by Roseann Vorce, Ph.D., 
Department of Pharmacology and Toxicology
Michigan State University 

In Florida, a naked man under the influence of “bath salts” is discovered eating the face of a homeless person, in a public place and in broad daylight.  A policeman’s bullet barely slowed him down, and he stopped only when killed by another bullet.  In Michigan, a young adult with an appetite for smoking “K2-Spice” recruited a friend to help him kill his family.  They bludgeoned the father to death and severely injured the mother and brother with baseball bats.  What the heck is going on?

The short answer is that a new category of psychoactive agents has appeared on the drug scene.  Dubbed “SLIDs” (Synthetic Legal Intoxicating Drugs) by a group at the Cleveland Clinic, these recreational pharmaceutical compounds generally are legal, easy to obtain, and relatively cheap, but they exert powerful effects on the central nervous system.  Use of SLIDs has been linked to many reports of behavior that can only be described as bizarre.  People under the influence of SLIDs experience a wide spectrum of effects, including hallucinations, delusions, seizures, hyperthermia, and cardiovascular crises.  Legislators are scrambling to make SLIDs illegal, and new legislation is being enacted around the country.

The subset of SLIDs known as bath salts were discussed in this forum earlier.  Today’s blog will introduce the synthetic cannabinoids, more commonly known as K2-Spice.

 Synthetic Cannabinoids

The synthetic cannabinoids comprise a group of related compounds that exert psychoactive effects similar to those produced by marijuana.  Known as K2, Spice, and many other names, these compounds often are sold as herbal incense in specialty shops and on the internet.  However, the synthetic cannabinoids are not found in nature, but are created in the laboratory and sprayed on various dried herbs.  The synthetic compounds are related to the primary psychoactive ingredient of marijuana, delta-9-tetrahydrocannabinol (THC).  THC is produced naturally by the hemp plant, Cannabis sativa, also known as marijuana.  When the leaves and buds of the hemp plant are smoked or ingested, THC is absorbed and produces the characteristic effects of the natural plant, including a sense of well-being and altered sensory perception.

The pharmacological effects of THC are mediated by cannabinoid receptors.  Because THC is only a partial agonist at the cannabinoid receptors, the effects of the natural compound are limited.  Regardless of the amount of THC absorbed, the receptors can never be fully activated by marijuana.  In contrast, the synthetic cannabinoids are full agonists, capable of producing effects that are much more intense than those of natural THC.  Unfortunately, the greater efficacy of the synthetic cannabinoids also causes more severe adverse effects.  Synthetic cannabinoids have been reported to cause dysphoria, agitation, anxiety, and paranoia, as well as adverse effects on the cardiovascular and nervous systems (elevated blood pressure, increased heart rate, psychosis, and seizures).  The severity of adverse effects caused by the synthetic cannabinoids is reflected in the increased incidence of emergency room visits and queries to poison control centers following use of these drugs.

Barriers to Legislative Action

The social and medical costs of SLIDs are substantial.  Legal loopholes have made it difficult to control the manufacture and distribution of these designer drugs.  Although SLIDs are very powerful drugs, they are not marketed as drugs and typically are labeled, “Not for human consumption.”  This deceptive practice has allowed the manufacturers and dealers of SLIDs to avoid regulation of their products.  Legislators have made some of these compounds illegal, but a simple re-design of the drug structure or preparation of a different salt allows manufacturers to skirt the law.  In addition, detection and quantification of SLIDs remains a challenge due to their structural diversity.  This situation has left analytic chemists scrambling to develop validated methods to analyze multiple chemical species simultaneously.

Recently, legislation was proposed in Michigan (Senate Bill 1082)  [signed into law 6/19/2012 by Gov. Rick Snyder] that will outlaw all derivates of synthetic cannabinoids, as well as variations of many other illicit drugs.  The bill was written to capture the predictable chemical changes that manufacturers are likely to make so that they can comply with current laws while continuing to supply SLIDs to consumers.  By using wording that covers a broad range of chemical entities, legislators hope to prevent manufacturers from continuously creating and selling new versions of illegal drugs.

In addition to Michigan, many other states have adopted or are considering legislation to outlaw derivatives of SLIDs.  Although legislation at the state level will not stop internet sales of SLIDs, it will keep K2-Spice, bath salts, and their pharmacological relatives out of local convenience and specialty stores.

References:
Jerry J, Collins G, and Streem D.  Synthetic legal intoxicating drugs:  the emerging “incense” and “bath salt” phenomenon (2012) Cleve Clin J Med. 79:258-64. http://www.ccjm.org/content/79/4/258.long

Cox AO, Daw RC, Mason MD, Grabenauer M, Pande PG, Davis KH, Wiley JL, Stout PR, Thomas BF, Huffman JW (2012) Use of SPME-HS-GC-MS for the Analysis of Herbal Products Containing Synthetic Cannabinoids. J Anal Toxicol 36:293-302.

