TOXIN: DESOMORPHINESTREET NAME: KROKODILKimberly Quam

Blake Sims

Katy Hughes

PURPOSE & INTENT• The purpose of this presentation is to bring awareness

to an EXTREMELY toxic drug that is not very well known.

• Many of us know about the drug crisis in Asia and the Middle East, but few have even heard of a fairly new drug called krokodil (pronounced crocodile).

• This drug is EXTREMELY toxic to the body and has been called the “drug that eats junkies”

• Krokodil is a crude form of desomorphine that is used as a replacement for heroin.

• To put it into perspective… Russia’s krokodil problem can be compared to New Mexico’s methamphetamine problem.

• Our intent is to explain exactly what desomorphine/krokodil is, how it effects the body, and what the future outlook is for users in Russia.

INTRODUCTION The importance of desomorphine:• Desomorphine was originally invented in 1932 in the U.S. as a

possible alternative to morphine. Scientists were looking for a strong analgesic with less side effects, they isolated both desomorphine and methadone.• Desomorphine has a quicker onset, decreased side effects (such as

nausea or respiratory depression), but a shorter duration as compared to morphine. • Even though desomorphine seemed to be a good morphine alternative,

researchers found that it lead to rapid addiction and ceased professional usage. • In the early 2000’s, desomorphine synthesis started to emerge on the

streets of Russia. Drug users found that they could easily produce desomorphine from cheap compounds that were fairly easy to obtain and combine.

INTRODUCTION (CONT.)• Like heroin, desomorphine is almost always injected intravenously. • The “home-cooked” substance was quickly nicknamed krokodil

because of the scaly, green appearance that users skin began to turn as they used the drug. • The term krokodil refers to the street form of desomorphine which is

highly toxic and impure.• Many heroin users in Russia have switched from heroin to krokodil

because it is significantly cheaper to produce. • Heroin is an expensive habit and users that do not have enough

money to sustain their addiction avoid withdrawal by switching to krokodil. Users cannot avoid the toxic and harmful effects of desomorphine and often die within 1-2 years of abuse.

WHAT IS DESOMORPHINE?• A semi-synthetic opioid: a chemical compound that binds to one or more opium receptors in the

body• Opium receptors are G-protein receptors; opioids are ligands.

• A derivative of morphine: • Morphine is a potent drug made from the opium poppy that is used for severe pain (isolated

in 1804).

• Biochemical composition of desomorphine: see figure 1• Starts with the compound α-chlorocodide (a derivative of codeine where the 6-hydroxy group

is replaced by Cl).• Catalytic reduction of a-clorocodide yields dihydrodesoxycodeine which is further

demethylated into desomorphine.

• A sedative: calming/sleep inducing drug

• An analgesic: pain relieving drug

figure 1

BLOOD BRAIN• Users inject desomorphine (krokodil) intravenously using a hypodermic needle

• Arm veins are initially used, then more dangerous spots like the femoral vein in the groin must be used as veins collapse

• The uptake of desomorphine in the brain is nearly complete after 30 seconds

• Desomorphine is converted to morphine by enzymes

• Morphine binds to opiate receptors in the brain• In the reward pathway [VTA, nucleus accumbens]euphoria• And in the pain pathway [thalamus, brainstem, and spinal cord] analgesia

• The thalamus and the brainstem are involved in opiate

addiction

• Withdrawal symptoms are generated when the opiate receptors

in the thalamus and brainstem are deprived of morphine

MECHANISM OF ACTION: OPIOID RECEPTORS

• Scientists have found 3 major types of opioid receptors in the body: μ, δ and k• All 3 produce analgesia when an opioid binds

• Morphine has a higher affinity for m receptors than for other opioid receptors • μ receptors produce physical dependence

• Opioid receptors are present in many regions of the nervous system involved in pain transmission and control

• Presynaptic action of opioids inhibit neurotransmitter release [this is their major effect in the nervous system!]

• Opioids produce analgesia in the nervous system by inhibition of neurotransmitter release from the primary afferent terminals in the spinal cord & activation of inhibitory controls in the midbrain

MECHANISM OF ACTION: INHIBITOR

• Opioids inhibit neurotransmitter release by inhibiting Ca2+ entry by enhancing outward movement of K + ions or by inhibiting adenylate cyclase [the enzyme that breaks down ATP to form cAMP]

• All 3 types of opioid receptors couple to adenylate cyclase. • Inhibition of adenylate cyclase results in inhibition of neurotransmitter release.

