Desomorphine, also known as 4,5-α-Epoxy-17-methylmorphinan-3-ol, is an opioid substance derived from Morphine. It has widely become the core agent of a homemade drug, Krokodil, thanks to its low cost budget and easy availability, especially in Russia, even if some cases of abuse have been already registered in northen Italy and U.S.A.
Krokodil history
Desomorphine was firstly synthesized in 1932 in the United States and used in Switzerland under the brand name Permonid for the treatment of severe pain.
Russia, expecially the southern, has always been a scale for the transport of eroin from Afganistan to Europe, becoming the state with the widely number of toxicodependants all over the world. When the price of eroin erased, desomorphine took its place and was declared an illegal narcotic analgesic in 1998.
However, while codeine-containing drugs generally need a prescription for being bought, in Russia due to economical interest of a great pharmacological industry, they were sold freely until June 2012.
Krokodil synthesis and chemistry
Morphine is an alkaloid, which the methylation of the hydroxyl group shown in red produces Codeine, while replacing the both red and blue hydroxyl with –OCOCH3 group (acetylation) produces Heroin.
With the addiction of Thionyl Chloride to Codeine or 3-methylmorphine, we obtain α-Chlorocodide. After a process of catalytic reduction of the 7,8 double bond and the formation of Desocodeine, we get Desomorphine by demethylation.
For reference see the following link to Desomorphine and Desomorphine chemistry from "U.S. National Library of Medicine - Toxicology Data Network"
Clandestine manufacture of desomorphine involves two steps:
- the extraction of codeine from pharmaceutical products.
- the synthesis of desomorphine from the codeine.
The extraction of codeine from pharmaceutical product
In the homemade process , the extraction of codeine involves boiling 80-400mg of codeine source with organic solvents such as benzene or paint thinner that may contain lead, zinc or ferrous agents, adding a strong base such as lye and then an acidic solution such as hydrochloric acid to produce water soluble codeine salts that will reside in the aqueous layer.
Furthermore toxic nitrogen oxides fumes emerge from the drug when heated.
The synthesis of desomorphine from the codeine
The extracted codeine is mixed with iodine, hydrochloric acid, and red phosphorus, which is scraped from the striking surfaces on match boxe, to reduce the codeine to desocodeine.
Subsequently the desocodeine is demethylated into desomorphine in a one-pot synthesis (strategy to improve the efficiency of a chemical reaction where a reactant is subjected to successive chemical reactions in just one reactor). This process would save time and resources that may take only 45 minutes.
One-pot synthesis strongly increase damages due to the byproducts and leftovers produced in the process which are not removed.
The final product is a suspension that contains desomorphine as the psychoactive core, along with all other agents involved in the production process. The desomorphine content of Krokodil’s samples may range from traces to 75%.
For reference see the following link to Krokodil Production & Synthesis from "Erowid"
Krokodil’s effects
An essential point we have to notice about this drug is that the toxic role is principally due to the substances added in the reactions rather than the Desomorphine itself.
This is why we can divide this study in two different parts:
- The effect of desomorphine
- The effect of the additives
Desomorphine’s effects
Desomorphine’s effects are similar to morphine’s ones but the chemical structural differences renders desomorphine more lipophilic favoring penetration in the brain and leading to a faster onset and a shorter duration of action. It’s from 8 to 10 times stronger than morphine and with a major toxicity except for a decreased risk of nausea and respiratory depression.
As an opiod substance, it affects the oppiate receptors that we are going to describe.
Opioid receptors and their distribution
Four opioid receptors have been identified: Mu (μ), kappa (κ), delta (δ) and the opioid receptor like-1 (ORL1).
μ, κ, δ receptors show a high omology between them, while the second and the third extracellular loops are divergent and cause the ligand selectivity.
Μ receptors are located in brain as cortex and thalamus but also in the spinal cord, expecially substancia gelatinosa but also in intestinal tract.
Its activation effects are:
- analgesia expecially to sopraspinal level
- myosis
- respiratory depression
- euphoria
- reduced gastrointestinal motility
- possible vasodilation
Morphine-like opiates, interact with highest affinity with the μ-receptor.
K receptors are located in brain expecially in hypothalamus but most of all in the spinal cord in substancia gelatinosa.
Its activation effects are:
- analgesia expecially to spinal level
- myosis
- respiratory depression
- disphoria
δ receptors are located in brain expecially in pontine nuclei and amygdala.