More information:

Advertisements
Whitney Houston (NY, 2009)

Whitney Houston (NY, 2009)

by Roseann Vorce, Ph.D., 
Department of Pharmacology and Toxicology
Michigan State University 

The headline was shocking – “Whitney Houston Found Dead”!  At age 48, the iconic singer was gone, found lifeless in a Beverly Hills hotel bathtub in a death scene we have seen too many times for the rich and famous.

Almost immediately, rumors began circulating that Houston’s death involved prescription drugs.  Some claimed that she died from a drug overdose; others claimed that she drowned while in a drug-induced stupor.  Toxicology test results will not be available for several weeks, and we might never know the full story.

Houston had a long history of substance abuse, and she had been in and out of drug rehabilitation programs for years.  With a history of using illegal drugs, many of which can cause death due to overdose, could Whitney Houston really have died due to the use of legally-obtained prescription drugs?

A vial of Xanax (alprazolam) was found in Houston’s hotel room, fueling speculation that prescription drugs caused her death.  Xanax is an anxiolytic drug that is commonly used to relieve stage fright, as well as anxiety caused by many other triggers.  A member of the benzodiazepine family of drugs, Xanax is one of the most frequently prescribed drugs in the United States.  The benzodiazepines work by increasing the effect of the endogenous neurotransmitter GABA (gamma-aminobutyric acid).  GABA is an important neurotransmitter that functions to inhibit activity in the central nervous system (CNS) by acting at the GABAA receptor.  The overall effect of GABA binding to the GABAA receptor is a dampening of activity in the CNS.  Benzodiazepines also bind to the GABAA receptor, where they enhance the effects of GABA on its receptor.  Because the activity of benzodiazepines relies on the presence of endogenous GABA, adverse effects of benzodiazepines are limited to impaired motor function (stumbling, difficulty walking), and drowsiness.  Only at very high doses can benzodiazepines cause death by inhibiting breathing.

Houston was seen drinking alcohol in the days prior to her death, and she reportedly indulged in champagne on the day she died.  Like the benzodiazepines, alcohol (ethanol) depresses the CNS.  Unlike the benzodiazepines, alcohol exerts a profound inhibitory effect on respiration.  The effects of ethanol poisoning include loss of consciousness (“passing out”), coma, and respiratory depression.  Ethanol poisoning is a medical emergency, and mechanical ventilation often is needed to maintain respiration.  Without treatment, a person suffering from ethanol poisoning can die.

Although Houston was reported to be drinking on the day of her death, there is no evidence that she was acutely intoxicated, nor is there evidence that she took an overdose of Xanax.  However, the combination of a benzodiazepine and alcohol can be deadly, even when the individual doses of each are not lethal.  Both alcohol and Xanax are CNS depressants, and their effects are additive.  Simultaneous administration of both can cause respiratory depression severe enough to stop breathing, a situation that ends in death if artificial ventilation is not initiated.  In contrast, some people die due to injuries suffered in accidents occurring secondary to intoxication with benzodiazepines and alcohol.  Automobile accidents, falls, and drowning in the bathtub all have been reported as the cause of death in people who are under the influence of benzodiazepines and alcohol.

We will not know the cause of Whitney Houston’s death until the results of toxicology testing are available. However, this story provides an opportunity to reinforce a warning that mixing prescription drugs with other drugs, including alcohol, can be very dangerous, and even deadly.

Additional links:

Hollenberg

Dr. Steven Brody, Ethel Brody, Dr. Paul Hollenberg & Dr. J.R. Haywood

Hollenberg Awarded 2011 Theodore M. Brody Lectureship

Paul F. Hollenberg, PhD, Professor and Chair of the Department of Pharmacology at the University of Michigan Medical School Ann Arbor, MI was awarded the 2011 Theodore M. Brody Lectureship on November 14, 2011.

The topic of his seminar was:

MECHANISM-BASED INACTIVATORS OF CYTOCHROME P450:PROBES OF STRUCTURE AND FUNCTION


Nancy Kanagy

Dr. Kenneth E. Moore & Dr. Nancy Kanagy

Nan Kanagy: 2011 Kenneth E. Moore Distinguished Alumna Awardee and Recipient of the “Golden Sovereign”

Nancy Kanagy, PhD, Professor, Dept of Physiology & Cell Biology

U of New Mexico Health Sciences Center – Albuquerque, NM was awarded the Kenneth E. Moore Distinguished Alumna Award on November 14, 2011.
Following her presentation, Dr. Gregory Fink presented the Golden Sovereign to Dr. Kanagy.

