AMPHETAMINE, ANOREXOGENICS AND ANALEPTICS

Behavior Pharmacology

Pavolv (1908) & Peter Dews(1955): learned animal behavior, or conditioned reflex
Thompson & Schuster in 1968: Behavioral Pharmacology or experimental psychopharmacology
[Ref] R Pickens. Behavioral Pharmacology: A brief history. in Advances in Behavioral Pharmacology vol.1 .. Thompson T and Dews PB
(eds),Academic Press, 1977,230.
Psychopharmacology : the study of the effects of drugs on behavior ( aggressive behavior, food and water intake, spontaneous motor activity,
schedule-controlled behavior, reward process & drug discrimination & learning ).
Behavioral mechanism of action is a " a description of a drug's effect on a given behavioral system expressed in terms of some more general
set of environmental principles regulating behavior" by Thompson and Schuster
Psychoactive drug : those drugs may alter mood, cognition, and behavior
Entheogen神化藥 ( PSYCHOMIMETIC 擬精神病藥, HALLUCINOGENIC迷幻藥, OR PSYCHODELIC (心靈用藥) DRUGS
 somatic symptoms : dizziness, weakness, tremors, nausea, drowsiness, paresthesias, & blurred vision
 perceptual symptoms : altered shapes and colors, difficulty in focusing on objects, a sharpened sense of hearing, and rarely,
synesthesias
 Psychic symptoms : alternations in mood, tension, distorted time sense, difficulty in expressing thoughts, depersonalization,
dreamlike feeling, and visual hallucination
Mechanism of Hallucinogen action
 5-HT2A receptor ( partial ) agonist activation ( head-twitch ) is blocked by MDL 100907 ( Glennon RA, et al. Eur J Pharmacol
91: 189-92, 1983 )
 rapid tolerance of the hallucinogen : after 4D almost complete loss of sensitivity to LSD
- rapid desensitization and downregulation of 5HT2 receptor after repeated treatment with DOM
 5HT1A receptor agonist action may elicit a greater effect on central visual processes than purely 5HT1A/2C agonist
 other receptort interaction are also involved : LSD bind with high affinity to 5HT ( 1A,1B, 1D, 2A, 2C, 6 , 7), DA ( D1 ,D2 ), 
(1,2 ); D2 & 2 have potentiating effect
Classification according Brawley and Duffield ( Pharmacol.Rev 24:31-66,1972 )
Class 1: all drugs at high doses induce toxic or metabolic disturbances, that is, organic brain syndromes accompanied
by psychosis.
Class II: drugs with potent anticholinergic and are capable of producing a specific delirium, the central anticholinergic syndrome
Class III: substances to produce varying degrees of a generic" psychotomimetic syndrome",e.g. usually without clouding
of consciousness or delirium.
Psychotogenic drugs : induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or
religious exaltation
1. Delirium-inducer : PCP,atropine, tricyclic antidepressants, phenothiazine, alcohol
2. Paranoid schizophrenia-inducer : cocaine, amphetamine, phencyclidine
3. Psychedelic state-inducer : LSD, mescaline, marihuana
- Drugs that induced affective disorder
1. Depression-inducer : reserpine, levodopa, propranolol, methyldopa, steroids
2. Mania-inducer : levodopa, corticosteroids
- Drugs that induced anxiety : sympathomimetic, antidepressant, antipsychotic, antihistamine
- Common Adverse Effects:
- Intense anxiety, panic or paranoid states to delusion, confusion, disorientation, e.g. Bad trip ( most common SE, 24
hr temporary panic) for atropine, PCP and MDA
- Drug-seeking behavior
- Social crime and violence for PCP, LSD ( drug abuse crises)

Table : Neurological ascending catecholamine systems Control of Behavior

Locomotor activity: N accu, med. & suprarhinal preforntal cortex, dorsal NEergic bundle; and not involved in caudate N
Stereotyped: caudate N, dorsal/ventrol NEergic bundle, and not involved in N accu
Conditioned reinforcement: N accu > caudate N
Unconditioned reinforcement: N accu, med prefrontal cortex, and not involved in caudate N, amygdala, area postrema
Anorexia : lat hypothalamus, amygdala, N accu, and not involved in caudate N, dorsal and suprarhinal prefrontal cortex
Short-term memory: lat hypothalamus, and not involved in hippocampus, med, and suprarhinal prefrontal cortex
Long-term memory: caudate N, hippocampus

Neuronal Mechanisms of Behavioral Sensitization of Amphetamine-like psychostimulants

 D1 receptor stimulation is necessary for the expression of behavioral sensitization

 Changes in DA receptor density do not appear to contribute to the long-term expression of behavioral sensitization
 Glutamate transmission in the nucleus accumbens is necessary for the expression of cocaine-induced behavioral
sensitization. It is less clear if glutamate plays a role in the expression of amphetamine-induced behavioral sensitization
  The blockade of AMPA receptors in the nucleus accumbens prevents the expression of cocaine-induced behavioral
sensitization, indicating a permissive role of AMPA receptor stimulation
 The change of DA transmission in prefrontal cortex is observed following sensitization of cocaine but may not occur in
animals sensitized to amphetamine
 Sensitized release of DA in the nucleus accumbens and striatum contributes to the expression of behavioral sensitization to
psychostimulants. However, this relationship is typical observed only following a week or more of withdrawal
 The increased releaability of DA in the nucleus accumbens is Ca-dependent and relies upon activation of Ca-dependent
protein, such as calmodulin and CaM-KII
[ref] Pierce RC, & Kalivas PW. A circuity model of expression of behavioral sensitization to amphetamine-like psychostimulants.
Brain Research Reviews 25: 192-216, 1997

The DA transporter is functionally upregulated during early withdrawal. This may explain the apparent lack of augmentation in the level of
extracellulat DA measured during early withdrawal with microdialysis.
Experimental Approach: schedule-dependent lever-pressing operant conditioning behavior
1. Drug discriminations : measuring subjective effects, e.g. a rat may be consistently reinforced with food pellet after pressing the left
level when under the influence of morphine and reinforced on the right level after receiving glucose.
2. self-administration : reinforcing properties. seeking behavior
In the 1950s, Olds and Milner discovered rat self electrical stimulation in brain induced "pleasure or reward".
3. Pavlovian conditioning in drug dependence, preclinical
e.g. dog" morphine-like behavior"

Addictive disease is diagnosed as the abuse of psychoactive drugs, including alcohol, which interferes with health, economic or social
functioning, characterized by compulsion, loss of control and continued use despite adverse consequences.
Addictive disease is diagnosed as pathological state with characteristic signs and symptoms and a predictable prognosis if untreated.
Addictive disease is a progressive and potentially fatal illness unless properly treated".
"Designer drugs " are analogs, or chemical cousins, of controlled substances that are designed to produce effect similar to the controlled
substances they mimic. By slightly altering the chemical formula of a controlled substance.... a new drug is created which will produce
the high or euphoria the user wants."

