescaline Chemical Specifics
NAME :Mescaline
3,4,5 Trimethoxyphenylethylamine CHEMICAL NAME :3 ,4,5-Trimethoxyben zeneethanamine
3,4,5 - trimethoxyphenylacetic acid: ALTERNATE CHEMICAL NAMES :3,4 ,5-
trimethoxypheneth ylamine; mezcaline
main metabolite: similar to diamine CHEMICAL FORMULA: C11H17NO3
oxidase MOLECULAR WEIGHT: 211.26
MELTING POINT: 183-186 C (Sulfate dih ydrate)
Suggested that there exist 30 other LD50: crystals : 212 mg/kg i.p.(mice)
LD50: crystals : 132 mg/kg i.p. (rats)
psychoactive chemicals in peyote: LD50: crystals : 328 mg/kg i.p.(guinea pigs)
inconclusive Fr om the Merck Index 12th Edition

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Ontology of Drugs Admonishment
Data extrapolation renders conclusion and
even speculation about specific drug action
Biobehavioral changes are preceded unreliable
by a combination of biochemical It is not easy to establish relationships
alterations and interaction with among psychedelic drugs,
neurotransmitters, brain activity, and states
external environment, which of consciousness. The brain is complex and
essentially defines the experiential role inaccessible to delicate experimental
of psychoactive drugs manipulation by chemical means
Lester Grinspoon
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Discriminative Stimulus Pharmacokinetics:


Properties of Mescaline Hallucinogenic Context
Present and pervasive ED50: Variable
LD50: Unknown
Diverse and various Ratio of LD50 to ED50: therape utic index: unknown/ N/A
Potenc y: absolute number of molecules of drug required to
Uncertain and unpredictable elicit a response: extrapolated, variable
Transitory and context-dependent Efficacy: Ma ximum effect obtainable in which additional
doses produce no effect: unknown
Multiple receptor systems involved Variability: individual differences in drug response, with some
persons responding at very low doses and some requiring
Compound discriminative stimuli influenced much more drug
by a variety of factors experimental and Of particular relevance with hallucinogens:
others Set/ Setting/ Experie nce/ Expectations :
Subjective/ Beha vioral Effects
Dose, sensitization, etc.
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Pharmacokinetics Pharmacokinetics
Ingested orally: absorbed rapidly and Maximum concentration in brain: 30 to 120
minutes
completely in gastrointestinal tract
Effects persist for up to 9 to 10 hours
Hallucinations: 300 - 600 mg Between 3.5 and 4 hours after ingestion,
20 mescal buttons: 600mg mescaline produces an acute psychotomimetic
state
10-30 times lowest dose producing Hallucinations persist for about 2 hours depending
behavioral effects may be lethal upon dose
Death in animals results from convulsions About half the dose is excreted unchanged after
six hours
and respiratory arrest
Others suggest that it is not metabolized at all
Mescaline is 1000 - 3000 times less potent before excretion
than LSD and 30 times less potent that
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psilocybin

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Pharmacokinetics Brain Imaging

Slow tolerance builds with repeated A hyperfrontal pattern with emphasis on


administration right hemisphere activity: questions
Cross-tolerance with LSD validity of the concept of hypofrontality as an
explanation for acute psychotic
Intoxication can be alleviated or symptomatology
stopped with chlorpromazine
(Thorazine): tranquilizer or diazepam Mescaline seems to selectively increase
neuronal activity, especially in the
(Valium)
striatolimbic system to the right hemisphere
Not antagonistic action however (as in schizophrenia)
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Physiological Effects: Usual


Oral Dose 5 mg/kg Physiological Effects
Sympathomimetic effects: mimic the Mild ataxia (coordination and reflex
effects of norepinephrine or epinephrine disruptions)
Increase heart rate/ increase temperature Hyperreflexia of limbs
Behavioral arousal/ trembling Muscle weakness/relaxation: sedation
Nausea/ dizziness
Vomiting
Heavy perspiration/ chills
Depressed heart rate,increase blood
Dilation of pupils (mydriasis)
pressure (hypertension), respiratory rhythm,
Dry mouth contract intestines and the uterus, cause
Anxiety headache, greater ataxia, dry skin with
itching, and tremors in higher doses
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Contingent Psychic Effects General Psychic Effects


