MEDICOLEGAL ASPECTS

OF DRUG-ABUSE

POMERANIAN ACADEMY OF MEDICINE

FORENSIC MEDICINE DEPARTMENT

KRZYSZTOF S. BOROWIAK

OPIUM

DRUG ABUSE HISTORYPOPE (OPIOIDS) known in Egypt since 1700 year b.Ch. – used with wine – both for therapeutic and addict useful

Ancient Egyptian mummies (XXI dynasty-1500 b.ch.) included low amounts of marihuana and Cocaine (S.Balabanowa -1992)

Ugarit and Mykeny since 1500 b.Ch. Were famous as market centers of wine , opium, Cannabis, Datura

Ramzes II was a havy tobaco smokers

Nicotiana tabacum

From ancient Greece - we know description of opium action on human from Homer

It is known that most of Romanian Cezars were regulary drug abusers

In wine of Cleopatra queen have been Pope and Datura stramonium (Horacy)

The spread of global status of drug abuse since 1908 r. – illegal opium smokers in Chinatown (N.Y.)

First International Low Regulation – 23th of January 1912 r. HAGA (with China )

Modern status of addiction problem result from Korean and Viet Nam wars nad cultural-habitual revolution in USA in 60. Of XX c.

In Poland National Edict from 1997 April 27

(Dz.U.75 poz. 468)

There are included 63 section in the 7 main Chapters and list of more than 450 substantions, chemical salts and chemicals need for synthesis of drugs

• profylactics and learning

• treatment and rehabilitation

• Supervision: agriculture, production, marketing

All illicit dealings with drugs in Norway are covered by All illicit dealings with drugs in Norway are covered by

the the Norwegian Penal Code Norwegian Penal Code § 162 Two Goverment-appointed committeesTwo Goverment-appointed committees

CUSTOMS SERVICE• STRATEGY OF PROFYLACTIC ACTIVITY

• SUPERVISION FOR PRODUCTION, DISTRIBUTION AND STORAGE OF NARCOTICS

• TREATMENT, REHABILITATION, READAPTATION OF ABUSERS

• LAW AND LOGISTIC POSSIBILITIES OF CUT THE ILLEGAL MARKET

• SUPERVISION FOR PLANT AGRICULTURE

- The National Investigation Bureau (NBCI) –strategy, analysis of narcotics, economics aspects, logistic activity

- Oslo Police Headquaters and local Police (Drug section) – operational assistance, technical, material and personal resources

- Ministry of Justice – promotion of central and regional projects

DETAIL LIST AS ADDICTION OF CODEDETAIL LIST AS ADDICTION OF CODE

LIST No 1 (About 150 substances)• GROUP I-R (ephedrin, ergometrin, ergotamin, pseudoephedrin

• GROUP IIA - R (Acetic acid, ethylic ether, piperidine,Antranil acid, fenyloacetic acid,nitroetan)

• GROUP IIB-R (aceton, aldehyd benzoesic, MEK, sulphuric acid, HCl, toluen, butanon)

LIST No 2 – ABOUT 200 SUBSTANCES AND SALTS• GROUP I-N (opiats & opioids and their salts, Cocaine,

Cannabis indica vel sativa – near 130 compounds)• GROUP II- N (codein and derrivatives /narcocodein, /

etylmorfin –Dionine, propiam• GROUP III-N (mixed pharmaceutics included codein concentration more

than 50 mg or 1,5% ) • GROUP IV-N (acetorfin , Heroin , THC,

LIST No 3 – PSYCHOTROPIC SUBSTANCES – about 150• GROUP I-P (LSD, psylocybin , amphetamine , metamphetamine, DOB, DET, DMA,

DMT, PCP, secobarbital, THC• GROUP II-P ( psychedrine, barbiturans, pentazoocyn )

• GROUPS III-P i IV-P (barbituranes, benzodiazepines, TLPD, mazindol, pemolin)

Governmental structures responsible for drugsGovernmental structures responsible for drugs• The Ministry of Health and Social Affairs is the responsible ministry for alcohol- and drug policy and the overall co-ordination of illicit drug abuse.

• Norwegian Directorate for the Prevention of Alcohol and Drug Problems - MH give its full attention to all social conditions that are related to trends in consumption of legal and illicit drugs

•The National Institute for Alcohol and Drug Research (SIFA) is an independent institute whose aim is to carry out scientific research on alcohol and drug issues with special attention to social science research.

