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Reinforced toxicity

More neurons are killed by using crack than by using cocaine



Smoking crack — a mixture of cocaine paste, baking soda and water — is more damaging to neurons than snorting pure cocaine. That is the conclusion reached by a group of São Paulo researchers led by Tania Marcourakis of the University of São Paulo (USP) School of Pharmaceutical Sciences, who since 2007 has been studying the effect of these drugs on brain cells. The negative effects of crack usage are more potent, because the individual inhales not just the cocaine, an alkaloid, but also an ester known as methylecgonidine or simply AEME. There is little data about the effects of the ester, which is produced when cocaine is burned at high temperatures and may cause, as the study suggests, the death of neurons.

The study was conducted on cell cultures of the hippocampus of rats exposed to various concentrations of ester and alkaloid, alone and in combination. The hippocampus is involved in the learning process and is rich in muscarinic cholinergic receptors that bind to the acetylcholine neurotransmitter, which is important for solidifying  memory. “We found that when neurons come into contact with cocaine and AEME for a period of 48 hours, there is a neurotoxic effect that is far greater than when the neurons are exposed to each of these substances individually,” says Marcourakis. Neurotoxicity occurs through different mechanisms. Cocaine induces neuronal death in two ways: by necrosis — the cell undergoes a sort of inflammation, swells and bursts, spilling its contents — and apoptosis, a programmed cell death in which the nucleus of the cell fragments, forming small bodies that are phagocytosed by the body’s immune cells. AEME only causes cell death by apoptosis. With support from FAPESP, preliminary results of the study were published in the April 2012 issue of the journal Toxicological Sciences.

The devastation in brain cells caused by crack use is related to the amount and frequency of use, because the ester remains in the body for a prolonged period of time. “The cumulative effect of AEME has not yet been evaluated. We found, however, that exposing a culture of neurons to the ester for 24 to 48 hours kills these cells. Whether or not this neurotoxicity can lead to neurodegeneration is a question we cannot answer right now,” says Marcourakis.

The effects of crack are quickly felt by the brain that experiences a short-lived pleasurable sensation. This leads users to increase the frequency of drug use and dependency develops quickly. AEME’s production during the act of smoking the drug seems to reinforce the user’s dependency. Cocaine inhibits the reuptake of dopamine, a neurotransmitter responsible for feelings of pleasure, and increases its concentration in the synaptic cleft, which is the communication point between two neurons. This mechanism is responsible for its stimulating effects. “Our theory is that AEME binds to type M5 muscarinic receptors in the ventral tegmental area [group of neurons located in the midbrain, the part of the brain related to vision, hearing, motor control, sleep and wakefulness and temperature control],” says Marcourakis. “This would stimulate the release of dopamine in the nucleus accumbens [brain structure linked to the feeling of pleasure], enhancing the process of cocaine dependency.” This theory will be tested at Vanderbilt University in the United States by Raphael Caio Tamborelli Garcia, a PhD student. The effects of cocaine on the nucleus are already known. “However, research shows that in the case of crack, there’s something else,” says Cleopatra da Silva Planeta of the São Paulo State University (Unesp) School of Pharmaceutical Sciences in the city of Araraquara.

Second largest market
Cocaine use, in its intranasal form or as a crack mixture to be smoked, has increased dramatically in Brazil: the country is already the second largest global consumer of the drug, with 2.6 million users, a third of them dependent on crack. These figures were collected by the Second National Survey of Alcohol and Drugs (Lenad), conducted by the National Institute of Public Policy for Alcohol and Other Drugs (Inpad) at the Federal University of São Paulo (Unifesp) with funding from FAPESP. “We have a larger consumer market than all of Europe and Latin America combined. We are second only to the United States,” says Ronaldo Laranjeira, Inpad’s coordinator.

Brazil holds this prominent position because of the drug’s low price. Here it costs a tenth of the US market value and one twentieth of the price charged in Europe, according to the Unifesp researcher. The proximity of the major cocaine producers — Colombia, Peru and Bolivia — and a vast drug distribution system in Brazil are other factors that favor its high consumption. The distribution network, made up of small dealers, is extremely efficient: consumption is highest in the Southeast, with 45% of users, but cocaine and crack use is found in the Northeast (27%), North and Midwest (10%) and South (7%). “This makes control much more difficult,” he says.

Cocaine used nasally is the most common form of consumption. According to research, 4% of the adult population has tried it. Two million Brazilians have used crack at least once in their lifetime and one in every 100 adults has smoked this substance within the last year, which exposes them to the double risks of cocaine and the AEME ester, also according to the survey by Unifesp. Almost half of all users tried cocaine for the first time before the age of 18.

The Health Ministry and the São Paulo state government have invested in the treatment of addicted individuals. “The state of São Paulo has pledged to expand the number of hospital beds in specialized clinics to 3700,” says Laranjeira. The numbers, however, leave no doubt that Brazil has ceased to be a transit country and has now become a drug consumer, which demands strong action together with drug producing areas. “We must adopt a policy of negotiating with these countries, since we are dealing with a production activity that represents a significant portion of GDP. That agreement would involve bilateral and multilateral relationships, given that we do not have the resources to close the borders.”

Scientific article
GARCIA, R. C. et al. The neurotoxicity of anhydroecgonine methyl ester, a crack cocaine pyrolysis product. Toxicological Sciences. v. 128, p. 223-34, July 2012.

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