Drug Addiction


“I don’t need help because if I can’t help myself I can’t be helped.” --Amy Winehouse

“Amy Winehouse found dead at her London flat…autopsy inconclusive…toxicology results expected in two to four weeks.” 

by Jane Maddox, Ph.D., Assistant Professor
Department of Pharmacology and Toxicology

Why do forensic toxicology results take so long? There are several reasons:

Multiple samples must be tested: blood, stomach contents, and urine are commonly first taken, but other tissues such as liver, brain, kidney, and vitreous humor of the eye may also be sampled.

If there are no obvious signs or symptoms linked to specific drugs or toxins observed at the time of death, testing for many different toxic substances must occur.

The tests must identify and quantify a wide repertoire of both legally prescribed drugs and illicit substances to determine if either any single drug or combination of drugs could have been the cause of death.

The initial tests would likely be immunoassays to screen for a wide variety of drugs suspected as the cause of death. These tests use antibodies to detect known drugs, but they can only measure a predetermined set of substances; therefore, if a new or unknown drug has been taken, it can be missed. Other analyses, such as mass spectrometry (that can identify unknown toxic substances) must also be performed.  Mass spectrometry is very sensitive and specific, but it also takes more time to complete.

Once potentially toxic substances have been detected, the concentrations in the sample must be compared with clinical data to determine if the dose, or combination of doses, was high enough to be lethal. In addition, samples may be retested in the same laboratory or sent to a second laboratory for confirmation. Again, these tests take more time. Confirmatory tests are important for several reasons: 1) to ensure scientific integrity of the data, 2) to defend against potential legal issues involved in cause of death, particularly in the case of a celebrity death.

As for the death of Amy Winehouse, it is complicated.

She was alone at the time of death, so no symptoms were observed, and it was reported that no drugs or paraphernalia were found on the premises. Therefore, important clues to direct the toxicology testing were lacking and the search could take some time to complete.

nicotine replacement therapy image

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Quitting cold turkey is a common regimen for kicking the cigarette smoking/nicotine habit.  Cold turkey does work for many cigarette smokers.  However, there are also many smokers who find that quitting is easy because they have done it hundreds of times.

Nicotine replacement therapy (NRT) is a common treatment for smokers in this latter category.  NRT comes in nasal sprays (very messy), chewing gum and “the patch”.  NRT involves a step down strategy over a 8-12 week period where the smoker gives up cigarettes and initially goes on a high dose nicotine treatment for 2-3 weeks followed by successive 2-3 week nicotine dose reductions.  This strategy is designed to gradually reduce the nicotine dependence and uncomfortable withdrawal symptoms (irritability, craving, disruption of sleep, etc.) until smokers no longer crave nicotine.  Studies have shown that NRT doubles the smoker’s chances of quitting by the end of the 12 week period although the success rate is still not great.  In placebo controlled studies, NRT produces about a 40% success rate while subjects on the placebo treatment quit about 20% of the time.  The big problem is that 80-90% of the quitters relapse in about 1 year. Current Food and Drug Administration (FDA) approval for NRT indicates a maximum 12 week treatment.

Part of the problem with cigarette smoking/nicotine addiction is the behavioral aspect of the addiction.  For example, the post meal coffee and cigarette is a very satisfying experience for smokers and there are strong social reinforcements associated with several smokers sharing this experience.  Studies have shown that even crack cocaine addiction has a strong behavioral-social component to the drug smoking experience and addiction.  So, unless the cigarette smoker changes his or her friends and family the smoker will continue to be exposed to the drug (nicotine)-related cues.

Drug addiction therapists and the FDA are beginning to re-think the 12 week limitation on NRT.  Nicotine raises blood pressure in some individuals but overall the data indicate that nicotine itself is not particularly dangerous to your health.  Cigarette smoking is clearly dangerous to your health as cigarette smoke contains an array of toxic chemicals.

Cigarette smoking is the major cause of lung cancer and it is also a major cause of deadly cardiovascular diseases such as high blood pressure, clogged arteries, heart attacks and strokes.  At this time, the long-term risks of NRT have not been studied in large groups of subjects.  However, the risks of cigarette smoking are unambiguous.  About 20% of Americans are cigarette smokers; this translates into 62 million people who are at great risk for lung cancer and cardiovascular disease which places a huge burden on our healthcare system.  It may be time to permit long-term NRT in an effort to reduce cigarette smoking relapse rates.  Of course this must be done with mechanisms in place to carefully monitor any unanticipated adverse effects that might appear when large numbers of people are using long-term NRT to kick the habit.

methylenedioxypyrovalerone

methylenedioxypyrovalerone

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

There has been a recent surge in reports of use and abuse of bath salts as psychoactive drugs that provide a cheap and easily accessible “high” (see for example: ‘Bath Salts’ A Growing Drug Problem, Officials Say‘).