Its activation effects are:
- analgesia
- antidepressant effects
- convulsant effects
ORL1 receptors are located in brain expecially in cortex, amygdala, hippocampus and hypothalamus, and also substancia gelatinosa.
Its activation effects are:
- anxiety
- depression
- appetite
For reference see the following link to Opioid receptors and their ligands from "U.S. National Library of Medicine- Pubmed"
Opioid receptors belong to metabotropic ones: thery are 7-transmembrane proteins that couple to inhibitory G-proteins.
Receptor signalling
After the activation by an endogenous (Endorphins, Enkephalins, Dynorphins) agonist, or by an exogenous agonists like morphine and their derivates the Gα and Gβγ subunits dissociate from one another and act on various intracellular effector pathways like the MAP Kinase pathway but the most important aspect of opioid receptor signal transduction relates to their ability to modulate calcium and potassium ion channels:
- Gα protein subunit interact with the G-protein gated inward rectifying potassium channel, Kir3
and inhibits tonic neural activity due to cellular hyperpolarization.
- the Gβγ subunit induce inhibition of calcium conductance contributing to the iperpolarization of cells. Moreover the acute administration of opioid agonists reduces Ca+2 content in synaptic vesicles, with compensatory upregulation of vesicular Ca+2 content during the development of opiate tolerance.
- receptors inhibits adenylyl cyclase activity and so cAMP-dependent Ca+2 influx is also reduced.
- then Arrestin molecules act on phosphorylated GPCRs to regulate their desensitization, sequestration, sorting and assist in determining receptor fate.
We can now shortly resume the side effects of opiates:
the peripheral side effects are constipation, urinary retention, hives, bronchospasm while the central side effects are a strong analgesia, sedation, respiratory depression, hypotension, nausea, miosis. Serious medical complications can include respiratory failure, allergic reactions, seizures, that joined to the physical and psychological dependency, can lead to death.
Tolerance and dependence
Tolerance to the effects of morphine is very quickly.
Tolerance develops with simple mechanism:
- the change of opioid receptor conformation due to phosphorylation
- the decoupling of receptors from G-proteins leading to receptor desensitization
- receptor internalization and/or receptor down-regulation reducing the number of available receptors.
Due to tolerance mechanism, the repeated use of any opiate requires increasing dose sto produce the same effect, leading to dependance.
Dependance
Morphine and its derivates activate the reward dopaminergic way.
Opioid receptors activation of the ventral tegmental area (mesencephalon), result in dopamine release in the nucleus accumbens that takes place in the basal forebrain rostral to the preoptic area of the hypothalamus.
The massive activation of dopaminergic receptors lead to an alterated gene expression in the mesocotical and mesolimbic projection, which the most important transcription factor involved is ΔFosB, a truncated splice variant of FosB, a proteins that can dimerize with proteins of the JUN family.
For reference see the following link to Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. from "U.S. National Library of Medicine- Pubmed"
The ΔFosB splice variant has been identified as playing a necessary and sufficient role in the development of many forms of behavioral plasticity and neuroplasticity involved in both behavioral addictions and drug addictions.
Toxico dependants abuse of it for the strong sensation of euphoria, sedation, and analgesia but also strong antidepressive, anxiolytic and antipsychotic effects.
When injected intravenously, the effects can be felt within seconds to minutes: a rapid euphoria is produced followed by a longer period of sedation lasting approximately 2 hours.
Withdrawal Symptoms
Cessation of dosing with morphine is not fatal by itself.
There are a six different stages:
- Stage I, 6 to 14 hours after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderate dysphoria
- Stage II, 14 to 18 hours after last dose: heavy perspiration, mild depression, crying, Rhinorrhea, dysphoria, and "yen sleep" that is a waking trance-like state
- Stage III, 16 to 24 hours after last dose: Rhinorrhea, dilated pupils, piloerection, muscle twitches, hot flashes, cold flashes, aching bones and muscles, loss of appetite, beginning of intestinal cramping
- Stage IV, 24 to 36 hours after last dose: Increase in all of the above including severe cramping and involuntary leg movements, loose stool, insomnia, elevation of blood pressure, increase in frequency of breathing, tachycardia, restlessness, nausea
- Stage V, 36 to 72 hours after last dose: Increase in the above, fetal position, vomiting, free and frequent liquid diarrhea, which sometimes can accelerate weight loss from 2 to 5 kg per 24 hours,
- Stage VI, after completion of above: Recovery of appetite and normal bowel function, symptoms in this stage are mostly psychological, but may also include increased sensitivity to pain, hypertension, colitis or other gastrointestinal afflictions related to motility.
