Neurotransmitter


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:

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Michael Jackson

Michael Jackson

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

Regardless of the final legal outcomes, it is sad that Michael Jackson was killed by inappropriate use of sedative drugs.  The ruling that his death was a homicide is suggestive of negligence and perhaps poor understanding of how drugs work.

It seems that MJ was taking a number of different drugs to help with his sleeping problems.  His doctor was using lorazepam and midazolam in addition to propofol to help MJ sleep but he was finding that each drug alone or in combination was not producing the desired results.  Lorazepan and midazolam are both Valium like drugs that can be used as anti-anxiety and sedative drugs.  They can be taken in pill form so the safety factor in terms of an overdose is reasonably good.  It is difficult to overdose accidentally.  Propofol can only be administered intravenously, so the risk for an accidental overdose is much greater with this drug.

A pharmacology lesson comes from a discussion of how these drugs work on the brain to produce their sedative effect.  All of these drugs act at receptors for the neurotransmitter GABA. GABA, lorazepam, midazolam and propofol all act to turn off or inhibit neuronal activity.  When we are talking about neurons in the parts of the brain that are responsible for anxiety, this is good as that is where these drugs produce their sedative actions.  However, when the neurons that control breathing or the heart beat are affected that is where an overdose becomes an issue.

It looks like drug tolerance may have played a big role in what happened to MJ.  His physician was administering lorazepam, midazolam and propofol but finding that they were not working well.  This is because each drug acts at the same site and the brain adapts to the continued presence of the drug.  The drugs become less effective over time and more and more drug is required to get to the same therapeutic effect.  As higher and higher doses are given, an overdose becomes more and more likely.

A beneficial strategy would be to use a sedative drug or drugs that act through mechanisms that are different from those used by lorazepam, midazolam and propofol.  There would be no tolerance to the new drugs and lower and safer dose could be used.  Knowledge of this basic pharmacological principle might have reduced the overdose risk for the King of Pop.

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