- A permanent co-ordinating body for law enforcement activities has been formed, comprising a representative for the Ministry of Justice and Police, the Director of Public Prosecutions, the Chief of the National Bureau of Crime Investigation and the Head of the Drug Section, Oslo Police force.

-This committee keeps abreast of the development in drug use, continuously evaluates law enforcement efforts, ensures that resources are available and from an assessment of priorities, select specific issues to concentrate on.

GENERAL SITUATION WITH THE FOCUS ON TRENDS/STATISTIC

Fig. 1 Number of seizures of drugs, opiates, cocaine, cannabis and amphetamines 1986-1996

The number of heroin seizures has steadily increased since the second half of the 1980s up to 1994. There was a large increase in the number of seizures in 1995 and 1996. At present the THC and Amphetamines (Ecstasy) are most popular drugs in Norway

GENERAL SITUATION WITH THE FOCUS ON TRENDS/STATISTIC

Fig. 2 Number of seizures of drugs, other drugs, 1989-1996

   

Heroin Cocaine Cannabis Amphetamines

Number of confiscations

1996 2340 75 4296 1775

1996 Ecstasy LSD Khat BDA/BARBIT

192 36 102 2197/0

GENERAL SITUATION WITH THE FOCUS ON TRENDS/STATISTIC

Fig 3 Percentage of young people in Oslo and Norway who say that they at some time have used different drugs in 1996

Fig. 4 Deaths caused by use of drugs, 1982-1996

GENERAL SITUATION IN THE OTHER SCANDINAVIAN COUNTRIES

• DENMARK – the most liberal low mostly similar to Duch solutions

• „Om euforiserende stoffer” 1955 (1996)

• National Penal Code § 191, § 88, § 191

• Penalty 2-10 years for possess 20-25 g of herroine, 100-125g morphine, 10-15 kg of Cannabis

• discussed phenomenon of Free town Christiana (1971) (part of Copenhagen) – 1000 -1500 citizen, non-formal group out of national low

• SWEDEN, FINLAND, ISLAND - law solutions strongly represive, restricted and trends of high criminalization for posses and dealing of narcotics is promoted

• general polytic is based on rule of „ zero tolerancy”

STIMULATION OF NEUROLOGICAL SYSTEMS• DOPAMINERGIC

• GABA-ERGIC

• STIMULANTS AMINOACIDS

• NO SYNTHESY

NEUROMOLECULAR MECHANISMS OF DRUG ABUSE

THE „PRICE, AWARD” BRAIN SYSTEM OF MOTIVATION

ACTIVITY DEPRESSION OF ADRENERGIC AND SEROTONINERGIC NEURONS

IN THE BRAIN OF ABUSE HUMAN THE HIGHER PSYCHOLOGICAL ACTIVITY ARE DEEPLY CHANGED

ABUSE STATUS IS CHRONIC AND BACKING DISEASE

NEUROMOLECULAR MECHANISMS OF ABUSE

DOPAMINERGIC SYSTEM

The main neurotransmission system due to abuse status. The mezzolimbic structure ( dopaminergic neurons - release of dopamine )

Cocaine,

Amphetamine,

Opioids

Ethanol (+ GABA)

Nicotine, THC

ADRENERGIC SYSTEM

acsons cells located in the limbic structure and cortical cells also

In the adrenergic neurons membrane - opioids receptors ( i ), 2adrenergic

NEUROMOLECULAR MECHANISMS OF ABUSE c.

SEROTONINERGIC SYSTEM

The midbrain structures, spinal structure the main role in the alcohol abuse syndrome inhibition of activity of system

GABAERGIC SYSTEM

The price agent is depression of panic and anxiety direct by GABA-ergic receptors, which modulate dopaminergic neurons activity

BDA i ethanol abuse

NEUROMOLECULAR MECHANISMS OF ADDICTION c.d.

STIMULATING AMINACIDES

• Important access of glutaminergic system in progress of addiction

• Postsynaptic receptors connected with NMDA, kainic acid and AMPA main in limbic area and cortex

• Addiction stimulation of receptors resulted in plastic and adaptaction changes of synapsas (memory, learning)

• Ethanol receptors NMDA

• Opioids, cocain AMPA

OPIOID SYSTEM

• Drug abuse substances rise of prodynorphine gen expresion in the CNS (stratium) and of density of opioid - receptors.