Additives’ effects
The destructive effect of krokodil drug is only for a little part due to Desomorphin’s effects.
Street desomorphine carries additional potentially fatal risks associated with injecting impure chemicals into the body.
As told before, several chemical substances are added in the homemade formation of Desomorphine, leading to a impure and highly toxic drug.
The other additives are:
- Iodine
- Gasoline
- Paint thinner
- Red phosphorus
- Hydrochloric acid
- Tropicamide
The related tissue damages that all these substances cause have named this drug “flesh eating drug” or simply “Krokodil” for the similarity to his bite or for the similarity of skin, damaged by the drug use, to crocodile leather: skin becomes green, scaly and bumpy like a crocodile's.
As the Krokodil is subministred by intravenous injection, these additives and the highly acid pH (almost 3), lead to phlebitis, sepsis, destruction of heart valves.
The strong deteriotating substances gradually decline veins and vessels reaching tissues. Moreover, is quite easy not to inject it correctly in the vein, damaging directly the surrounding tissues.
This process leads to the formation of small like cigarette-burns, that rapidly increase their dimension causing infection, abscesses, pain, skin discoloration that turns to green and peeling (**scale-like skin**).
Thanks to iodine, muscles are deteriorated together with the soft tissues, going to necrosis and gangrene, often leaving uncovered bones.
High level of iodine can cause lacrimation and salivation, rhinitis, weakness, and skin eruption but also goiter, thyroid gland inflammation and cancer.
Getting several grams can cause fever, stomach pain, nausea, vomiting, diarrhea, weak pulse and coma.
For reference see the following link to Iodine from "U.S. Department of Health & Human Services"
High concentration of phosphorus also determines osteolytic deterioration of bones and loss of teeth: phosphorus leads to secretion of Parathormone by Parathyroids glands leading to the release of calcium from the large stock contained in the bone by osteoclasts.
Moreover, the gangrene also usually leads to bone infections (osteomyelitis) and often it requires amputations.
The face is compared to zombies’ ones: original structure of the jaw and facial bones is lost, meanwhile sores and ulcers on the forehead and skull appear as well as rotting ears, noses, lips, gums and loss of teeth.
In order to get other recreational effects, it is often added Tropicamide, also known as N-ethyl-3-hydroxy-2-phenyl-N- (pyridin-4-ylmethyl) propanamide, which is an anticholinergic drug prescribed as an ophthalmic solution to induce short-term mydriasis and cycloplegia.
Through intravenous injection; its effects last from 30 minutes to 6 hours and include slurred speech, persistent mydriasis, unconsciousness/unresponsiveness, hallucinations, psychomotor agitation, tachicardia.
For reference see the following link to Recreational misuse of tropicamide collyrium from "U.S. National Library of Medicine- Pubmed"
Users are at increased risk for exhaustion due to sleep deprivation, memory loss, and problems with speech.
Also increasing blood-borne virus transmission as HIV/HCV is due to needle sharing.
For reference see the following link to Krokodil drug from "Drugs.com"
Krokodil Withdrawal
Withdrawal is savage, much worse than heroin.
Heroin can cause sickness and pain for up to ten days but withdrawal from krokodil can result in a month of unbearable pain.
Extremely strong tranquilizers are used during withdrawal so the addict does not pass out from the pain. Doctors dealing with addicts say that this is the strongest level of addiction and the hardest to cure.
For reference see the following link to Krokodil withdrawal from "Narconon"
Conclusions
As the cost of heroin increased Krokodil became a more dangerous substitute: while heroin costs from £20 to £60 per dose, desomorphine can be “cooked” from codeine-based headache pills that cost £2 per pack.
Addiction is an obvious problem with krokodil use due to desomorphine high potency and short duration of effect. Frequent administration may lead to binge patterns that can last for days.
As with most opioids, death can occur at high doses because of respiratory depression.
Street desomorphine carries additional potentially fatal risks associated with injecting impure chemicals into the body.
But while the life expectancy of a heroin addict is four to seven years, life expectancy of a krokodil addict is just a year or rarely two.
Between 2009 and 2011, the amount of krokodil seized by law enforcement increased 23-fold. In just the first three months of 2011, 65 million doses were seized, making it the “The World's Deadliest Drug” as “Time” named it.