Erika SparkenbaughSparkenbaugh Earns PhD, Accepts Post-Doc Position at UNC

Congratulations to Erica Sparkenbaugh on completing the requirements for a PhD and the successful defense of her dissertation.

Dr. Sparkenbaugh conducted her PhD research in Dr. Robert Roth’s laboratory.  She will be moving to the University of North Carolina in Chapel Hill to start a postdoctoral fellowship in the McAllister Heart Institute.


“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.

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

Chantix (Varenicline) is one of the most popular smoking cessation drugs available by prescription.  However, a number of problems with this drug have been identified and this has led to many restrictions on its use.  These problems include an increased incidence of depression, suicidal thoughts, lightheadedness and fainting.

Results of a recent study published in the Canadian Medical Association Journal add another potential problem for Chantix.  These investigators conducted a meta-analysis of 14 published papers describing the beneficial and negative effects associated with Chantix when used to treat nicotine addiction.  The investigators included only double-blind randomized controlled trials in their analysis.  This means that subjects and investigators did not know who was receiving Chantix vs. placebo (simply a sugar pill with no active ingredients) and subjects were assigned to the Chantix or placebo group randomly.  This reduces the chance that subjects at risk for cardiovascular problems were assigned more frequently to the Chantix group.  The investigators analyzed data from 8,216 subjects.  Their study revealed a small but statistically significant increase in the risk for cardiovascular problems such as heart attacks or strokes in the subjects taking Chantix.  Although there was a difference, it was small.  In the Chantix group 52 of 4908 (1.06%) subjects experiences a so called adverse cardiovascular event while in the placebo group 27 of 3308 (0.82%) subjects experienced the same kind of event.

There are some points worth discussion here.  Firstly, it is not surprising that Chantix might be associated with cardiovascular complications.  Chantix is a nicotine replacement therapy.  Therefore, Chantix shares many of the same pharmacological actions of nicotine.  Cigarette smoking does increase the risk of cardiovascular disease partly because cigarette smoke contains nicotine (cigarette smoke also contains carbon monoxide and other toxins which are not present with Chantix).  Nicotine increases blood pressure and increase blood clots which can cause heart attacks and strokes and Chantix may do this as well.  Secondly, although the increased risk for adverse events in the Chantix group was small, the overall sample size was also small (<5,000 subjects).  Worldwide, there are millions of people using Chantix to help kick the smoking habit and therefor a much larger number of patients might be at risk worldwide.

Finally, it is important to remember that all drugs cause side effects (some worse than others).  When deciding whether or not a drug should be used, the doctor and patient must consider the risk vs. the benefit.  Chantix might produce a small increase in the risk for a heart attack or stroke in a patient trying to kick the nicotine habit.  But, what is the heart attack/stroke risk for that patient if he/she continues to smoke?  Many smokers become former smokers without the need for drugs like Chantix but there are also many smokers who have quit hundreds of times.  This is the subset of people who are most likely to benefit from nicotine replacement treatments.  Larger studies will likely reveal the real risk/benefit ratio of Chantix when used to treat nicotine addiction.

In the meantime, the wise person will discuss these issues with their doctor before using Chantix to help kick the smoking habit.

 

Additional information available can be found at:

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

Nicotine is a highly addictive drug and kicking the smoking habit has proven to be extremely difficult for many cigarette smokers.

Several smoking cessation strategies work reasonably well in the short term (3 months or so) but relapse rates are greater than 80% after 1 year.  There are a variety of reasons why smokers relapse but a strong relapse predictor is body weight gain, particularly in women.

Nicotine does decrease body weight and it does so by several mechanisms.  Nicotine acts in the brain to inhibit the brain regions that regulate appetite.  Nicotine also acts on fat cells to stimulate fat breakdown and it also stimulates energy expenditure (metabolism) by cells throughout the body.  Without nicotine onboard, appetite increases, fat breakdown and metabolism decrease and before you know it, the ex-smoker has put on 10 or more pounds.  After a peak in the mirror, the ex-smoker becomes a former ex-smoker.  If there was some way to prevent the weight gain, smoking relapse rates would likely fall and this would be beneficial for the individual smoker and for the overall health profile of the U.S population.

Science Magazine cover

A new study published in Science magazine may provide some hope that the appetite and body weight gain can becontrolled in the abstinent smoker.  These studies were done in mice where food intake and body weight were monitored after treatments which stimulated or blocked receptors for nicotine were tested.