figure 3

MECHANISM OF ACTION: G-PROTEIN SIGNALING PATHWAY

• Opioid receptors are coupled to G-proteins

• Morphine binds to the G-protein receptor

• [system is turned ON] GDP dissociates from the a-subunit and GTP takes its place conformational change causes desomorphine to dissociate from the receptor a-subunit bound to GTP dissociates from the β and γ subunits produces the effect enzymatic activity of the a-subunit causes GTP to be converted back to GDP a-subunit re-associates with the β and γ subunits to return the complex to its normal state [system is turned OFF]

figure 2

DESOMORPHINE EFFECTS

• Therapeutic:• Intense euphoria• Transcendent relaxation• Reduces severe pain• Inhibits coughing

• Adverse:• Intense physical dependence• Inability to communicate effectively• Extremely nephrotoxic• Mild hallucinations• Risk of contracting HIV/Hep C/other bloodborne diseases increases

RUSSIA & HEROIN/KROKODIL DEPENDENCE

• Russia has the highest documented rate of heroin abuse in the world

• Low socio-economic status and high levels of poverty are major contributors to this problem

• Efforts to reduce the flow of Afghan heroin into Russia bring limited success• This has caused street prices of heroin to increase • Those addicts who can't afford their next hit turn to krokodil

• Krokodil use is worse in isolated parts of Russia where users are less likely to be able to find heroin

• Codeine based tablets are easy to find and (until June 2012) available over-the-counter

*krokodil refers to the “home-cooked,” highly toxic form of desomorphine in Russia

“KROKODIL” [HOME MADE DESOMORPHINE] IN RUSSIA

Krokodil is synthesized using the following compounds:

• Codeine: obtained from over the counter cold medications (tablets) such as: Codterpin, Codelac, Sedal M.

• Iodine: obtained often illegally in the form of iodine crystals

• Red Phosphorus: found in matchbook strike plates, flame retardants

• Lighter Fluid

• Industrial Cleaning Oil*Caffeine, paracetamol, and diphenhydramine may also be added to the mix. Tropicamide (found in eye drops) may also be added to prolong the experience.**Preparation takes about 30 minutes to an hour to achieve final product. These “ingredients” are fairly easily obtained and the cost to produce krokodil is negligible.

“KROKODIL” [HOME MADE DESOMORPHINE] IN RUSSIA

• Krokodil is extremely toxic due to crude production methods and little purification.

• Krokodil synthesis is very similar to methamphetamine synthesis • Meth is made with pseudoephedrine while desomorphine is made

with codeine• But desomorphine made this way (by cooking it illegally) is highly

impure and contaminated with various toxic and corrosive byproducts

• Heroin v. Krokodil• Heroin users spend roughly $100/dose• Codeine tablets are available for ~$7/pack in Russia.

CODEINE: THE MAIN INGREDIENT

• Codeine [3-methylmorphine] is an opiate and an isomer of morphine

• Codeine has analgesic, sedative properties, and suppresses coughing. • It is also an antitussive, antidiarrheal, antianxiety, and

antihypertensive

• Codeine adverse effects:• Drowsiness, constipation, itching, nausea, vomiting, hypotension,

dehydration, urinary retention, depression• Prolonged usage can lead to: diminished libido, apathy, memory loss

• Codeine morphine transformation occurs in the liver by cytochrome P450 (specifically CYP2D6)

KROKODIL TOXICITY• Red phosphorus destroys bone and damages the central nervous

system which can lead to brain damage.

• Iodine weakens muscle contractibility resulting in atrophy.

• Harmful chemicals used to synthesize desomorphine disrupt the normal balance of minerals and build up in the liver and kidneys• causes organ failure• teeth typically rot away • skin tone discolors to a shade of green and becomes scaly• tissue necrosis often progresses to the point where bone is visible• gangrene is common and amputation is often necessary• more than one-third of users become ill with hepatitis C, and most

die within one to two years

*See the following slide for supplementary figures (WARNING: GRAPHIC)

TOXIC EFFECTS

These are examples of the harmful physical effects of krokodil abuse on the body.

DESOMORPHINE: “POOR MAN’S HEROIN”

DESOMORPHINE HEROIN

Potency:Duration of effects:Length of withdrawal:Physical withdrawal pain:

Life expectancy:

8-10x more potent than morphine30-90 minutes1 month1 month (often addicts are given a strong tranquilizer to keep pain at an endurable level)1-2 years

3-5 hours5 days5-10 days

6-8 years

• Krokodil addicts are trapped in a 24 hour cycle of cooking and injecting the drug to avoid unbearable withdrawal symptoms. It often becomes their “job” to feed their addiction.

