Does Ketamine Cause Bladder Damage?

Special K and Cystitis.

Normally, Addiction Inbox steers clear of alarmist stories about drug use. A lifetime of wildly overstated verbiage about “false drugs,” as the Firesign Theatre comedy group once delightfully phrased it, has left me wary of drug scare stories. Even obvious cases, like Fetal Alcohol Spectrum Disorder and crack babies, are more nuanced problems than most coverage has alleged.

For years now, rumors about bladder problems in recreational users of ketamine have periodically surfaced. These stories go all the way back to the adventures of Dr. John Lilly, famous for dolphin research, as well as sensory deprivation experiments with LSD, ketamine, and other drugs (wildly overdramatized in the movie, “Altered States”). According to hipster lore, Lilly went through a long period of hourly ketamine ingestion in the 1970s, and ended his days in adult diapers, having lost control of his bladder due to ketamine damage.

To the best of my knowledge, this story has never been officially confirmed. But in the last two years, research has surfaced that tends to bolster the Lilly anecdote. What is disturbing is that today, unlike 40 years ago, ketamine has become a fairly common party drug among young users. The drug technically produces a state of “dissociative anesthesia.”  Treated like a hallucinogen, ketamine was originally a tranquilizer used in veterinary medicine. In 1970, the FDA approved the use of ketamine for humans for the maintenance of anesthesia.

The journey from horse tranquilizer to party drug has eluded drug researchers until quite recently. However, in early 2008, researchers sat up and took notice of a report published in BJU International, a urology journal. “The destruction of the lower urinary tract by ketamine abuse: a new syndrome?”

The report details the discovery by physicians in Hong Kong of 59 ketamine abusers who had been admitted to urology units in local hospitals from 2000 to 2007. Interstitial cystitis, also known as painful bladder syndrome, can vary from mild to severe, and its cause is often not known.  Symptoms include painful, frequent, or urgent urination. The researchers found that 71 % of the patients “showed various degrees of epithelial inflammation similar to that seen in chronic interstitial cystitis. All of 12 available bladder biopsies had histological features resembling those of interstitial cystitis.”

The authors conclude that “secondary renal damage can occur in severe cases, which might be irreversible, rendering patients dependent on dialysis.”

Scary stuff. If this were the only study available, it would be tempting to question the results. As it turns out, the Hong Kong study was neither the first nor the last. What is believed to be the first official report of the problem appeared in 2007 in Urology, documenting the case of nine Canadian ketamine users with bladder complications. The authors, affiliated with the University of Toronto, conclude: “As illicit ketamine becomes more easily available, ulcerative cystitis and potential long-term bladder sequelae related to its use may be a more prevalent problem confronting urologists.”

This year, similar reports from Bristol in the UK were published in Clinical Radiology. Researchers with the National Health Service and the Bristol Royal Infirmary discovered “a series of 23 patients, all with a history of ketamine abuse, who presented with severe lower urinary tract symptoms.”  Various imaging techniques revealed smaller bladder volume, bladder wall thickening, inflammation, urethral strictures, and other bladder pathologies. The patients all reported symptoms similar to those reported by the earlier Hong Kong ketamine users.

The report concludes that “many users are well aware, but are often not forthcoming with this information.” They also maintain that “the key to the effective management of ketamine-induced bladder pathology is early diagnosis.”

 Frequent recreational use of ketamine appears ill advised until more research can confirm the true scope of the problem.

Chu, P., Ma, W., Wong, S., Chu, R., Cheng, C., Wong, S., Tse, J., Lau, F., Yiu, M., & Man, C. (2008). The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU International, 102 (11), 1616-1622 DOI: 10.1111/j.1464-410X.2008.07920.x

Mason K, Cottrell AM, Corrigan AG, Gillatt DA, & Mitchelmore AE (2010). Ketamine-associated lower urinary tract destruction: a new radiological challenge. Clinical radiology, 65 (10), 795-800 PMID: 20797465

Graphics Credit: http://theintelhub.com/

Psychedelics Back in the Spotlight

But will it be any different this time?

Two papers on the use of psychedelics for the treatment of mood disorders surfaced last week in the prestigious journals Science and Nature. The articles have garnered a great deal of publicity, especially the results having to do with the effect of ketamine on depression. I cannot pretend to offer more insightful coverage than the posts and articles listed below have already done, but I do think it’s profitable to take a closer look at the Nature piece by Franz X. Vollenweider and Michael Kometer. This paper looked at both dissociative anesthetics, like PCP and ketamine, AND “classical hallucinogens,” like psilocybin and LSD.