• chronic use activity of peptide synthesis neurons acting against to opioids: cholecystokinines and thyreoliberines

NEUROMOLECULAR MECHANIZM OF ABUSE c.

BY G-PROTEIN ACTING

ACTIVITY DISTURBANCES

CYKLIC

NUCLEOTIDES

ENZYMES ACTIVITY IN THE PHOSPHORILATION PROCESES

The funcjonal changes of , , substructure G proteins due to genes expression changes which coded this structures

( tolerancy)

NEUROMOLECULAR MECHANISMS OF ABUSE c.

GENETIC CHANGES DISTURBANCES

PLASTIC ACTIVITY OF BRAIN

LEARNING AND MOTIVATION

NUCLEUS TRANSCRIPTION AGENTS that proteins connected with specyfic DNA seqency in the promotor’s part of genes. They are stimulated by cAMP mainly CREB (cAMP response element binding protein). Changes of that agents release adaptation proceses in the neurons

MEMORY PROCESES

Plastic changes in memory processes of learning and motivation

After break of using stimulation of aversion processes

GENETIC MECHANISMS OF ABUSE c.

FIRST PERIOD OF DEPENDANCE DEVELOPMENT

Genes activity in the early cells answer induced by drugs abuse using in the short time

Binding proteins cAMP (CREB) C-fos C-jun

After chronic using - started chronic genes - FRA (fos related antigen), which due to induction of chronic adaptation

SECOND PERIOD

GENETIC MECHANISM OF DRUG ABUSE c.d.

GENOTYP CHANGES IN THE PERSONS WITH ETHANOL ABUSE SYNDROME

Polymorphism of DRD2 gene egzon 8 RFLP higher frequency of drinking, depression, suicides motivation

Short DRD4 alleles of 3VNTR egzons well treatment motivation

Allel A9 of dopamine gen frequent 2x more in the patients with tremors

Depletion of serotonine gen SL C6A4 disturbances of asocciation personality

Variants of egzons GABAB personality disturbances

IN THE 1974 r. WHO FOUNDED

8 BASIC DRUG ABUSE CLASSES

TYPE I MORPHINIC Included natural pope alkaloids derrivatives of Papaver somiferum: morphin, codein and tebain

(phenantren derrivatives) papaverine, narkotine, narceine (izochinoline derrivatives) and synthetic and halfsynthetic

• Opioids: heroin (also oksykodon, fentanyl, pentazocyne)

Way of introduce: vein injection (everywere vessels)

Characteristic signs: strong and fast tolerancy nad psychological and somatic abuse, full syndrome withdrawal, high organs toxicity

HEROINA

Symptoms after single dose: narcotic status, somnilence, piupils, locomotive coordination disturbances

TYPE II barbituranes – alcohol

Ethylic alkohol, volaitlable anesthetics and all psychotropic drugs

Barbituranes (phenobarbital, cyclobarbital...)

Benzodiazepines (diazepam, oksazepam, nitrazepam, alprazolam)

Neuroleptics (chloropromazyna, promazyna, pernazyna ...) TLPD (doksepin, imipramin,

amitryptylin ....)

Strong psychological abuse, phisical different (ethanol), slight tolerancy,

OTHERS– antihistaninic (cetrizin, astemizol), depressed foot neccessity (isolipan, mazindol), using in the locomotion disease (aviomarin)

TYPE III COCAIN

Cocaine hydrochloride

(Columbian, snow)

Crystalic cocain

(crack, dumex)

Erythroxylon coca

Way of introduce: per os (leafs chewing), by membrane syrfaces: (by nose,by vagina) smoking, inhalation, intra venous

Leafs, cocain lavada, hydrochloride salt, cristalic (coca, freebase, crack, powder)

Cocain pasta (lavada)

Sympatomimetic stimulant. release i back - keep of epinefryny i nor - E oraz AP in the presynaptic adrenergic neurons, and dopamine and serotonine in midbrain. Local anesthetic ( ester group) – blocked kanałnatrium channels . T ½ 0,5-1,5 hrs. Benzyloecognine 5-8 hrs. Strong abuse both psychical and physical , fast tolerancy, withdrawal syndrome, high organs toxicity, cardiotoxic action. Coctylen interferention with ethanol.