Enhanced emotional responses Dissolution of ego boundaries
Sensory-perceptual distortion: space and time
Altered perception of colors, sounds, shapes, etc. Visual hallucinations
Complex hallucinations: animals, people Dimensions of oceanic
Dreamlike feelings
boundlessness
Depersonalization
Somatic effects: (tingling skin, weakness, tremor) Anxious passivity experiences
Synesthesia: mixing of senses
Euphoria: ecstatic state
Otherwise sensorium is normal and insight retained!
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Pharmacodynamics:
Hallucinogenic Contingency Psychopharmacology
Placebo Effects: significant reaction Medial forebrain bundle in mesolimbic
depending upon environment/ mental set: system: neurobiological site of action
Mechanisms: conditioning, expectancy, Catecholamine neurotransmitters:
self-liberation of endogenous facilitative effect mediated by
norepinephrine and dopamine systems
neurotransmitters, particularly endorphins &
adrenaline-like catecholamines. Nucleus accumbens
Evidence for the inhibition of cholinergic
Psychophysiological self-regulation transmission by blocking release of
induced by powerful hallucinogens. acetylcholine.
Glutamatergic transmission altered

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Catecholamine (Phenethylamine)
Psychedelics Implicated Neurotransmitters
Structural resemblance NE, DP, and the amphetamines:
contain basic phenyl ring, an ethyl side chain with attached Norepinephrine: alpha and beta
nitrogen or amine ring
As variant as they are, these groups confer psychedelic Serotonin: 5-HT2a; 5-HT2 receptor 6
properties: methoxylation of the benzene ring e xerts
amphetamine-like psychostimulant actions, presumably on
dopaminergic and 5-HT2a receptor subtypes
Dopamine
Psychedelic actions: full agonist action at post-synaptic

serotonin 5-HT2a receptors Glutamate


Combination of catecholamine and serotonin actions points to
a complex interaction between dopamine and serotonin,
explaining their intermediate position between stimulants and
LSD-like hallucinogens

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Norepinephrine Action: Norepinephrine Action:


Beta Receptors Beta Receptors
Waves of incoming impulses stimulate the cell
Poised to modulate memory, m otor, and sensor y functions
Most dense in the hippocampus (especially the C A1 region)
into stronger excitatory synaptic responses
where they influence data-processing functions Studies of behavior illustrate that physiological
NE acti vates Beta receptors, initially s lowing down cells
(due to the beta receptors suppression of spontaneous constraints are soon placed on unrestrained
background firing) excitability
However, this brief inhibition is followed by im provement of
the signal-to-noise ratio (efficienc y/strength) of the post Despite an increase in EEG response activity, the
synaptic cell inherent side effects of excessive arousal act to
Ultimately: Excitation
slow to individuals behavioral reaction times

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Norepinephrine Action:
Alpha1-Receptors Serotonin Action
More direct approach: rather than the typical Mescaline: indirect agonistic action; increased
synaptic excitation of tens of milliseconds, affinity
excitation lasts for hundreds of milliseconds
5-HT2a stimulation promotes glutamate release
Once NE activates the A1-receptors; however, indicated by increase in EPSPs in the cerebral
these long-lasting A1 responses are not
sufficient in prompting the next nerve cell to cortex: causing cognitive, perceptual, and affective
fire: no (EPSP) activation distortions produced by hallucinations
Rather than initiating this system of action, NE acts Selectivity for 5-HT2 receptor 6
on its A1 receptor as a neuromodulator on the Activation of 5-HT2a receptors causes a
target cell (which receives major excitatory input transient increase in intracellular Ca+2
concurrently), thereby amplifying some other
major transmitter function which is already going K+ conductance may also be affected
on
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Dopamine Action Glutamate

Mild stimulant and reinforcer Mescaline (via 5HT2a receptors) enhances


glutamatergic transmission
Mescaline: mixed/ indirect agonist Alternative schizophrenia models based
action upon psychotomimetic properties of
Greater implication in LSD action antagonists of the NMDA subtype of the
glutamate receptor suggest that the effects
of NMDA antagonists not only involve
5HT2a but may also be mediated through
excess activity at non-NMDA (i.e.
AMPA/kainate) glutamate receptors
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Norandrenergic Effects LSD/ Mescaline Juxtaposition