Traditionally, LSD has been thought of as a relentlessly serotonin-active drug, while ketamine was more actively involved with NMDA and other glutamate receptors. There is accumulating evidence, the researchers believe, that a common mechanism undergirds the operations of both kinds of psychedelics. “Despite their different primary modes of action,” they write, “classical hallucinogens and dissociative anesthetics both modulate glutamatergic neurotransmission in the prefrontal-limbic circuitry that is implicated in the pathophysiology of mood disorders.”

It’s worth noting that Vollenweider and Kometer maintain that almost all depressed patients relapse within two weeks after a single dose of ketamine. In studies of patients with advanced cancer, say the authors, psilocybin improves mood just as effectively, and lasts longer, than ketamine.

While there are significant differences between the subjective effects of ketamine and LSD, there is also “a set of overlapping psychological experiences.” The two trips are different, but not completely different—they share effects such as distortion of perception, visual and auditory hallucinations, a sense that the boundaries of self have softened, and often an ecstatic experience or sense of profound unity. The serotonin-glutamate connection leads the authors to assert that “classical hallucinogens are potent modulators of prefrontal network activity that involves a complex interaction between the serotonin and glutamate systems in prefrontal circuits.”

Alternately, these drugs can trigger a classic “bad trip” in certain users--time, place, circumstance, and innate biology depending.  As the authors put it: “The same hallucinogen might produce a pleasurable loss of ego boundaries combined with feelings of oneness or might lead to a more psychotic ego dissolution that involves fear and paranoid ideation.”

And there you have it: In the case of psychedelics, there are certain extenuating factors which may forever limit the use of these substances for therapeutic purposes. The primary problem is that the drugs are clinically unreliable. With psychedelics, it is always, in a sense, the Lady or the Tiger.  “The strongly dissociative effects of ketamine may limit clinical use despite its reported efficacy,” the researchers conclude. Which is, I think, putting it mildly--and which brings the authors to suggest that pharmacology-assisted psychotherapy might require some tweaks.

Specifically, the hunt is now on for psychedelics that are, well, less psychedelic. In the same way that pharmacologists seek to dial down the euphoric effects of pain medication to lessen the chances for black market abuse, researchers are now looking for ways to tone down the mental fireworks often associated with the use of ketamine, LSD, or psilocybin, on the assumption that these represent nothing but unwanted side effects, rather than the core of the experience that alleviates depression, OCD, and addiction—at least for awhile. These drugs are among the most powerful mind-altering compounds on the planet. So good luck with that project. Studying the behavioral effects of these drugs in the first place is a bit like trying to pin down a writhing fire hose with a pair of tweezers.

Curing or successfully treating chronic ailments like depression and addiction with a power psychoactive medication is both an old and an exciting idea. The Nature opinion piece also documents studies, beginning in the 1960s, which showed that psilocybin and LSD were effective treatments for Obsessive-Compulsive Disorder (OCD).  Other studies have shown alleged successes using low-dose ketamine for heroin addiction. And some of the earliest LSD studies of all showed impressive results when LSD and psychotherapy were combined as a treatment for alcoholism.

 By 1965, the authors claim, there were more than 1,000 published clinical studies on the therapeutic effects of psychedelics.  But many, if not most, of the early studies were marred by procedural problems, lack of control groups, and the fact that researchers from a dozen different disciplines, representing a dozen different experimental methods, predictably emphasized different kinds of experiential results.  The authors suggest that novel neuroimaging techniques combined with an increased understanding of molecular mechanisms of action mean that it will be different this time. If the only real result of the ketamine studies is increased funding for research on psychedelic drugs after a long hiatus, that is still progress, and it’s long overdue.

Resources

David Biello, Scientific American

Maia Szalavitz, New Scientist

and MSN Health and Fitness

Scicurious at Neurotic Physiology

Neuroskeptic at Neuroskeptic

Eugene Rubin, Psychology Today

Jonah Lehrer at Frontal Cortex

Photo Credit: http://cherished79.wordpress.com/

Tracking Synthetic Highs

UN office monitors designer drug trade.