Mechanisms of action and i biological effects of substances from tobaco and

Cannabis

THC THC

THC

THC Nic

Nic

NicNic

Different action of main activ alkaloids

tetrahydrokanabinol nikotynaSimilar effects for gas (smoke) aromatic hydrocarbons, irritant and cancerogenic substances,

CO, NO

80% amount of ROS, and 81% conc. of intracelular glutathion

M.Roth - marihuana due to strong P4501A1 ( CYP1A1) mRNA i aktywności tego układu

Irritant, corrosive, proastmatic, cancerogenic i teratogenic action

70 meroterpens (Mechoulam, 1973) THC (Δ-9–THC, Δ-8–THC), kanabidiol (CBD), kanabigerol (CBG), kanabinol (CBN), kanabichromen (CBC), olivetol

Kinetic of Nicotin and THC Kinetic of Nicotin and THC

,9 -15 mg nikotyn - esrum concentration 130-200 nmol/l

150-500 mg marihuana, serum concentration 2- 8 ng, in urine > 50 ng/ml

Fast dystribution

to CNS

Slight absorption in the mouth and pharyngx

Fast absorbed in the lungs

In serum conc. for 10 min. And fast (T1/2 - 10 min)

After 1-2 h. - slow conc. (oxidation to kotynine - estimation of nicotinic abuse

biotransformation in the cyt. P-450 for active 11-hydroksy -THC, and non active11-nor-9-karboksy-delta-9-THC

Slowly released in to blood

Slowly released from tissue for several days

Fast absorbed in the lungs and deposed in the fatty tissue

RECEPTOR ACTION OF THC

CB 1, (hipokamp, cerrebelum)

Psychostymulation panic, anxiety

activity of mezolimbic dopaminergic neurons adenyl cyklaze Ca (N i P/Q) channels K channels protein kinase activated of mitosis

CB 2 - regulation influence to CB 1 and

distal: circulation, immunological cell

activity

SPLEEN ENDOTHELIC

CELLS

BIOLOGICAL ACTIVITYBIOLOGICAL ACTIVITY

sensitivity of sens neurons (pain relief)

release of lyphopolisacharides (LPS) and IL-6 by macrophags (anty-inflamatory action)

vomeeting necrosis peripheral neurons

apoptosis and astrocites)

THCTHC Hipothermic action on the

way of cooperation with 5-HT i D2 receptors Peripherial receptor CB 2

– immunosupressive ( activity of lymphocites)

endocannabinols – are release in to blood while rapidly blood preasure

Anandamide together with EDHF – regulation of homeostasy of cardio-vascular system

Wypalenie 1 papierosa lub skręta Wypalenie 1 papierosa lub skręta to wprowadzenie do organizmu to wprowadzenie do organizmu

około 1,5-2,0 mg nikotyny lub THCokoło 1,5-2,0 mg nikotyny lub THC

Short action katecholaminemia and

sympatykotonia short tachycardia and RR Higher useof oxygen by

heart Corronary vessels spasm Psychical effects

to 48 hrs action 3-6 hrs euphoric Change of time and perspective

estimation well feeling RR, tachycardia hypotermia

Efekty i skutki ...

THCNIC

Adverts effectsAdverts effects of of tobacotobaco andand marimarijjuanuanaa

Strong addiction (stimulation of mezzolimbic pathway -release of dopamin)

Fast involved peripheral tolerancy

small tolerancy for CNS action

Abstynency sympotoms: irritation, agression, depletion of psychomotoric activity and sleepless

psychical and phisical addiction

tolerancy involved after 6 -12 months

Periodic apathy, sleepness Depletion of memory,

concentration, and orientation

Muscle tens decrease and locomotive coordination

acute psychose symptoms Sexual impotency and

reproductive possibilities Immunosupresive action

DangerousDangerous of of tobaco andtobaco and marimarijjuanuana a smokingsmoking (cont.) (cont.)

