CNS stimulants and

psychotomimetic drugs
PharmDr. Martina ekov, Ph.D.
Department of Pharmacology and Toxicology
Charles University in Prague
Pharmaceutical faculty in Hradci Krlov
22-5-2014
Drugs that predominantly stimulate CNS
1. Psychomotor stimulants
- affect mental functions and behaviour
- produce excitement and euphoria, restrict sensation of fatigue, increase
motor activity
2. Psychotomimetic (hallucinogenic) drugs
- Affect thought patterns and perception, distore cognition in a complex
way
1. PSYCHOMOTOR STIMULANTS
AMPHETAMINES and related drugs
- Drugs with similar chemical and pharmacological characteristics
amphetamine, dextroamphetamine
methamphetamine
methylphenidate
- Release monoamines (D, NA) from nerve terminals in the brain
acute effect
- Prolonged use - neurotoxic effect, degeneration of amine-containing
nerve terminals, cell death
Pharmacological effect
Central effects
euphoria and excitement
locomotor stimulation
Insomnia, increased stamina
anorexia
Peripheral sympathomimetic action
- increased blood preasure, inhibition of gastrointestinal motility
Feeling of anxiety, irritability and restlessness
paranoia and panic (at high doses)
The amphetamine effect can be blocked by pretreatment with 6-
hydroxytryptamine (depletion of NA, D), -methyltyrosine (inhibition
of catecholamine biosynthesis)
MAOI potentiate amphetamine effect
(x reserpin does not block the behavior effect of amphetamine)
Adverse effect
Chronic administration, tolerance and dependence
Repeated administration of amphetamine over the course of few days