Produced by the United Nations Office on Drugs and Crime (UNODC), the Global SMART Update  (PDF) for October provides interim reports of emerging trends in synthetic drug use. The report does not concern itself with cocaine, heroin, marijuana, alcohol, or tobacco. “Unlike plant-based drugs,” says the report, “synthetic drugs are quickly evolving with new designer drugs appearing on the market each year.” The update deals primarily with amphetamine-type stimulants, but also includes newer designer drugs such as mephedrone, atypical synthetics like ketamine, synthetic opioids like fentanyl, and old standbys like LSD.

I have summarized some of the findings below:

The first methamphetamine lab in 15 years has been discovered in Japan. Japanese law enforcement seized a suspected residential methamphetamine laboratory outside of Tokyo, the first such seizure since 1995. Two Iranian nationals were arrested. Given the continuously high price of imported crystalline methamphetamine in Japan, there is an increased likelihood that more domestic manufacturers could emerge.

Record ketamine seizures and use has been reported by Taiwan province of China. The FDA reports that ketamine seizures in the first five months of 2010 alone totaled 1465 KG, nearly 300 KG more than last year. Concurrent increases in use were also noted.

The first methamphetamine laboratory in Turkey was discovered. Local media reported the seizure of the lab, in the southern part of the country. The facility reportedly planned to manufacture 100,000 tablets for retail sale at USD 13.40 apiece. In 2009, Turkey reported its first seizures of methamphetamine totaling 103 KG at Istanbul’s airport, which has become a transit point for methamphetamine traffic from Iran to markets in East Asia.

Law enforcement faces unique challenges when dealing with synthetic drug analogs. Customs officers at Prague’s Ruzyne airport reported arresting a Polish national for transporting a substance initially testing positive for ephedrone, a controlled synthetic stimulant. Confirmatory tests, however, revealed the substance to be mephedrone, an analogue not under international control. The event illustrates the challenges law enforcement face when encountering new synthetic substances not under national or international control.

Amphetamine breathalyzer tests may soon be possible, say Swedish researchers. The June issue of the Journal of Analytical Toxicology report reported that the first breath test for methamphetamine and amphetamine detection was successfully conducted in Sweden. Drugs in the exhaled breath are captured in a filter and analyzed using a combination of liquid chromatography and mass spectrometry. Experimental trials on amphetamine-dependent patients admitted to hospital urgency rooms for overdose provided the same results as traditional drug tests.

The U.S. is expanding controls on precursor chemicals for fentanyl and LSD. The Drug Enforcement Administration (DEA) has designated a compound called ANPP as a precursor chemical for fentanyl, an extremely potent synthetic analgesic. Earlier this year, the DEA proposed new controls over ergocristine, a chemical precursor sometimes used in the manufacture of LSD. Clandestine laboratories in the United States employ it as a substitute for ergotamine and ergometrine, both of which are already under international control.

The U.S. indicts 15 people in one of the largest MDMA busts ever. The U.S. Department of Justice announced that a federal grand jury indicted 15 men linked to one of the country's largest ecstasy manufacturing and trafficking rings. Two storage facilities were also seized during the investigation, yielding about 710,000 MDMA tablets. Law enforcement authorities seized more than 1.1 million tablets in all. Authorities believe that the group had been responsible for the distribution of hundreds of thousands of MDMA tablets each month.

Belize stops large shipments of methamphetamine precursors bound for Mexico. Customs authorities in Belize reportedly stopped two large shipments of phenylacetic acid (PAA), or roughly 46 metric tons. Phenylacetic acid can be used in the manufacture of methamphetamine. Reports suggest the chemical came from China and was ultimately destined for Mexico.

Graphics Credit: http://www.unodc.org/

A Few Words About Glutamate

Meet another major player in the biology of addiction.

The workhorse neurotransmitter glutamate, made from glutamine, the brain’s most abundant amino acid, has always been a tempting target for new drug development. Drugs that play off receptors for glutamate are already available, and more are in the pipeline. Drug companies have been working on new glutamate-modulating antianxiety drugs, and a glutamate-active drug called acamprosate, which works by occupying sites on glutamate (NMDA) receptors, has found limited use as a drug for alcohol withdrawal after dozens of clinical trials.