Classification of CNS Stimulants

1. Analeptics ( Convulsants)
Doxapram: respiratory stimulants, safe, acting on medulla respiratory center
Nikethamide: like doxapram; use for CO2 narcosis
Pentylenetetrazol
Strychnine
Picrotoxin
Bicuculline
2. Psychomotor stimulants
Amphetamine & Methamphetamine
Methylphenidate ( Ritalin ): action mechanism like cocaine, less potent than amphetamine as a stimulant or
anorexia
Pemoline: mild stimulant with anoretic action
Cocaine
Phentermine
Fenfluramine
Phenylpropanolamine
3. General cellular stimulants
Methylxanthines derivatives: adenosine A1 receptor antagonist
Caffee: Caffeine
Tea: Theophylline
Chocolate: Theobromine
- Action mechanisms:
1. Intracellular Ca translocation
2. cyclic nucleotide accumulation (cAMP)
3. Adenosine receptor inhibitor
4. inhibit PG synthesis
5. decrease catecholamine non-neuronal uptake ( uptake II)
4. Clinical antidepressant
MOI inhibitor: tranylcypromine
Catecholamine reuptake inhibitor : imipramine, amitriptyline
5. Psychotomimetic (Hallucinogenic) drug
Hallucination: a false perception, and exaggerated sensory phenomena including visual, auditory and tactile
hallucinations.
Hallucinogens comprise some of the most interesting compounds from both a structural and
pharmacologic standpoint. Although they have demonstrable action on specific receptors, their net effect
on consciousness arises from a combination of effects on many systems, primarily dopamine and
serotonin.

LSD and mescaline analogs

LSD and mescaline and their respective analogs act most strongly as dopamine agonists or releasers,
and simultaneously as serotonin agonists or antagonists. These compounds are notorious for their strong,
hallucinatory effects on visual neurons and the CNS.
Mescaline, anhalonodine and gigantine occur in various species of cactus, while psilocybin occurs in
mushrooms and bufotenine as an exocrine secretion in some species of toad. TMA occurs in the calamus
root.
Mescaline appears to have serotonin antagonist activity (5-HT2 receptors) and has been tried against
schizophrenia in place of the traditional dopamine blocking neuroleptics. MDMA is a serotonin-releasing
stimulant with hallucinatory properties. 2-CB and DOM are related compounds with similar actions.
LSD is an extremely potent synthetic psychotropic; typical doses may be as low as a microgram.
Naturally occurring LSD homologs occurring in ergot fungus, which infects bread grains, especially rye,
account for the historical "St. Anthony's fire." The monoethyl amide is found on Morning Glory seeds.
Although it seems to act as a serotonin antagonist peripherally, it may perform a dual service int he
CNS, facilitating release while simultaneously blocking post-synaptic sites.
Ergot alkaloids (e.g. bromocryptine), altered to reduce their dopamine activity, are used as serotonin
antagonists in migraines. Other compounds have been tried against Alzheimer's as nootropics.

PCP, ketamine and ibogaine

 The PCP hallucinogens operate on NMDA neurons common to asparate and glutamate systems,
shutting down the ion gates of excitatory neurons in the CNS. Effects of sub-anesthetic doses are
euphoria, grandiosity, and psychotic behavior. This action is not blocked by haldol nor exacerbated by
amphetamine and would appear to be not directly dopamine related.
Ketamine ("Special K") and other structural analogs function similarly. Metomidate and etomidate are
used as surgical anesthetics. The doses required for anesthesia are greater than those used for
intoxication, but patients awakening from anesthesia under these compounds may undergo dysphoric
intoxication states on waking.
Ibogaine also appears to antagonize NMDA receptors. It has been tried as an aid to narcotic withdrawal,
implicating some activity at opiate sites (possibly through interaction with underlying glutamate receptors).
As with other hallucinogens, several mechanisms probably contribute to its spectrum of action. African
hunters have historically used the drug as both an arrow poison and as a stimulant for the hunt.

harmala, blowfish & wolfsbane

The harmala alkaloids are -carbolines, derivatives of serotonin which antagonize GABA
benzodiazepine receptors and cause short-term MAO inhibition. Harman has been isolated in in tobacco
smoke, hydrogenated harmaloids in urine. The harmaloids are said to be strong visual hallucinogens,
though typically at doses of several hundreds of milligrams. Recreationally, these drugs are used to
potentiate other drugs such as DMT by MAO inhibition (the mixture is called ayahuasca).
Fugu (blowfish) contains the sodium channel blocker tetrodotoxin. Some claim it imparts psychedelic or
aphrodisiac properties.
Aconitine, mentioned by Sagan in his Dragons of Eden, has been used as a deliriant by "witches" for
centuries. In small doses it activates sodium channel transport centrally and peripherally, but in high doses
it interferes with transport, inducing cardiotoxic effects including slowing, arrhythmia, or arrest of the heart.
Boiling the herb may convert the most toxic alkaloids to less toxic variants.

Drug Addiction and Drug Abuse

PSYCHOMIMETIC DRUGS

Characteristics: Induced states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or religious
exaltation. e.g. 1. Mystical thinking and conversation, to an extreme, 2. Hallucinations, 3. Changes in the appearance of the eyes
( illusion : abberrations of sensory information )
Classification:
Class I: all drugs at high doses induce toxic or metabolic distrubances, that is, organic brain syndromes accompanied by psychosis
Class II: drugs with potent anticholinergic and are capable of producing a specific delirium, the central anticholinergic syndrome
Clsss III: substances to produce varying degrees of genetic "psychotomimetic syndrome" e.g. usually without clouding of consciousness
or delirium
1. Delirium-inducer : PCP, atropine, tricyclic antidepressant, phenothiazine, alcohol
delium ( confusion, disorientation, hallucination and short-term memory deficits ): caused by Musarinic blockade
2. Paranoid schizophrenia-inducer : cocaine, amphetamine, PCP
3. Psychedelic state-inducer : LSD, mescaline, marihuana
** Psychedelic : meaning mind manifesting , mind-expanding, cause marked cognitive, affective, and perceptual disturbances
while leaving orientation largely intact.
** Hallucinogens have shown a high correlation between hallucinogenic potency and affinity for the 5HT 2 receptor. ( highly
concentrated in or near layer 5 interneurons of the frontal and occipital (visual ) cortex )
** entactogens: The Greek roots "en" for within, and "gen" meaning to produce, and the Latin "tactus" for touch. These drug
promote a " touching within ". This is generally regarded as a relaxed, meditative state in which the inner working of their
own psyche can be explored ( dose-related illusion and hallucination ) while maintaining a clear sensation and able to
interact with their physical surroundings.
** Psychotomimetic : meaning in imitation of psychosis
 4. Depression-inducer : reserpine, levodopa, propanolol, methyldopa, steroids
5. Mania inducer : levodopa, corticosteroid

Genertic Psychomimetic Drug

LSD Hofmann of Sandoz Lab. in 1938 synthesized D-lysergic acid diethylamide (LSD-25 , Delysid) .
- The most widely used and the best-known hallucinogenic drug
- LSD is by far the most active hallucinogen known or psychomimetic drug. < 50g, onset <1h, smoking <5'
- source: semisynthetic of ergot fungus Claviceps purpurea grows on grain, especially by Rothlin in 1938 (ergotism: low dose induce
tingling, burning sensation of skin, to tremor or convulsion, mania, dellirium & psychosis ) high dose: gangrenous (dark leg )
- Beginning of Psychomimetic: In 1943 it was found accidentally by Dr Albert Hofmann working on ergot alkaloid in Sandoz Pharm Lab of
Basel, Switzerland with his own experience, oral effective, less S.E.