o amphetamine psychosis similar to the atack of schizophrenia

(hallucinations with paranoid symptoms and aggressive
behaviour)
o repetitive stereotyped behaviour
o when the drug administration is stopped - deep sleep, after
awaking letargia, depression and anxiety
Rapid tolerance to euphoric and anorectic effects (but more slowly to
locomotor stimulation and peripheral sympathomimetic effects
Dependence consequence of the insistent memory of euphoria and
unpleasant after- effect ( desire to repeated dose)
Pharmacokinetic aspects
Amphetamine absorbed p.o.
for increased intensity of the hit snorted, injected (in crystal form also
smoking)
Free penetration through BBB, duration of the stimulation effect few
hours
Urinary excretion acceleration by urine acidification
Clinical use
ADHD (attention deficit hyperkinetic disorder)
o metylphenidate - part of complex therapy
o (another drug in this indication: atomoxetin inhibitor of
NA re-uptake)
Narcolepsia
modafinil (inhibitor of amine uptake)
sodium oxybate (sodium salt of -oxybutyrate - CNS depressant)
Unwanted effects of amphetamines
Hypertension (cerebral hemorrhagia), insomnia, anorexia, tremors,
cognitive impairment
COCAINE
alkaloid in the leaves of Erythroxylon coca
Pharmacological effects
- cocaine inhibits active uptake of monoamines dopamine and
noradrenaline into nerve terminals:
increased peripheral effect of sympathetic nerve activity
remarkable psychomotor stimulant effect
- Euphoria, increased motor activity, magnification of pleasure, users
feel alert, believe in enhanced mental capacities
- Amphetamine-like effect, but less tendency to produce stereotype
behaviour, hallucination, delusions and a paranoia
- Peripheral sympatomimetic activity (vasoconstriction, increased
blood preasure, tachycardia)
Excessive dosage
tremor, convulsions, tachycardia, respiratory and vasomotor depression;
vasoconstriction, increased blood preasure
Chronic use, dependence and tolerance
Strong psychological dependence
(craving drugs euphoric and stimulatory effect)
No clear cut-off syndrome, but depression, dysphoria and fatigue occur
after initial stimulant effect
Adverse effects
Acute cardiovascular events (dysrhythmia, infarction, hemorrhage),
progresive myocardial damage heart failure
Severe impairment of brain development in utero, malformation of limbs,
ischemic and hemorrhagic lesion of brain; increased incidence of
sudden infant death
Pharmacokinetics
- rapid absorption
- hydrochloride nasal inhalation and i.v. administration
- free base (crack absorption through the large alveolar suface
enhanced CNS effect)
- Stimulatory effect duration - 30min
- Fast hepatic biotransformation
- Deposites of cocaine metabolite in hair monitoring of cocaine
consumption pattern
METHYLXANTHINES
caffeine, theophylline
in beverages like tee, cofee, cocoa low central stimulatory effect
Pharmacological effects
CNS stimulation
Diuresis (vasodilatation of afferent glomerular arteriols)
Stimulation of cardiac muscle
Relaxation of smooth muscle (bronchi)
Mechanism of action:
o Inhibition of phosphodiesterase increased cAMP efect similar to
adenylate cyclase stimulation (mimics - adrenergic stimulation)
o Antagonism of adenosine on A
1
and A
2
receptors (CNS stimulatory effect)
o At higher concentration (> 10mmol/l) stimulation of rhyanodine receptors
(RyRs)
Minimal tolerance and dependence development
Clinical use
caffeine in some preparations for treating headaches (with aspirin) and
migrena (with ergotamine)
Theophylline (aminophylline) bronchodilatator (asthmatic attack)
OTHER STIMULANTS
Arecoline
in the betel nut (Areca catechu) in India,
Thailand, Indonesia..
cholinergic agonist, mild stimulant, improves
learning and memory
Cathine
in the leaves of katha edulis (SE Africa)
chewing the leaves
2. PSYCHOTOMIMETIC DRUGS
(HALUCINOGENS, PSYCHEDELICS)
- Affect though, perception and mood, without causing marked
psychomotor stimulation or depression
- Distorted thoughs and perceptions (dream-like)
- more complex change in mood (not only simple shift in the direction of
depression or euphoria)
- Do not cause dependence
Drugs:
Acting on 5-hydroxytryptamin (5-HT) and its receptors - LSD, Psilocybin,
mescalin; MDMA
Inhibiting NMDA glutamate receptors Ketamin, fencyklidin
Stimulating cannabinoid receptors (CB) THC
Stimulating opioid rcp Salvinorin A
LSD derivative of lysergic acid
Exceptionally potent psychotomimetic drug strong effect in doses lower
than 1g/kg
mescaline chemicaly related to amphetamine, derived from a Mexican
cactus
psilocybine obtained from fungi(magic mushrooms) - Psilocybe
mexicana
Pharmacological effects
- Main effect on mental function:
Alteration of perception
Visual, tactile, olphactory and auditory hallucination
x the person still retains insight that the effect is drug induced
bad trip (especially in anxious persons)
Mechanism of action
agonists on 5HT receptors (mainly 5HT
2
)
Dependence and adverse effects
Fast developement of tolerance
Aversive rather than reinforcing properties
Unpredictability of action(danger of
precipitating mental disorders, attacks of
schizophrenia)
Unexpected flash-back
> criminal behaviour, suicide attempts
MDMA (ecstasy)
= 3,4-methylenedioxymethamphetamine central stimulant with mild
hallucinogenic effect
Pharmacological effects
- Inhibition of monoamine transporters increased monoamine
concentration and depletion of neuromediators in some parts of brain
- 5-HT psychotomimetic effect
- NA a D euphoria (followed by dysphoria)
Does not lead to dependence
However, it carries serious risks
- Acute hyperthermia(demage of skeletal muscle and renal failure)
- Escess water intake and water retention(ADH release- desorientation,
collaps)
- Heart failure
- After-effects depression, anxiety, irritability, increase aggression
- Deterious effects on memory and cognitive functions in heavy users
KETAMIN, PHENCYCLIDINE
Ketamine disociative anaesthetic recreational drug
Phencyclidine (angel dust)- analogue of ketamine
- Feeling of euphoria
- At higher doses desorientation, hallucination, psychotic states
(in experimental animals produce a model of schizophrenia)
- Blockade of NMDA receptor channel
- Combination of ketamine with depressants (alcohol, heroin..)
dangerous overdose
OTHER PSYCHOTOMIMETIC DRUGS
Salvinorin A hallucinogen contained in Salvia divinorum
- Agonist on receptors
- herbal ecstasy, delirium in high doses
DMT (dimetyltryptamin), DOM (2,5-dimethoxy-4-metamfetamin)
efect similar to LSD
Ibogain in the root bark of iboga shrubs users reported
reduced desire to tak other drugs (cocaine, heroine)
investigated as potential treatment for drug craving
CANNABINOIDS (MARIJUANA)
Substances contained in Canabis sativa plant
tetrahydrokanabinol (THC)
the main active constituent the most effective psychoactive
component
Precursors cannabidiol and cannabinol
Abused forms:
hashish - resinous substance secreted by glands on the leaves and female
inflorescences
marihuana dried canabis leaves
Pharmacological effects
- Psychotomimetic and depressant actions
- Euphoria, feeling of relaxation, sharpened sensory awareness
(sights, sounds more intense)
- (objective tests: impairment of learning, memory and motor
performance, impaired driving ability)
- Analgesic and antiemetic effects, useful in spasticity of Parkinson
disease, sclerosis multiplex
Peripheral autonomic effects (vasodilatation, bronchodilatation,
decreased intraocular pressure)
Cannabinoids are less liable than opiates, nicotine or alcohol to
cause dependence, but have long-term psychological effects
nabilon antiemetic effect (used in anticancer therapy)
rimonabant selective CB1 antagonist - treatment of obesity
Endocannabinoids
Anandamide
2-arachodinoylglycerol