Glutamine detoxifies ammonia and combats hypoglycemia, among other things. It is also involved in carrying messages to brain regions involved with memory and learning. An excess of glutamine can cause neural damage and cell death, and it is a prime culprit in ALS, known as Lou Gehrig’s disease. In sodium salt form, as pictured---> it is monosodium glutamate, a potent food additive. About half of the brain’s neurons are glutamate-generating neurons. Glutamate receptors are dense in the prefrontal cortex, indicating an involvement with higher thought processes like reasoning and risk assessment. Drugs that boost glutamate levels in the brain can cause seizures. Glutamate does most of the damage when people have strokes.

The receptor for glutamate is called the N-methyl-D-aspartate (NMDA) receptor. Unfortunately, NMDA antagonists, which might have proven to be potent anti-craving drugs, cannot be used because they induce psychosis. (Dissociative drugs like PCP and ketamine are glutamate antagonists.) Dextromethorphan, the compound found in cough medicines like Robitussin and Romilar, is also a weak glutamate inhibitor. In overdose, it can induce psychotic states similar to those produced by PCP and ketamine. Ely Lilly and others have looked into glutamate-modulating antianxiety drugs, which might also serve as effective anti-craving medications for abstinent drug and alcohol addicts.

As Jason Socrates Bardi at the Scripps Research Institute writes: "Consumption of even small amounts of alcohol increases the amount of dopamine in the nucleus accumbens area of the brain—one of the so-called ‘reward centers.’ However, it is most likely that the GABA and glutamate receptors in some of the reward centers of the basal forebrain—particularly the nucleus accumbens and the amygdala—create a system of positive reinforcement.”

Glutamate receptors, then, are the “hidden” receptors that compliment dopamine and serotonin to produce the classic “buzz” of alcohol, and to varying degrees, other addictive drugs as well. Glutamate receptors in the hippocampus may also be involved in the memory of the buzz.


Writing in The Scientist in 2002, Tom Hollon made the argument that “glutamate's role in cocaine dependence is even more central than dopamine's.” Knockout mice lacking the glutamate receptor mGluR5, engineered at GlaxoSmithKline, proved indifferent to cocaine in a study published in Nature.

In an article for Neuropsychology in 2009, Peter Kalivas of the Medical University of South Carolina and coworkers further refined the notion of glutamine-related addictive triggers: "Cortico-striatal glutamate transmission has been implicated in both the initiation and expression of addiction related behaviors, such as locomotor sensitization and drug-seeking," Kalivas writes. "While glutamate transmission onto dopamine cells in the ventral tegmental area undergoes transient plasticity important for establishing addiction-related behaviors, glutamatergic plasticity in the nucleus accumbens is critical for the expression of these behaviors."

The same year, in Nature Reviews: Neuroscience, Kalivas laid out his “glutamate homeostasis hypothesis of addiction.”

A failure of the prefrontal cortex to control drug-seeking behaviors can be linked to an enduring imbalance between synaptic and non-synaptic glutamate, termed glutamate homeostasis. The imbalance in glutamate homeostasis engenders changes in neuroplasticity that impair communication between the prefrontal cortex and the nucleus accumbens. Some of these pathological changes are amenable to new glutamate- and neuroplasticity-based pharmacotherapies for treating addiction.

This kind of research has at least a chance of leading in the direction of additional candidates for anti-craving drugs, without which many addicts are never going to successfully treat their disease.


Graphics credit: http://cnunitedasia.en.made-in-china.com/

Review: Memoirs of an Addicted Brain

“I’m a drug addict turned neuroscientist.”

What’s it like to swallow 400 milligrams of dextromethorphan hydrobromide, better known as Romilar cough syrup? “Flashes of perception go by like clumps of scenery on either side, while you float along with the slow, irresistible momentum of a dream.” Marc Lewis, a former addict, now a practicing neuroscientist, further muses: “But what was Romilar? It sounded like an ancient kingdom. Would this dark elixir take me to some faraway place? Would it take me into another land? Would it be hard to come back?”

In Memoirs of an Addicted Brain: A Neuroscientist Examines his Former Life on Drugs, Dr. Marc Lewis follows his description of his gateway Romilar drug experience with the neurological basics of the matter: “The problem is that the NMDA receptors in my brain are now clogged with dextromethorphan molecules! The glutamate isn’t getting through. The receptor neurons aren’t firing, or they’re not firing fast enough…. Drugs like DM, ketamine, PCP, angel dust, and those most damaging of substances, glue and gasoline, are called dissociatives, because they do exactly what drugs are supposed to do: they dissociate feeling from reality, meaning from sense—and that’s all they do.”

