CNS stimulants and

psychotomimetic drugs

PharmDr. Martina Čečková, Ph.D.

Department of Pharmacology and ToxicologyCharles University in Prague

Pharmaceutical faculty in Hradci Králové

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 effectCentral 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), α-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 γ-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 drug´s euphoric and stimulatory effect)

No clear cut-off syndrome, but depression, dysphoria and fatigue occur after initial stimulant effect

Adverse effectsAcute – 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 β- adrenergic stimulation)

o Antagonism of adenosine on A1 and A2 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 κ – opioid rcp – Salvinorin A

LSD –derivative of lysergic acid

Exceptionally potent psychotomimetic drug – strong effect in doses lowerthan 1µg/kg

mescaline – chemicaly related to amphetamine, derived from a Mexicancactus

psilocybine – obtained from fungi(„magic mushrooms“) - Psilocybemexicana

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 5HT2)

Dependence and adverse effects

Fast developement of tolerance

• Aversive rather than reinforcing properties

• Unpredictability of action(danger ofprecipitating mental disorders, attacks of

schizophrenia)

• Unexpected „flash-back“

• > criminal behaviour, suicide attempts

MDMA (ecstasy)

= 3,4-methylenedioxymethamphetamine –central stimulant with mildhallucinogenic 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 κ – 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 také 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