RUSSIA: A COUNTRY IN CRISIS• Russia is plagued with heavy smoking, extreme alcoholism, pollution, high

poverty levels, low birth rates, and an increasing amount of HIV/AIDS cases

• The United Nations project that the Russian population will shrink to 116 million by 2050 • The population is currently142 million • Moscow now awards money to mothers bearing two or more children

• Moscow has a ban on methadone and a heavy prison sentence for anyone caught with the synthetic opiate• This is a major problem in treating heroin addiction• This causes doctors to medicate heroin addicts with tropicamide (an ingredient in

eye drops)

• It is estimated that about 3 million Russians are drug addicts• Most between the ages of 18-39

• 90% of HIV/AIDS cases in Russia are due to needle sharing (estimated 1 million Russians have HIV/AIDS)

RUSSIA’S WAR ON DRUGS• Only recently has Russia acknowledged and

started to deal with their huge drug problem

• Krokodil abuse is second to heroin in Russia

[remember, Russia has the highest rates of heroin

abuse in the world]

• The government attributes the drug problem to

the fall of the Soviet Union• They blame the Taliban in Afghanistan as the reason why intravenous use of

heroin has skyrocketed • It is estimated that 90% of the world’s opium is grown in Afghanistan

• Russian authorities have urged the U.S. military to bring the war on drugs to Afghanistan to try to limit the amount of heroin entering into Russia• The American military influence in Afghanistan has not limited the amount of

opium produced

• As of June 1, 2012, all codeine based tablets in Russia are now prescription only. Over-the-counter sales have been banned.• This is the direct response to the growing production of krokodil in Russia

• Reportedly this has not negatively effected the production of krokodil

• This is the most the Russian government has done to resolve the problem

RUSSIA’S WAR ON DRUGS

OUTLOOK FOR USERS SEEKING TREATMENT

• Rehabilitation facilities in Russia are either privately owned or funded by foreign countries

• Russia’s drug treatment technology is referred to as "narcology" • Narcology is basically an old branch of Russian psychiatry • Treatment consists only of detox• Treatment may be followed with a course of antipsychotic medications or

barbiturates • Krokodil addicts are given strong tranquilizers while they detox

• Any sort of psychological evaluation with supplementary behavioral therapy is rare

• Addicts are also rarely taught about how to live a drug-free lifestyle after detox

• Treatment centers that offer more extensive treatment likely use hypnosis to implant the idea if the addict uses drugs again, they will die

OUTLOOK FOR USERS SEEKING TREATMENT

• Rehab centers in Russia resemble jails more than treatment facilities • Patients may be shackled to beds or placed in cells for the duration of

“treatment”• Only about 1/3 of Russia has treatment facilities at all

• Some studies show that about 90% of addicts relapse within a year after treatment

WRAPPING IT UP

• Desomorphine is a potent semi-synthetic opioid that was invented in the U.S. in 1932, but deemed too addictive for professional use.

• Once desomorphine makes it into the bloodstream, it is enzymatically converted into morphine. Morphine binds to a G-protein receptor where it turns on the signaling pathway and causes both analgesic and sedative effects.

• Krokodil is a home-cooked version of desomorphine which started to appear Russia in the early 2000’s.

• Krokodil is used as a substitution for heroin; called “poor man’s heroin”. Heroin is expensive and can be hard to obtain in Russia.

WRAPPING IT UP• Krokodil is crudely made from codeine, iodine,

red phosphorous, and other toxic chemicals. The mixture is hardly purified and extremely toxic.

• Krokodil addicts experience gangrene leading to amputation, tissue necrosis, organ failure, and often death within 1-2 years.

• Krokodil users in Russia have a bleak outlook. Treatment programs are hard to come by and rarely effective.

• The Russian government has recently opened their eyes to the epidemic, but much more needs to be done in order to successfully help citizens with severe drug addictions to toxic drugs like krokodil.

Himmelsbach, C.K. “Studies of certain addiction characteristics of (a) dihydrommorphine (“paramorphan”), (b) dihydrodesoxymorphine-d (“deso-morphine”), (c) dihydrodesoxycodeine-d (“desocodeine”), and (d) methyldihydro-morphinone (“metopon”).” Journal of Pharmacology and Experimental Therapeutics 67.2 (1939): 2239-249.

Wright, C. and Barbour, F. A. “The respiratory effects of morphine, codeine and related substances V> compounds derived from morphine and dihydromorphine by substitution in the 6-carbon

position.” Journal of Pharmacology and Experimental Therapeutics 61.4 (1937): 422-439.

Savchuk, S.A., Barsegyan, S.S., Barsegyan, I.B. “Chromatographic study of expert and biological samples containing desomorphine.” Journal of Analytical Chemistry 63.4 (2008): 361-370.

Lee, L.E. “Studies of morphine, codeine, and their derivatives XVI. Clinical studies of morphine, methyldihydro-morphinone (metopon) and dihydrodesoxy-morphine-d (desomorphine).” Journal of Pharmacology and Experimental Therapeutics 78.4 (1943): 375-385.

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