My field of vision wavered and was distorted like the image in a curved mirror... like the reflection in an agitated sheet of water ...
with my eyes closed, colourful and changing fantastic images invaded my mind continuously. It was especially remarkable how all
sounds... were transposed into visual sensations, so that with each tone and noise a corresponding coloured image, changeing in
form and colour like a kaleidoscope was produced.
10 g: euphoria and decr. inhibition
50-100 g: the minimal hallucinogenic dose
400-500 g: full hallucinogenic effects ( peak 2-3 hr with a duration of 8-12 hr )
- Therapeutic Use: aid in psychotherapy (?)
- History:
1. In the early 1960s experiment by 2 Harvard University psychology professors, Drs Richard Albert & Timothy Leary, who
invited others to "turn on, turn in and drop out" of the existing social institutions. Their unorthodox religious orientaton to the
LSD experients is present in the manual call "The Psychedelic experience". This manual became the bible of the psychedelic
drug movement.
 2. In the 1960s taking LSD became a fashionable component of hippie life style(披頭四的名曲”露西帶著鑽石漫遊天際
Lucy in the sky with diamonds “.
3. In Aug 1965, Sandoz discontinue production of LSD25, as well as psilocybin, psilocin, and related congeners
4. CIA involved in Dr Frank Olsen (biochemist) suicide by LSD on Nov 28, 1953 reported by Rockefeller Commission in 1975.
The courts awarded his family $750,000 in damages in 1976; also discovered nearly 585 soliders and 900 civilians involved
during 1956-1967. The LSD research project at Timothy Leary's university had been funded by the CIA.
5. 1968 National Institute of Mental Health prohibits in-house human experiments of LSD
6. In 1970, LSD as a Schedule 1 controlled substance in USA.
Pharmacology
A. CNS effects: the term psychotomimetic was first appear Within the brain: hypothalamus, limbic system, auditary and visual
reflex area take up high concentration.
1. Psychic mood changes: dose-related, perceptualor sensory information process disturbance
( psychedelic ), hallucination (illusion more precisouly), distortion of body image, visual sensation, subjective sense of
time, space, etc. Duration: 6-9 hr
**Psychedelic (mind manifestating): capacity to induce or compel states of altered perception, thought, or feeling not
otherwise experience except in dreams or mystical exaltation (Jaffe,1980)
**Synesthesia (Cross-sensing) : hear pretty colours or see sounds, such as wind
B. autonomic: mydriasis, pilomotor reaction, resp depression, nausea
Increase HR, BP, and BT; decrease appetite, motor incoordination ( Initial stage 20 min)
C. rapid tolerance, no withdrawal symptoms & physical dependent, but may become psychologically dependent.
D. Peripheral : constriction of smooth muscle of uterus, blood vessels, bronchioles 5-HT antagonist
E. S. E.: convulsion, chromosomal breakage (?),brain degeneration
F. Species difference: elephant, rabbit more sensitive
G. Action: hallucination mechanism is still unknown
5HT2 receptor competitive antagonist e.g. ritanserin (or partial agonist?); release is blocked. affect the balance of NE, DA
and 5-HT in the RAS of the brainstem. DAergic effect

Psilocybin & Psilocin-active metabolite (Maxico): like LSD

Psilocybin ( 4-phosphoryl-N,N-dimethyltryptamine) 0.2-0.5%
Psilocin ( 4-hydroxy-N,N-dimethyltryptamine )
Source: alkaloid from Psilocybe mexicana "Sarcred mushroom"; Teonanacatl means "God flesh" or "meat of the God"
a. First report from Dr Franciso Hernandez ( court physician to King Philip II of Spain) in 1570-1575, the plant identified by
Gordon Wasson (New York banker-turned-ethnobotanist) in 1955; and the active extract by Dr Albert Hofmann, a Swiss
chemist (also synthesis LSD) in 1958; the First clinical trial by F. Gnirss & W. Rummele in 1959, Basle
b. Timothy Leary & Dr Richard Alpert: Good Friday internal freedom study "Psychedelic Era" at Harvard University in 1960-61
 and in 1966 Leary strated his religion, the League of Spiritual Discovery

c.
Action: psilocin block the 5-HT release, but unlike LSD it is not a DA agonist. Less potent than LSD ( 4-8 mg, po ) induced
uncontrollable violence, panic or attempt to suicide

N,N-Dimethyltryptamine (DMT): short-acting (10-20') haullicinogen, 60-150 mg

source: Virola tree bark, cohoba seeds in Haiti,
oral ineffective, snuff or smoking "Businessman's trip"
Most frequently induces agitation and nonpsychotic panic state
MAO inhibitor

Bufotenine ( 5-hydroxy-N,N-dimethyltryptamine )
Source: toad skin or Amanita muscaria mushroom "fly agaric" as well as etc.

1/1000 x less potent than LSD

onset: 1hr; twitching and trembling of the limbs
pseudohallucinogen , light euphoria(i.v), violent but not cross BBB
active component: DMT , ibotenic acid, muscimol in Amanita muscaria

Harmine (Peganum harmala) & Harmaline

 ß-carboline alkaloid,
MAOI and 5-HT antagonist activities
Small doses (25-50mg) act as mild and therapeutic cerebral stimulant, sometimes producing drowsy or dreamy state for 1-2 hours.
Larger doses up to 750mg may have hallucinogenic effects, the intensity of which varies widely with the individual.

Myristicin ( 3-methoxy-4,5-methylenedioxyamphetamine or MMDA)

source: dried dark-brown or purple seed of the nutmeg tree Myristica fragrans ( Myristiceae) in Grenada, Indonesia
Botany: a bushy tree, 30-40 ft high, with spreading branches and a yellow freshly fruit. When the husk splits, scarlet aril appear
covering a single glossy brown seed.

Psychologic effects: changes in self-awareness, mood, and intellectural function, without any sensory distortion at all.

Mescaline (3,4,5-trimethoxy-phenylethylamine), Peyote cactus.