Shorten live Cancerogenesis risk Pulmonary system

deseases Cardiovascular

deseases Ulcerus risk Earlier menopause and

osteoporosis (woman) Influence to pregnancy,

higher death factor, worse psychofisical maturation of child to 7. year

zaburzenia psychiczne (depresje, psychozy, napady lęku)

zaburzenia osobowości zespół braku motywacji objawy ze strony układu

sercowo-naczyniowego (hipotensja,tachykardia)

podatność na infekcje ryzyko konwersji

nowotworowej (faza gazowa) procesów nekrozy i

apoptozy

POSSIBILITIES OF CLINICAL TREATMENT POSSIBILITIES OF CLINICAL TREATMENT WITH WITH THC DERRIVATIVESTHC DERRIVATIVES

Nabilone (syntetic analog of THC) use in tratment of vomiting durring chemiotherapy

Dronabinol – as an analgetyk for chronic cancer pain

Dexanabinol – treatment of nusea, vomiting and for save the brain –blood border,when cranial and brain injuries

clinical test for treatment Sclerosis multiplex (SM) Alzheimer disease depresion after injury asthmatic patients patients with AIDS

There are preclinical test to use an CB1 receptor antagonists in treatment: bullimia schisophrenia ,

TYPE V AMPHETAMINE (PSYCHEDRINE)

ECSTASY – postacie tabletkowane MDMA

Siarczan amfetaminy i fosforan metamfetaminy

(biały proszek, porcje użytkowe)

Now on the market 30 derrivatives amphetamine and metamphetamine

fluid hydrochloride (ice, boon), sulphuric or phosphoric salts powder and tablets as ecstasy (MDMA)

TYP V AMFETAMINOWY c.d.

symptoms: deep psycho-locomotive stimulation, agresion, changes of mentality, high temperature and RR, tachycardia.

Second after THC as popularity – psychical and physical stymulation, strong psychical abuse, fast increase tolerance.

Way of introduce: by nose membrane, smoking in the pipe, per os (peels, ice)

Chronic effects: sleep disturbances, depression and psychoses agresion, , cardiac arrest

TYPE V AMPHETAMINE MECHANISMS

ACTION: by serotoninoergic receptors 5-HT2A i 5-HT2C/2B dopamine release in the straiatum

Specyfic regulation by the same receptors (activation) DA receptors of midbrain neurons

ANSWER DEPRESION by NMDA: direct action on the na kompleks cholinergic channels complex (N)

Depresion GABA – ergic synaptic neurotransmision by D2 receptors (amphetamine,cocain)

TYP V AMPHETAMINE

Letal dose for adult not user that 200- 300 mg. After per os intake 10 mg max. Concentration in serum (after 1-2 hrs) that 20 - 50 ng/ml

First Single dose 100 - 200 mg. Drug abuser after 3- 6 months take 10-15 doses its mean 1-1,5 g of narcotic.

Most deal doses that only 30 - 50% of amphetamine – other that waste and dilute substances as meal, sugar, tablets powder...

T ½ 4-12 hrs, metabolism phenylaceton benzoesic acid hipuric acid (1% norephedrine)

TYP VI KHAT

Kathin acting as psychostimulants closely simmilar as cocain and hallucinogenic as well as LSD

Khata edulis – bush growing in North-East of Afric

Leafs contain alcaloid - katine (katin, [+] norpseudoephedrin)

Strong psychical addiction. There is no observed phisical addiction and tolerancy

EXTREMELY RARE TYPE IN EUROPE

TYPE VII HALLUCINOGENIC SUBSTANCES

Znaczki-kalkomanie z LSD-50

SEVERAL NATURAL and SYNTHETIC COMPOUNDS (psychodisleptic)

INTAKE RESULTS IN : hallucination, religian vision , changes of mentality status-

Characteristic flashback syndrome - even after several days

The rapid increase of

popularity in the 90. - simple

access, low price

Psilocybe muschroom,

Datura stramonium ,

NATURAL AND SYNTHETIC HALUCINOGENSNATURAL AND SYNTHETIC HALUCINOGENS

INDOLOALKILOAMINES DERRIV. LSD-25 dietylamid Lizergic acid Psilocin, psilocibin (mushroom

Psylocibe) psylo, Harmina, harmalina, bufotenina (

Amanita muscaria, skin of bananas) Lunch time, businessman lunch

PHENYLETYLAMINE DERRIV. Meskaline (Lophophora

wiliamsi, peyotl,) hoop, megi, meskal

Miriscyne, elemicyna miristica, muscade

Hioscyjamin, atropin, skopolamina (Datura stramonium, Hioscyamus niger, Atropa belladonna)

S Y N TH E T I C

PHENYLETYLAMINES MDMA , MDA (ecstasy) love,

love pill, hormony miłości, adam, techno, disco biscuites

MDEA, STIP – eva, dom

PIPERIDINE DERRIV. PCP (fencyklidyne) angel dust DITRAN Ketamine - jet, kay, super acid