There are many bath salts provided by different commercial suppliers and many of these products contain mephedrone and methylenedioxypyrovalerone.  Subjects abusing these products have reported psychedelic experiences and amphetamine-like stimulant responses (see links below).

Abusers have also reported episodes of self-mutilation while under the influence of these substances.  There is now a growing movement to ban mephedrone and methylenedioxypyrovalerone but the Food and Drug Administration reports that it will take sometime before the regulations can be developed and implemented.

What are mephedrone and methylenedioxypyrovalerone (MDPV) and how do they produce their psychostimulant effects?

Mephedrone (4-methylmethcathinone) is derived from cathionine, the active ingredient in the African Khat plant (SpringerLink – Psychopharmacology, Online First™).  Although mephedrone is a relatively recent addition to the drug of abuse portfolio in the U.S. it has been popular for sometime in the United Kingdom.  Cathionine and mephedrone have amphetamine-like effects on the brain and the peripheral nervous system.  These effects include stimulation of release of the neurotransmitters dopamine and norepinephrine in the brain.  Dopamine is a neurotransmitter in the brain’s reward pathways while norepinephrine is a neurotransmitter in brain areas that control attention and appetite.  These effects account for the addictive (reward), stimulant and appetite suppressing properties of amphetamine-like drugs.  Mephedrone users also report rapid heart rate and this effect is caused by norepinephrine release from the nerves that supply the heart.  Norepinephrine speeds up heart rate.

bath salts

Methylenedioxypyrovalerone is contained in some bath salts - and is easily obtained via the internet

MDPV is also a cathionine derivative with pharmacological properties similar to mephedrone.  Both of these substances can be purchased over the internet, but recent analysis of these substances from different suppliers has revealed a wide range of purity.  This is part of the danger associated with mephedrone and MDPV abuse, the buyer is never quite sure what he/she is purchasing and ingesting.  Another substantial concern is that the interaction of these drugs with other drugs of abuse is unknown.  This is a problem because most drug abusers or polysubstance abusers.  Drug-drug interactions can cause unpredictable psychoactive or toxic responses.

So, clichés are clichés for a reason: let the buyer beware.

Additional information:

by James J. Galligan,  Ph.D., Associate  Chair,
Department of Pharmacology and  Toxicology

Cigarette smoking is one of the most difficult addictions to quit.  This is partly because nicotine so effectively stimulates the brain’s dopamine reward pathway and partly because cigarettes are so accessible.  The costs to individuals and to society associated with nicotine addiction are enormous.  These costs include shortened life spans, reduced quality of life due to a decline in health and also increased healthcare expenses.  There is great interest in developing treatments that would help nicotine addiction subjects to kick the habit.  There are several choices available right now. These include “The Patch”, Zyban/Wellbutrin (buproprion) and Chantix (varenicline).

The Patch is a step down system in which the individual applies nicotine containing patches to the skin.  The nicotine is absorbed from the patch and the nicotine supplied by this approach reduces the craving for cigarettes.  Over several weeks, the individual reduced the “dose” of nicotine until they no longer experience nicotine cravings.

buproprionBuproprion is a complicated drug that acts as an antagonist for the receptors for nicotine and it is a dopamine and norepinephrine reuptake inhibitor.  Buproprion blocks the rewarding actions of nicotine by blocking the nicotinic receptor.  Buproprion also activates the endogenous reward pathway by increasing the availability of norepinephrine and dopamine in this pathway.

Varenicline

Varenicline is also an antagonist of the nicotinic receptor in the reward pathway in the brain.  These drugs all reduce the reward associated with cigarette smoking and this makes it easier to kick the habit.  These drug treatments all have reasonable success rates with up to half of the subjects off cigarettes after 4-12 weeks of treatment.  However, the relapse rate is high after the smoking cessation treatment is stopped and about 90% of people are back on the cigarettes at 1 year.

The problem described above has spurred interest in the development of nicotine vaccines.  This requires multiple nicotine treatments which activate the immune system to produce antibodies against nicotine.  This is an extremely useful strategy as the treated individual becomes immune to the rewarding effects of nicotine.  Antibodies bind to nicotine preventing its movement into the brain where nicotine acts to stimulate the reward system.  Relapse rates would be lower as the individual is permanently immunized against nicotine.  Recent clinical trials of NicVax, a nicotine vaccine, have yielded very positive results (http://www.cnn.com/2010/HEALTH/04/21/nicotine.vaccine.nicvax/index.html) and treated subjects have been able to maintain abstinence much longer than placebo treated groups.

These preliminary results are promising but the outcome of the full trial is still about 1 year away.  If the data from the final study match data from the preliminary results then it may be possible to immunize current cigarette smokers with the goal of getting them to kick the habit in the long-term.

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