- an alkaloid extracted by Louis Lewin ( a German pharmacologist) in 1886, isolated from dried tops (tufted with whitish "hair" and is green
tipped) cut from Peyote cactus (Lophophora williamsii (Cactaceae) in Maxico.
Botanical description: a small blue-green spineless cactus (3-10cm) with well-defined ribs and furrows, pinkish flowers, and a large
cyclindrical perennial rootstock, small dome-shape heads and sliced off and dried as peyote buttons.
- Peyote: Aztec word "Peyotl" which means "divine messenger", an integral of religious ceremonies since 810-1070BC, was brought to
Europe from America by the Missionary Bernadino De Sahagun in 1499.
 - History:
a. The first report was made by Dr.Francisco Hernandez of the court of King Philip II of Spain., The Spanish missionary Padre
de Leon directed priests to ask their Indian converts to confess to use of peyoat, which he believed they used to conjure up
demons. De Leon was the priest who boastfully informed th Pope that he burned all the Mayan codex manuascripts, because,
he clamied, they were records of pagan rites.
b. Aztecs and Maxican Indians ritual ceremony as sacramental or a "divine messenger" to help them communicate directly with
the gods. During the last hundred years, the use of peyote in religious ceremonies has been adopted by many North
American Indian tribes including the Comanches, Apaches and Kiowas, and it is currently used by the Indian members of the
Native American Church as a sacrament in their religious services.
c. First pharmacological experiment in 1888 by L. Lewin, and the First human experiment in 1895 by D.W. Prentiss and F.P.
Morgan in America, and shortly after World War I, the active component mescaline was isolated.
d. The oldest psychomimetic drug, the usually dose 250-500 mg
- Psychomimetic Effects : 1/1,000 of LSD; 1/30 of psilocybin
Usual dose:300-600 mg, peak: 30-120' duration:9-10 hr
mydriasis, temp incr, anxiety, visual hallucination (>2Hr), and alteration of body image. The last effect is a type of hallucination in
which parts of body may seem to disappear or become grossly distorted ,vomiting, muscle relaxation
No after effects or drug hangover at low doses.
High dose: cardiac depression, headaches, resp depression, contraction of GI, uterus.
Cause of death: convulsion and resp arrest.
- Initial: rapidly absorbed, mild GI distress ( nausea, vomiting), 30-60'.
followed by sympathomimetic effect, tremor, and perspiration
- Delay : up to 12h, peak: 4-6h, visual pseudo-hallucination, sensation of weightlessness, and distortion of time and space
Action mechanism: like LSD ; does not appear to affect all the 5-HT neurons, unlike LSD and DMT, alter turnover of 5-HT and
depression of NE.
- Tolerance develop rapidly
- Treatment: like LSD intoxication, a quiet, dark and calm environment

Marijuana or Cannabinoids ( pot, hemp )

Source: marijuana (or marihuana) from the flowering top and leafy material from Cannabis sativa L.of India by Carolus Linnaeus, a
Swedish botanist in 1753. a 4.6 m, both male & female form, large leaves ( 5-11 leaflet with serrated margins), annual herb ( an
unstable genus ).

Background : gods in the Hindu pantheon are thought to have a taste for drink and drugs, and bhang ( a drink made with cannabis) is a
 favourite of Shiva. However, cannabis is more often associated with the Ethiopian Zion Coptic Church based in Jamaica.
The word is said to be derived from the Portuguese mariguango, which means " intoxicant".
Bhang : made from dried leaves and flowering shoots of the plant. This preparation is used mostly in the form of a drink and has
low potency
Ganja : it is prepared by making a homogeneous mass from small leaves and resins of the plant. It is about 3 times more potent
than bhang.
Hashish or Chira (Charas in India ): the dried and pressed flowers and sticky yellow resin from female plant, 4 -10 % THC, with
5-10 x higher potency than bhang hashish oil or "red oil" : it is a crude extract from pure pressed resins from the dried
flowers. It is about 5 times as potent as bhang ( up to 10-20% of THC ); and it is used mostly for smoking.
Common name: truly hallucinogenic (Isbell), The 2nd most widely abused in USA ( "grass, weed "; "Bhang" in
India, "Ganja" in Jamaica) as a "cigarette (Joint), pipe smoking, It had reported that 68% of age 18-25 have ever used in
1985 (NIDA reported)
**Joint : like a hand-rolled cigarette, usually the ends are twisted
Marijuana is probably the most controversial drug of our times. A prisoner of narcotic legislation classification. ( schedule I ). Each
marihuana researcher was required to obtain registration with the Bureau of Narcotics and later with DEA
Cannabis-has a long history characterized by usefulness, euphoria or evil-depending on one's point of view. To the agriculturists,
cannabis is a fiber crop; to a physician of a century ago, it was a valuable medicine; to a physician of today, it is an enigma; to a
user, a euphoriant; to a police, a menace; to a trafficker, a source of profitable danger; to a convict or parolee and his family, a
source of sorrow. written by Mikuriya TH. Calif Med 110: 34-40,1969
Active principle: Marijuana contains about 400 chemicals with THC as the principal, most potent component. Its receptors are found mainly
in the basal ganglia, cerebellum and hippocampus, which partly responsible for its euphoric and cognitive effects. Few
receptors are found in the cerebral cortex and virtually none in the brainstem.
delta-9-THC (delta-9-tetrahydrocannabinol, not alkaloid ) discovered by Gaoni Y & Mechoulm R in 1964, synthesis by
Petrzilka T. & Sikemeier C. in 1967
30-50 mg/kg, iv; 50 mg/kg, inhaled, 120 mg/kg, po.
active metabolite:11-hydroxy-THC
Action mechanism: poorly understand, incr presynaptic DA efflux ( DA reuptake blocker ); incr membrane fluidity
- Cannabinoid receptor is been clonned in 1990 ( Ref. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC & Bonner TI. Nature
346:561-564, 1990 )
- Inhibit adenylyl cyclase activity, phosphodiesterase, phospholipase C and ion channels
- Involved in cognition, memory, movement and reward
Psychomimetic effects: Biphasic : euphoria ( predominant: low to moderate dose ) followed by depression
a. disordered or slowing time and space perception
b. false sense of ability, color seems brighter & music more pleasant
c. precipitation of ego alterations (depersonalization, paranoid ideation, dysphoria or anxiety, depression, panic psychoses,
hallucination)
** the perceptual changes brought about by LSD are primarily in the visual field whereas perceptual changes in schizophrenia are
most common in the auditory field. Distortion of body image is common with LSD but only occasionally seen in schizophrenia.

