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 5HT2 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. < 50g, 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

Smoking produces a high that lasts 8-24 hours

50% of the drug is removed from the body in 12 hours

Limited medical use

Plant-derived

Smoking produces a high that lasts 20-30 minutes

50% of the drug is removed from the body in 1 hour

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:

Increased attention and decreased fatigue

Increased activity

Decreased appetite

Euphoria and rush

Increased respiration

Hyperthermia

Long-term effects can include:

Dependence and addiction psychosis

paranoia

hallucinations

mood disturbances

repetitive motor activity

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