Nicotine does have specific targets (receptors) in the brain where it produces its addictive actions.  The nicotinic receptors are found on neurons in the ventral tegmental area that use dopamine as a neurotransmitter and these neurons are in the reward pathways in the brain.  However, receptors for nicotine are also found in a region of the brain called the hypothalamus which is responsible for regulating appetite (among other things).  The study in Science revealed that the nicotinic receptors were found on a subset of neurons called POMC neurons and nicotine and a related drug activated these neurons.  POMC is an abbreviation for a protein known as pro-opiomelanacortin.  This in an interesting protein because it breaks down into three important smaller proteins: endorphin (the body’s natural opiate), melanocortin and adrenoccorticotrophin (which stimulates the adrenal gland).  The connection between endorphin and adrenocorticotrophin and nicotine induced appetite regulation was not investigated in this study.  However, it looks like melanocortin may be a key player here because when receptors for melanocortin were “knocked down” nicotine was no longer able to suppress feeding in these mice.

These studies were done in mice and there is a long way to go before these results can be translated into safe and effective treatments for nicotine addiction in human smokers.

These studies were also done in nicotine naïve mice; they were not nicotine addicted.  It is known that nicotine changes the nervous system in nicotine-addicted mice and humans so the role of melanocortin in appetite regulation needs to be studied in nicotine addicted mice.  However, these studies do provide new and important data about the complex mechanisms that regulate appetite and feeding behaviors and how these mechanisms may overlap with the reward pathways in the brain.  This could eventually lead to effective suppression of appetite in nicotine abstinent smokers leading to more appealing reflections in the mirror.

by James J. Galligan, Ph.D., Associate Chair,2c-i image from wikipedia
Department of Pharmacology and Toxicology

There was a recent news story about 1 death and several hospitalizations that might have resulted from the use of a drug known as 2C-I.  This happened after a spring break house party in suburban Minneapolis.

What is 2C-I?  2C-I is 2,5-dimethoxy-4-iodophenethylamine.  The key part of this chemical name is “phenylethylamine”.  This is important because the brain neurotransmitters, norepinephrine and dopamine are also phenylethylamines.  The brain neurotransmitter, serotonin is also very similar in chemical structure to the phenylethylamines.  Many legal and illegal drugs are also phenylethyamines including: amphetamine, methamphetamine and MDMA (“Ecstasy).

Let’s first discuss methamphetamine and amphetamine.  These drugs are stimulant drugs as they increase alertness.  This effect is caused by activation of the norepinephrine systems in the brain.  Amphetamine and methamphetamine also activate norepinephrine nerves that supply the heart and blood vessels.  Amphetamine and methamphetamine stimulate the heart to beat faster and they contract blood vessels.  These effects cause an increase in blood pressure and they also make some people susceptible to altered heart rhythms and potential heart attacks.  Both drugs cause pleasant feelings (euphoria) and this is what makes them addictive.  The euphoria is caused by activation of dopamine systems in the brain.

While MDMA is similar to amphetamine and methamphetamine in chemical structure, it has little activity at the dopamine and norepineprhine systems.  Instead, MDMA prefers to interact with the serotonin system.  The serotonin system is partly responsible for feelings of anxiety and also for monitoring visual and auditory (sound) sensations.  This is why MDMA is classified as a hallucinogen (like LSD-25) but also why it is used as a “club drug”.  MDMA reduces anxiety and increases feelings of interpersonal warmth and empathy.

Back to 2C-I:

Although 2-CI is a phenylethylamine, it does not have the same level of activity at the norepinephrine or dopamine systems as amphetamine and methamphetamine.  2C-I is more like MDMA in its pharmacological effects as 2C-I prefers the serotonin systems.  So, 2C-I can produce hallucinations (like LSD-25) and also feelings of interpersonal warmth and empathy.

LSD-25 is a Schedule I drug and this means it has no legitimate medical use.  MDMA does have some legitimate medical uses but it is still highly regulated and it is illegal to sell these drugs over the internet.  2C-I is chemically different from these regulated drugs and therefore it does not fall under the same stringent controls.  This makes it possible to sell 2C-I through online chemical suppliers or as a research chemical.  The problems arise in unknown quality control in producing the chemical so it difficult to know how much of the active drug is actually in the sample increasing the risk of overdose.  In addition, MDMA can be toxic to serotonin neurons in the brain and 2C-I may also kill serotonin neurons.

Let the buyer beware!

  • Additional Pages

  • Online MS / PSM Programs

    Deadline for Fall 2014 applications to the online MS / PSM programs is June 1st, 2014. For additional information, contact the Student Office at phmtox.ms@msu.edu or 517/884-3553.

    Visit our site for more information.

  • PhmTox @ Twitter

    Error: Twitter did not respond. Please wait a few minutes and refresh this page.

  • Enter your email address to subscribe to this blog and receive notifications of new posts by email.

    Join 612 other followers

  • Categories

  • Archives