** Timothy Leary, a hippies' psychologist at Harvard University until his dismissal in 1963 . LSD as a sacramental or
psychedelic-hallucinatory drugs provide a quick and efficient route to religious ecstasy. He set up IFIF (Institute for the
Investigation of Inner Freedom ) and LSD ( League for Spiritual Discovery), but neither flourished. He translated the Tibetan
Book of the Dead, a hippies' book of spiritual guidance, like Beatles' record Revolver: "Turn off your mind, relax and float
downstream. It is not dying. "
Physiological effect:
a. reddening of the eyes, no significant effects on respiration , CV & blood chemistry.
b. delta 9-THC depress FSH, LH, testosterone, overation, delay ejaculation & thermoregulation
c. CV: tachycardia ( clear-cut clinical fact, HR > 160 ) postural hypotension
 mild tolerance,no physical dependence,no withdrawal syndrome
In animal studies, it has tranquilizing effect on aggressive mice, and causes a sleepy, dreamlike state in dogs.
The LD50 in cat: 3g/kg of charas, 8 g/kg of ganja, or 10 g/kg of bhang.
S.E.:
acute: panic, (most common), dec in learning ability and short term memory, dec. driving skill
chronic: apathy, impair short-term memory, loss of motivation, bronchitis, decr.sperm motility & protein synthesis
the reddened conjunctivae are one of the surest way to identify the marijuana user.
Clinical: experimental for wide-angle glaucoma; nausea vomiting for cancer chemotherpy pts; e.g. Nabilone ( Cesamet, Lily ) for
antinausea; Levonantrodol (Pfizer ) for antidepressant, Nibitan ( Burroughs-Wellcome ) for anticonvulsants..
endogenous substance of cannabinoid receptor : anandamide ( ethanolamide of arachidonic acid , ananda : the Sanskrit word for bliss)
- Source: bovine brain
- Pharmacological effects :
1. inhibit L-type calcium channel in brain and cardiac membrane ( inhibit binding of 1,4-dihydropyridine )
2. inhibit G-protein coupled adenylyl cyclase in barin & peripheral
3. inhibit forskolin-stimulated cAMP production in CHO cells transfected with either rat or human cannabinoid receptor.

Phencyclidine(PCP, angel dust, peace pill, cadillac, crystal joints, DOA)

History: synthesized in 1957 by Parke-Davis Lab, with chemical structure similar to ketamine, as anesthetic. withdrawal from market:
1960s
Action Mechanism:
high affinity to sigma receptor (haloperidol sensitive) and PCP receptor (haloperidol insensitive)
S.E. : violent postoperative psychosis (nightmares and frank delirium with frightening hallucination and
delusions), and muscular rigidity,
Schedule II, like morphine, amphetamine
1. low dose (< 2.5 mg): mild euphoria, stimulation to body-wide anesthetic ( leg and feet especially); slurred speech, out-of-body
experience
2. moderate dose (2.5-5 mg): muscular rigidity and immobility (catatonia)
Nystagmus and hypertension are hallmarks of PCP intoxication
Other signs: Salivation, hyperthermia, tachycardia, incr. resp. rate
3. high dose ( > 10 mg):generalized tonic-clonic seizures and status epilepticus {Diazepam}; decrease gag and corneal reflex
Cause of death: Resp depress, seizure or CV collapse.
Psychological effects:
spatial distortion, decr touch(two-point discrimination), pain and position sense. auditory, visual hallucination, delusions and paranoid
thinking can occur at any dose, and can last weeks or months
Most significant observable change is the personality ( mood, thinking and judgment), ambivalent and unpredictable.

PSYCHOMOTOR STIMULANTS
General effect: increase alterness, and changes in mood (increase nervousness and anxiety, and also euphoria) in human.

Amphetamine
History:
1. First synthesized in 1887 by Edeleanu L. in Germany, the precursor Ephedrine isolated from Ma Huang ( Ephedra ) by Nagai N.
in 1887, Chen KK and Schmidt CF : pharmacological effect of Ma Huang in 1920s, Patent by Dr. Gorden Alles in 1932
assigned to SKF Lab.
2. Amphetamines were first introduced in Benzedrine (brand name) inhaler: as a over-the-counter product for the treatment of
asthma in 1932, prescribed for hyperactive children in 1937, and appetite depressant in 1939, replaced by Benzedrex in
1949, banned in 1959
3. CNS psychostimulant effect demonstrated by Hauschild until 1938
4. US, Great Britain, Germany, and especially Japan military used during World War II. Methamphetamine as OTC drug to
"elimination of drowsiness and repletion of the spirit" after War, and caused abuse( 1.5 million in 1954), From 1941 Hitler
received daily morning injection of methedrine (inj. form of amphetamine )
5. Sweden legal prescribed of amphetamine for narcotics in 1965, stopped 1967
6. Abuser such as astronant Gordon Cooper in 1969, athletic in Olympic. The stimulant, euphoric, and anorectic effects of
amphetamine were recognized quickly, leading to its abuse. In 1937, a report stating that amphetamine could enhance
intellectual performance through enhanced wakefulness further contributed to the popularity and early abuse of amphetamine.
Recreational abuse of amphetamine has been used to achieve a euphoric state.
7. Common name: Brain, superman (feeling of increased energy), and confidence ( feeling well-being) pill in USA;
Wakeamine in Japan
Amphetamine Methamphetamine Methcathinone
 8. Therapeutic use: FDA restrict to 1. narcolepsy, hyperkinetic behavior and short-term weight reduction programs , banned by
Controlled Schedule II, 1970
anorectic ( appetite suppressant ) :
phenylpropanolamine ( norephedrine ): an OTC drugs ( for cough and cold )
fenfluramine ( Pondimin, Wyeth-Ayerst Lab. ) : an amephetamine derivative
- site of action: VM hypothalamic n.
- HT1B receptor agonist
- not truly a drug of abuse
- with significant pulmonary and neurologic toxicity
aminorex fumarate ( related compd) widely prescribed during the early 1960s,
- withdrawn from market , due to pulmonary hypertension S.E.
Pharmacology:
1. Indirect acting sympathoimetic
Methamphetamine (speed, "crystal", Methedrine ): more potent CNS effect, Schedule II ; presumably because of the prolonged
half-life (10-12 hr) and increased CNS penetration.

Although both methamphetamine and cocaine are psychostimulants, there are differences between them.

Methamphetamine vs. Cocaine

Man-made Plant-derived
Smoking produces a high that lasts 8-24 hours Smoking produces a high that lasts 20-30 minutes
50% of the drug is removed from the body in 12 hours 50% of the drug is removed from the body in 1 hour
Limited medical use Used as a local anesthetic in some surgical
procedures

Hydroxy amphetamine : no CNS effect, for mydriatic use

Onset: < 1hr, T1/2=10hr, withdrawal depression: 48-72 hr
2. Interacts with transmitter release, uptake and metabolism. Both the releasing and uptake-inhibiting action of amphetamine are
mediated by the catecholamine ( especially DA ) uptake transporter in presynatic neurons .
** DA transporter, which is involved in producing cicaine’s distinctive pleasure “ rush”.
- Increase extracellular DA induced by cocaine, nomifensine and bupropion ( uptake inhibitor ) are almost entirely
eliminated by TTX ( Na channel blocker, which block the AP, and therefore blocks the impulse-dependent release );
while increases in extracellular DA induced by amphetamine occur in the presence of TTX ( 66%).
- The amphetamine-induced behaviors are inhibited by blockade of DA synthesis with tyrosine OHase inhibitor,
-methyl-p-tyrosine (AMPT), but not by reserpine, suggesting that the effect of amphetamine are mediated by nonvesicular
newly synthesized pool of DA. At high dose ( > 5 mg/kg ), amphetamine-induced DA release both vesicular and cytoplasmic
stores.
- Changes in mood, excitation, motor movements, sensory perception, and appetite appear to be mediated more directly by
central dopaminergic alterations. It has been postulated that serotonin alterations contribute to the amphetamine-related
mood changes, psychotic behavior, and aggressiveness
 - Amphetamine also inhibit the MAO ( relative weak in vitro when compared to irreversible & noncompetitive MAO inhibitor
iproniazid )
- CV effect: is L-from > d form. caused hypertensive crisis, tachycardia, pupil dil, perspiration or chill, and convulsion
- CNS effect : sti. Medulla resp. center, cortex, RAS ( D form (Dexedrine) > 4~5X L-form )
- Behavioral effects : motor activity, ingestive behavior ( anorectic agent ), sleep, attention, aggression, sexual behavior, learning
and memory, classical conditioning, operant behavior ( as a reinforce in self-administration ),
5-50mg: In addition of euphoria, stimulation, relief of fatigue, and suppression of appetide (anorexia), other excitatory effects
include increasd BP (incr. systolic & diastolic pressure & reflex bradycardia) and insomnia.
>100mg: Amphetamine psychosis caused paranoid mania ( Experimental model of schizophrenia); symptoms: paranoid
ideation, stereotyped behavior, hallucination, and thought disorder
- Psychological effect ( large dose ):
** single acute psychosis: confusion and disorientation, visual hallucination
** repeated-use phychosis : repetitive and complusive behavior, social withdrawal, delusions and paranoia
with auditory hallucination