Norandrenergic effects include input Highlight the complexities of


from the LC projects to layer V pharmacological research of
pyramidal cells in the neocortex (as do hallucinogens and gaps in our current
understanding
5HT inputs from raphe nuclei)
Understanding the scope, structure,
Noradrenaline acting via alpha 1 functioning, and differentiation
receptors also induces an increase in between various psychoactive sites
glutamate release Taken from Austin, J.H. (1998)
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LSD/ Mescaline Juxtaposition..
LSD/ Mescaline Juxtaposition.. Alternate Mechanisms of Action?
Hallucinogens share action on second messenger LSD stops the firing of ST nerve cells in the
systems; however, not all psychoactive drugs act in
and on the same receptor mechanisms raphe nuclei: hypothesized mechanism of
For example, LSD does stimulate the enzyme action (hallucination)
which makes cyclicAMP, but mescaline and
psilocine do not However, general inhibition of ST cells of
LSD has additional properties as a dopamine the raphe nuclei shows no direct
agonist, neither psilocine nor mescaline acts as a relationship with LSD-induced behaviors
direct DA agonist
However, mescaline does release some DA from Tolerance to LSD results quickly in humans,
DA nerve terminals and indirectly suppresses the no longer producing psychic changes after
firing of ST nerve cells, without acting directly on
them the fourth daily dose
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LSD/ Mescaline Juxtaposition..


Sites of Action? LSD/ Mescaline Juxtaposition..

Mescaline, too, causes hallucinations, Microinjection of LSD or mescaline


but when applied locally in the RN into the locus ceruleus results in the
does not inhibit ST cell firing inhibition of background firing of NE
Other compounds (lisuride) do block cells
the firing of cells in the dorsal RN but
Ultimately results in increased NE cell
do not cause hallucinations
sensitivity to peripheral stimulation
LSD also enhances the actions of NE
indirectly thought to result from an increase in
signal-to-noise ratio
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LSD/ Mescaline Juxtaposition


Hyperfrontality Examined? LSD/ Mescaline Juxtaposition..
LSD and mescaline activate ST2 receptors Another set of impulses return from such
on the post-synaptic element far distant far distant postsynaptic target cells travel
from the neurons in the locus ceruleus
back down to the brain stem to again make
Evidence suggests that these ST2
receptors on distant cells play a crucial role NE cells fire faster in response to stimuli
in producing hallucinations caused by arriving from the outside
various psychedelic drugs Several avenues exist through which an
ST cells of the dorsal RN are thought to initial activation of ST2 receptors can
target higher cells of the frontal cortex
which are rich in ST2 receptors. But the translate, indirectly, to an increased
process does not stop here release of NE
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LSD/ Mescaline Juxtaposition..
Possible Regional Structures? LSD/ Mescaline Juxtaposition..
In primates, dense networks of NE terminals So what is actually occurring??
envelop most sensory pathways, so whichever ST
mechanism causes more NE to be released can Largely uncertain specific action
soon go on to influence perceptual functions
throughout many vital regions
Increased release of NE in regions such as the
pulvinar, lateral posterior thalamic nuclear group,
caudal parietal cortex, superior colliculus, and the
reticular nucleus of the thalamus could contribute
to the remarkable sensate phenomena caused by
LSD or mescaline

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Plausible Mechanisms of Drug


Action: Hallucinations Salvia divinorum
Elaborate mixture of interactions at sites both
presynaptic and postsynaptic among ST, NE, and
DA nerve cell systems
Dynamic mixture modulates chiefly the excitatory
properties expressed by the other major transmitter
systems
Secondary metabolic processes cascade, carrying
potential to modify mental functions, especially
space/time perception
Psychophysiological ordeal triggers emergency
responses commiserating in a variety of sensations/
perceptions triggered through ancient circuitries.

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Salvia divinorum: Salvinorin A Salvia

Soft-leaved green plant native to Mexico:


Labiatae: Mint Family
Psychoactive chemical: Salvinorin A & B
Presents significant research and
therapeutic potential in fields such as
psychopharmacology, psychiatry, and
complementary disciplines such as herbal
medicine research may pinpoint unique
antidepressant action (Hanes 2001).
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Salvia Salvia
Low potential for abuse: No CSA Schedule status
thus far: no substantial similarity to other illicit
Traditionally employed by Mazatec molecular compounds
Indians in medico-magical divination Salvinorin As chemical structure entirely
unique among psychoactive molecules:
ceremonies: numerous demonstrated diterpenoid agent devoid of nitrogen
therapeutic applications Precise neurotransmitter receptor with affinity for
salvinorin A discovered in August of 2002: Kappa
E.g.- Administered for diarrhea, Opioid receptors
headache, rheumatism, and anemia Psychoactive effects are inconsistent and
evanescent: individual differences/ sensitivity

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Salvias Psychic Effects Salvias Psychic Effects