In animal behavior
0.25-1.0 mg/kg: general activation of sniffing ( stereotypic locomotor activity ), locomotion and rearing
1 - 10 mg/kg: decrease locomotion and rearing, so only sniffing remains
10 mg/Kg: Sniffing become max, stereotyped and accompanied by licking & biting that is typically performed in a
confined area at the bottom of the cage.
- After selective 6-OHDA lesions of striatum: amphetamine-induced non-locomotor stereotypy is decreased, whereas stereotyped
locomotion is increased relative to control.
- After selective 6-OHDA lesions of N accumbens : amphetamine-induced locomotion, sniffing, and rearing
**It suggest that N accumbens mediates amphetamine-induced locomotion, and striatum mediates amphetamine-induced oral
movements.

Short-term effects can include: Long-term effects can include:

Increased attention and decreased fatigue Dependence and addiction psychosis

Increased activity paranoia
Decreased appetite hallucinations
Euphoria and rush mood disturbances
Increased respiration repetitive motor activity
Hyperthermia Stroke
Weight loss

Action mechanism:
- block neuronal catecholamine (DA,NA),5HT & a 2 re-uptake carrier process (Ca-independent, not influenced by presynaptic
receptor)
- DA and 5-HT agonist activity
- Degeneration of DA neuron, and Monoamine oxidase inhibitor (large doses): 6-OHDA (selective neurotoxin)
Uses: few therapeutic applications, narcolepsy and hyperkinetic children ( attentional-deficit hyperactive disorder )
illege stimulant, short term anorectic (appeitide-suppressant), nasal decongestant
S.E.
1. wakefulness, anorexia
2. Excessive sympathomimetic activity: hypertension, severe tachycardia (10 mg), hyperpyrexia, delirium and convulsion (30 mg)
3. Tolerance : to euphorigenic, anorectic, hyperthermic, and lethal action
4. High potential for psycho-dependence and addiction (drug abuse); e.g.
Design drugs [ Controled Schedule I]:
 TMA (3,4, 5-trimethoxyamphetamine = -methyl mescaline )
- psychomimetic effect (160-200 mg ): > 10x of mescaline, but less stimulant than amphetamine
- it produces not entactogenic emotional effects, but rather "anger, hostility and megalomanic thoughts", sensory
hallucination and moderate sympathomimetic stimulation.
- SAR: 4 of catechol ring : modified the duration, intensity and character of entactogenic effects
insert of inert chemical group in 5: abolish the hallucinogenic effect
MDA " love drug" ( 3,4-methylenedioxyamphetamine) 100-150 mg, mild euphoria lasting for 8 hr
- the use of MDA in psychotherapy is described by Claudio Naranjo The Healing Journey : New approaches
to consciousness in 1973
- m spasm and clonic convulsion, inc HR,Temp, BP ( 500mg, p.o.) intensification of feeling ( 3-
dimension music), heighten tactile (touch) sensation, no visual & auditory distortion.
- Schedule I drug
S.E.: physical exhausion, lasting 2D ( bad trip)
nerve damage of tryptaminergic( long-term use)
NDMA "Ecstasy" "Adam" (N-methyl-3,4-methylenedioxymethamphetamine) 50 mg
- relaxed euphoria ( increase sensitivity to touch, and lower inhibition) , lasting for 2 hr.
- schedule I controlled drug in 1985
nerve damge like MDA
[ref] Shulgin AT. The background and chemistry of MDMA. J Psychedelic Drugs 18 (4): 291, 1986.
MDE " Eve" ( N-ethyl-3,4-methylenedioxymethamphetamine)
DOM "STP" ( 2,5-dimethoxy-4-methylphenylisopropylamine) , < 3mg
- HR increase, pupil dila, BP and temp increase
- mild euphoria ( peak: 3-5 hr, duration: 8-12 hr)
- psychomimetic effectis 40-50x more potent than mescaline. It caused serenity, tranquillity and peace or
like STP motor oil, and is a popular psychomimetic drugs in illegal society
5. psychosis ( amphetamine-induced paranoid schizophrenia )
6. Neurotoxicity: decrease striatum DA uptake and neuronal degeneration

Clinical detoxication
1. Ammonium chloride ( pH decrease)
enema
2. haloperidol

Cocaine

The word “coca” comes from the Aymara “Khoka” , meaning “ the tree”
Cocoa “可可”與coca無關
History:
1. Incas( Peru) called the coca plant a "gift of the Sun God", reserved for ceremonial or religious purposes since 6th century
AD. Now, coca leaf chewer "Coquero" has found in Peru, Bolivia, Ecuador & Colombia. Peruvian . Indians chews coca
leaves ( together with a little lime powder made from crushed shells) to increase their endurance and capacity for work.
"exaltation of spirit, freedom from fatigue, and a sense of well being" . In Bolivia, cocaine is currently one of the a mainstays
of extremely shaky economy.
2. Isolated from Erythroxylon coca, Erythroxylaceae (1%, cultivated) by Albert Niemann (Australian chemist ) in 1855, Angelo
Mariani (Franch chemist): Mariani's coca wine since 1860s. Pope Leo XIII is said to have been " supported in his ascetic
retirement by a preparation of Mariani's coca " and later he presented Mariani with a gold medal, citing him as a benefactor
of humanity.
3. Sigmund Freud:1956-1939 (1885), the founder of psychoanalysis, and probably the most influential psychologist in the 20th
century. He evaluated the dose-response relationship and the duration of mood, hand strength by himself ( CNS stimulant &
euphoriant), at University of Vienna, caused a life-long dependent on morphine. He gave it to his friends, fiancee, sisters
 and patients. He wrote "The exhilaration and lasting euphoria which in no way differs from the normal euphoria of a healthy
person" " The result is enjoyed without any of the unpleasant after effects that follow exhilaration brought about by alcohol "
In a letter to his fiancee he described as "a song of praise to this magical drug" Sigmund Freud is one of the more
famous early proponents of the drug. Thomas Edison also believed in cocaine’s miraculous effects. France exported Vin
Mariani, or coca wine, to these shores, and
4. In 1886, John Pemberton introduced Coca Cola, named after the drug that gave the original formula its kick
5. Karl Koller : local anesthetic for eye surgery by himself, Auguste Bier : lumbar puncture for local anestheia, the first spinal
anesthesia in 1898; Cocaine "can supply the place of food, make the coward brave, the silent eloquent" noted by
Parke-Davis Pharmaceutic Co, and called it a " wonder drug". John Styth Pemberton : Coca Cola " the intellectual beverage
and temperance drink" in USA, 1886. and came to symbolize the American way of life itself. The cocaine was taken out of
the drink in 1906, and by 1909 the American Bureau of Food and Drugs was able to initiate a legal action against the
company producing the drink. In 1914, cocaine sales were banned in the United States under the Harrison Act.
6. David Garnett ( English novelist) recounted his one & only experience: I took a pinch, sniffed the powder and felt my nostrils
turn ice-cold as little crystal evaported. My heart began to beat faster and faster with a terrifying acceleration. I lay flat on
my back and listened. In a few seconds my heart-beats become almost indistinguishable, like the ripple of mechine-gun fire.
I was frightened
7. Common name: "crack" or "rock" : free alkaloid base form + baking soda, popular smoking
"nose candy", "coke", "snow", "gold dust", "lady" : cocaine-HCl
"base", "pasta", "pitillo" and "buscuso" : coca paste
The common routes of administration: smoking pasta, snorting, " base pipe" (a modified water pipe ), iv, crack smoking

7. In 1988, 5% of young adult ( 18-25 ) in USA using cocaine, social crime

Pharmacological Action

Legend

RED Results from self-administration experiments.

BLUE Results from conditioned place preference experiments.

Amyg Amygdala

Hipp Hippocampus

LH Lateral Hypothalamus

mPFC Medial Prefrontal Cortex

NAc Nucleus Accumbens

 PPT Pedunculo-Pontine Tegmental Nucleus

VTA Ventral Tegmental Area

Site of action: monoaminergic ( especially DA) transporter and inhibiting normal synaptic uptake.
1. In animal experiments, It was found that D3 DA-receptor appears to be a central factor in cocaine use. D3 selective agonist may
reduced self-administration by enhancing cocaine’s reinforcing properties. [Ref] Caine SB & Koob GF. Science 260: 1814-16,
1993; Behavior Pharmacology 6: 333-347, 1995
2. Like amphetamine 12-16 mg, iv.= 10 mg of D-amphetamine , Onset:5-10sec by smoking, 30-120sec by iv, and 1-3min by
intranasally.. T½ : 2-5 hr (route dependent), oral ineffective
Sympathomimetic actions predominate at lower dose( 1mg), while local anesthetic actions are more likely at higher
doses. Acute increase HR, BP, meta. rate, constrict blood vessel, mydriasis.
Euphoriant effect: 0.3-1.5mg, snorting 1.5 mg/kg induced a peak level of 1.6mg; at dose of 10 mg, iv: onset: 2' paek: 5',
duration: 15-25'
most common are tactile ("cocaine bugs" in the skin) and visual ("snow lights")
dying: >20 g, 1.2 g ( cardiac failure)
3. Schedule II: cause psycho-dependence, without physical dependence or tolerance

Toxicity:
1. Behavior pathology ( psychomotor activation) e.g. paranoia, anxiety, stereotyped complusive repetitive behavior, vivid visual, auditory
& tactile hallucination (fully developed paranoid ideation with visual hallucination within 24 Hr) including delusions, disturbance of
eating and sleeping, depression "Cocaine bugs".
2. BT increase, mydriasis
3. Cardiac disorder: high risk of arrhythmias, ischemia, congestive heart failure
4. Vasoconstriction: norcocaine responsible
5. Neurological complication : lower the seizure threshold
6. Craving of drug or seeking behavior: a).mesolimbic or mesocortical DA pathway mediated. b). DA cell body in ventral tegmental area
are a principle source of innervation to the N, accumbens, and further projects to ventral pallidum (locomotor control). c). Lession of N.
accumbens or 6-OH DA resulted in supression of cocaine self-administration. d). sulpiride ( postsynaptic D2 receptor antagonist),
but not atropine, propranolol induces supression of reinforcing effect. e). Flupenthixol decanoate ( non-selective DA
antagonist),Mazindol (DA uptake blocker): experimental drug for the treatment of crack smokers. f). buphenorphine ( partial agonist
of opioid receptor): for the treatment of "speedball" ( heroin + cocaine or amphetamine )
Uses :
local anesthesia
Brompton's cocktail for severe chronic pain in terminal cancer patients ( 10 mg cocaine, 5-20 mg morphine & 2.5 ml alcohol in 20 ml
syrup) in England
**No medications are approved for treating cocaine abuse and dependence
** Proposed pharmacotherapies for cocaine abuse:
Acute agents Chronic agents
Early severe symptom relief anticarving/prevent relapse
Neuroleptics Desipramine
Benzodiazepines Serotonergic agents
Withdrawal symptom relief Fluoxetine
Sertraline
Dopaminergic agents
Amantadine Gepirone
Bromocriptine Dopaminergic agents
L-Dopa Bupropion
Tricyclic antidepressants Block reinforcing properties
Desipramine Dopaminergic antagonist
Flupenthixol
Neurotransmitter precursors Substitution medications
Tyrosine Dopamine agonists
Tryptophan Methylphenidate
Mazindol
Miscellaneous agents
Carbamazepine
Naltrexone
Disulfiram
**GBR 12909 ( antidepressant, inhibit DA transporter) reduces cocaine craving while not suppressing normal desires ( e.g. hunger )
[Ref] Baumann MH, Char GU, De Costa BR & Rice BR. JPEP 271: 1216-22, 1994; 280: 541-50, 1997; J Neurosci 16: 7416-27, 1996

Ibogaine (Endabuse)
 - an psychoactive indole alkaloid from the root of African shrub Tabernanthe iboga.