Dissociative state: out-of-body POSITIVE


experience short duration (when smoked)
Geometric shapes in vision radical perspective shifting
Hallucinations: vivid imagery, increase in sensual and aesthetic
encounters with beings, travel to other appreciation
places, planets or times, living years creative dreamlike experience
as the paint on a wall or experiencing
the full life of another individual insight into personal issues

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Salvias Psychic Effects Salvias Psychic Effects


NEUTRAL
powerful open and closed eye visuals
NEGATIVE
general change in consciousness overly-intense experiences
altered perceptions
change in body temperature (?) fear, terror and panic
sensation of physical push, pressure, or wind increased perspiration
sensation of entering or perceiving other
dimensions, alternate realities possible difficulty integrating
feeling of 'presence' or entity contact experiences
dissociation at high doses, walking or standing

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SalviaPharmacokinetics SalviaPharmacokinetics
Ingested orally: chewed leaves: juice held Dosages: Leaf Potency: smoked
in mouth: intense bitterness: slower onset
Smoked: extracts 5x, 6x, and 10x Light: .25g; Common: .5g; Strong: .75g
concentration most efficient
Dosages: 5x extract: smoked
Single inhalation of concentrated extract
may produce transient effects Light: 1/20 1/10g
Steep learning curve: psychoactive Common: 1/15 1/10g
effects associated with large doses aversive
No cases of dependency: few repeat Strong: 1/10 1/4g
experience

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SalviaPharmacokinetics Salvia Pharmacodynamics

Smoked Salvia divinorum: No cases of psychotic deterioration


Onset: 20-60 seconds or other medical compilations: lack
any known toxicity, gastrointestinal, or
Coming Up: 1-2 minutes
cardiovascular impairment.
Plateau: 5-10 minutes
Danger: anxiety reactions: usually
Coming Down: 20-30 minutes limited due to brief duration of effects
After Effects: 15-20 minutes { Extraneous noise/ opening eyes may
terminate the psychoactive effects.
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Salvia Pharmacodynamics Salvia Pharmacodynamics


Salvinorin A is a potent kappa-opioid Research suggests the possibility of specific kappa-
receptor agonist opioid antagonists acting as anti-psychotics: may
KOR previously known for its ability to cause represent a novel class of psychotherapeutic
strange psychoactive effects not expected compounds
from the opioid system: Suggested that KORydynorpin peptide system
{ Mediate psychotomimetic effects functions to modulate human perception
Salvinorin As effects are entirely unique and Future research on whether naltrexone (general
thought to act independently of 5HT2a opioid antagonist) might eliminate/reduce effects of
Salvinorin A
systems, which most visionary drugs act on
Also whether other KOR antagonists such as
enadoline cause effects similar to Salvinorin

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Salvia Conclusions References
Her mle, Leo; Gousoulis- Mayfrank, E.; Spitzer M. (1998) Blood flow
Education aimed at raising awareness and cerebral laterality. Phar macopsychiatry. Vol. 31 (2) Jul. 1998, 85-
91.
of the plants unpredictable and Oepen, G.; Fuenfgeld, M.; Harrington, A.; Her mle, L. (1989) Right
hemisphere involvement in mescaline-induced psychosis. Psychiatry
occasionally upsetting psychoactive Research Vol. 29 (3) Sep. 1989, 335-336.
Tacke, U.; Ebert, M. (1991) Hallucinogens. Clinical Manual of
effects, rather than criminal prohibition, chemical dependence. P.259-278
Winter, J.C.; Fiorella, D.J.; Timineri, D.M.; Filipink, R.A.; Henlsley,
is the key to reducing individual and S.E.; Rabin, R.A. (1999) Serotonergic receptor subtypes and
hallucinogen-induced stimulus control. Phar macology, Biochemistry,
social harm with respect to S.
& Behavior Vol. 64(2) Oct. 1999, 283-293.
Marek, G.J.; Aghajanian, G.K. (1998) Indoleamine and the
divinorum and its active principle phenethylamine hallucinogens: mechanisms of psychotomimetic
action. Drug & Alcohol Dependence Special Issue: Neurobiology of
Addiction Vol. 51(1-2) Jun-Jul. 1998, 189-198.
Executive Summary (2003)
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Aghajanian G and Marek G. Serotonin model of
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the plant and active principle. 04/10/2003
www.cognitiveliberty.org
Julien, R.M. (2001) A Primer of Drug Action. 9th Ed . Worth
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