- History:
1. Griffon du Bellay , a surgeon, described in 1864 " In small quantities it is an aphrodisiac and a stimulant of the nervous
system, warriors and hunters use it constantly to keep themselves awake during night watches.
2. Professor Henri Baillon described the botany and name in 1889 session of the Linnaen Society in Paris, Dybovsky and
Landrin (1901) as well as Haller and Heckel ( 1901): first isolated ibogaine; and the structure was first established by
Taylor in 1957.
3. Ibogaine was never widely used in clinical.
4. Lambarene ( extract of the root of the iboga relative Tabernanthe manii, which contained about 8 mg of ibogaine),
was marketed in France during the 1930's. as a " a neuromuscular stimulant, promoting cell combusations and getting rid
of fatigue, indicated in cases of depression, asthenia, in convalescence, infectious disease. Later, Iperton was used as
tonic or stimulant.
5. In 1970, the US FDA classified ibogaine as a Schedule I substance ( all nonresearch use forbidden )
- Active metabolite: noribogaine, a chemical related molecule R-coronaridine
- NMDA antagonist, voltage-dependent Na channels activator, decrease DA turnover & anticholinesterase. "multiple loci"
The neurochemical basis for the putative " antiaddictive" actions of ibogaine remains unclear.
- Howard Lots of first patented in 1985
- on trial for heroin and cocaine addition beginning in 1985, ibogaine (4-25 mg, p.o.) as a interrupting addiction to narcotic,
cocaine, amphetamine, nicotine and polydrug dependency syndrome.
[ref] Popik P, Layer RT, and Skolnick P. 100 years of Ibogaine: Neurochemical and pharmacological actions of a putative
anti-addictive drug. Pharmacol Rev. 47:235-253, 1995.

Cathine
Khat ( Arab, Yemen); Miraa ( Africa, Kenya): young & fresh leaves and stem of Catha edulis Forsk.; reddish color

Active principle : phenylethylamine alkaloid. e.g. cathine (d-norpseudoephedrine, stereosiomer of NE)

Euphorant active component: cathinone or (s)-2-aminopropiophenone
inotropic and chronotropic effect: 2X of amphetamine
mydriasis and analgesia

PCP ( phencyclidine) : ketamine derivative , Schedule II since 1978

History: Sernyl from Parke Davis in 1950s for its anesthetic and analgesic, and voluntarily discontinue in 1963.
Comon name: "Angel dust", the 3rd most frequently abused street drug after alcohol and cannabis in 1980's
sigma receptor agonist, 5HT2
Action site: bind to recognition site inside the ion channel of NMDA receptor in hippocampus ( Trend in
Pharmacol Sci 7:448-451, 1986 )
Antagonist of N-methyl-D-aspartate induced long-term potentiation
 uptake inhibitor of NA, DA & 5-HT
Pharmacological effects:
a) produce stimulant and depressant (isolation & helplessness), analgesic, dissociative anesthetic and
hallucinogenic effect (dependent on doses).
80% of the 1st time user had pleasurable experience
potent psychomimetic ( 5-20 mg ), lethal dose ( 150-200 mg).
b) Psychomimetic syndrome:
-delirium, euphoria, relaxation, dissociation from enviorment, unreality, distortion of time, space, and
body image,
- impair of both proverb interpretation (symbolic cognition) & serial evens ( sequential thinking), as well
as depersonalization, a sense of unreality, and inability to distinguish between self and nonself stimuli
- visual ( less kaleidoscopic) and auditory distortion ( high dose)
- dissociation boarding on schizophrenia state ( unpredictable, violent behavior). The psychotic phase may
last several weeks after single dose
c). Therapeutic : anticonvulsant, anesthetic & protective action against hypoxia-induced brain damage
d).PCP-induced schizophrenia, including blocking tangentiality, loose associations, body image disturbance,
religious preoccupation, paranoid delusions, ideas of reference, hallucination, inappropriate lability and
catatonia. without the classical tachycardia, hypertension or nystagmus.
Toxic Effects:
- overdose : cause sweating, slurred speech, muscle rigidity, motor seizure, convulsion and coma ( eye
remain open )
- chronic : persistant difficulties with recent memory, speech for 6 M to 1Y
- craving : self-administration in monkey like cocaine, unlike LSD
- cause of death: behavior toxicity ( agitation, combativeness, depression, impulsiveness ) which caused both
accidental and self-inflicted trauma
Endogenous ligand : endopsychosin ( Prog Clin Biol Res 192:495-8, 1985)

[ref]
Cox TC, Jacobs MR, Leblanc AE, & Marshman JA. Drug and drug abuse: A reference taxt. Alcoholism and
Drug Addition Research Foundation, Toronto, 1983
Gossop M. Living with Drugs. 2nd Ed. Wildwood House, Hants , England, 1987

ANALEPTICS (CNS CONVULSANTS)

1. Pentylenetetrazol (Metrazol), synthetic

Pharmacological action:
- affects all levels of cerebrospinal axis (brain stem) but requires more for spinal animal.
- No selective action on respiratory center.
Action mechanism:
interfering with GABA-mediated inhibition, the exact mechanism is unknown

Metrazol (50-100 mg/kg)-induced seizure in mice

1. with latent period : 15"-1'
2. myoclonus twitch ( facial or forearm muscle twitching)
3. clonic seizure (hindleg flexion)
hindleg clonic seizure (flexion) and/or tonic extension
4. recurrent clonus

Uses: essential screening test for anticonvulsants

amplification of EEG for epileptic test ( sub-convulsive dose + flash light)

2. Strychnine
The principle alkaloid from the seed of Strychnos nux-vomica [Fan-Mu-Bai] in India.
Pharmacological action:
Spinal level convulsant, fully aware of sensory stimuli.
Tonic and sustained convulsion of the hind limb: tonic and clonic extension without flexion.
Symmetrical extensor thrust (inhibits polysynaptic and Renchaw cell inhibitory interneuron at at anterior horn,
glycine as mediator) -Blockage of negative feedback inhibition.
Strychnine (2 mg/kg)-induce seizure in mice
initial stage: Stiff face and neck m ---increased reflex excitability and any external sensory stimulus may
 produce violent secondary motor response.
secondary stage: coordinated extensor thrust to full tetanic convulsion, so-called opisthotonos (only the crown
of the head and the heel touching the ground).
Action mechanism:postsynaptic glycine receptor competitive antagonist, block the generation of IPSP (block
postsynaptic inhibition).
Toxicity: death result from medulla paralysis (hypoxia): 30-50 mg
Treatment: diazepam (10 mg) with support respiration and active charcoal.

3. Picrotoxin
isolated from the berries of Anamirta cocculus [Mu-Fan-Gi] in East Indies.
Pharmacological action:
Affects all portion of CNS, no effect until convulsive dose
Clonic & incoordinated convulsion to tonic-clonic seizure (tonic flexion to extension)
Action mechanism:
GABA-A receptor antagonist ( not a competitive antagonist, bind allosterically to a modulatory site of the
receptor complex)
Direct action on chloride channel
Block both pre- and postsynaptic inhibition mediated by GABA.

4. Bicuculline
Pharmacological action:
like picrotoxin
Action mechanism:
competitive GABA-A receptor antagonist
bind mainly to hydrophobic accessary sites that surround the polar core of the GABA recognition site.
Scale of Bicuculline (0.15-0.3 mg/kg,i.v.)-induced Seizure
0: no seizure activity 0.5: facial or forepaw myoclonus or clonus
1.0: clonic seizure with loss of righting and/or strong spinal torsion
2.0: explosive clonic seizure with running
3.0: tonic seizure with fore limb extension
4.0: seizure with tonic hind limb extension

[reference]

Balfour DJK. Psychotropic drugs of abuse. In International Encyclopedia of Pharmacology and therapeutics.
Section 130. Pergamon Press, New York, 1990