Speaking of the self-reinforcing cycle “through which calamities of the mind arise from vulnerabilities of the brain,” Lewis argues that dissociatives only produce an absence. As a friend of his puts it with regard to another popular dissociative, “Nitrous oxide doesn’t give you consciousness. It takes it away.” And then, the friend adds: “Just bonk yourself on the head with a baseball bat if you want to lose consciousness.”

Lewis ultimately turns to opioids. “The emotional circuitry of the ventral striatum seems to derive its power from an intimate discourse between opioid liking and dopamine wanting.” In the end, this partnership does more than produce pleasure. It also, Lewis points out, “gets us to work for things.” And by doing that, addictive drugs demonstrate “the fundamental chemistry of learning which really means learning what feels good and how to get more of it. Yet there’s a downside: the slippery slope, the repetition compulsion, that constitutes addiction. In other words, addiction may be a form of learning gone bad. For me, this neurochemical sleight of hand promises much more pain than pleasure in the years to come.”

Lewis does a good job of capturing the feeling of existential despair brought on by uncontrolled addiction: “Contemptible. That’s what I was. Unbelievably stupid, unbelievably irresponsible: selfish, selfish, selfish! But that wasn’t quite it. What described me, what this inner voice accused me of, wasn’t exactly selfish, not exactly weak, but some meridian of self-blame that included both, and also, dirty, disgusting… maybe just BAD.”

How did heroin feel? “I feel relief from that pervasive hiss of wrongness. Every emotional wound, every bruise, every ache in my psyche, the background noise of angst itself, is soaked with a balm of unbelievable potency. There is a ringing stillness. The sense of impending harm, of danger, of attack, both from within and without, is washed away.”

And Lewis provides a memorable summation of the reward system, as dopamine streams from the ventral tegmental area to its targets, “the ventral striatum, where behavior is charged, focused, and released; the orbitofrontal cortex, where it infuses cells devoted to the value of this drug; and the amygdala, whose synapses provide a meeting place for the two most important components of associative memory, imagery and emotion.” In fact, “dopamine-powered desperation can change the brain forever, because its message of intense wanting narrows the field of synaptic change, focusing it like a powerful microscope on one particular reward. Whether in the service of food or heroin, love or gambling, dopamine forms a rut, a line of footprints in the neural flesh.”

And, of course, Lewis relapses, and eventually ends his addictive years in an amphetamine-induced psychosis, committing serial burglaries to fund his habit. “You’d think that getting busted, put on probation, kicked out of graduate school, and enduring a kind of infamy that was agonizing to experience and difficult to hide—all of that, an the need to start life over again—would be enough to get me to stop. It wasn’t.”

Not then, anyway. But Lewis has been clean now for 30 years. “Nobody likes an addict,” he writes. “Not even other addicts.”

If drugs are such feel-good engines, what goes wrong? Something big. “Because when drugs (or booze, sex, or gambling) are nowhere to be found, when the horizon is empty of their promise, the humming motor of the orbitofrontal cortex sputters to a halt. Orbitofrontal cells go dormant and dopamine just stops. Like a religious fundamentalist, the addict’s brain has only two stable states: rapture and disinterest. Addictive drugs convert the brain to recognize only one face of God, to thrill to only one suitor.”  The addict’s world narrows. Dopamine becomes “specialized, stilted, inaccessible through the ordinary pleasures and pursuits of life, but gushing suddenly when anything associated with the drug comes into awareness…. I wish this were just an exercise in biological reductionism, or neuro-scientific chauvinism, but it’s not. It’s the way things really work.”

Photo Credit: http://ebookstore.sony.com/

Dr. David Nutt on Alcohol

Rebutting industry myths.

A couple of years ago, the European Alcohol Policy Alliance, known as EuroCare, put together a brochure addressing the common messages the liquor industry attempts to drive home through its heavy spending on advertising. The messages are not just designed to sell product, but also to influence alcohol policy at the political level. According to EuroCare, the “industry”—the alcohol and tobacco companies—“has traditionally worked closely together, sharing information and concerns about regulation. They have used similar arguments to defend their products in order to prevent or delay restrictions being placed on them.”

I wrote a blog post on EuroCare’s list of alcohol untruths called “7 Myths the Alcohol Industry Wants You to Believe." Here they are:

Message 1: Consuming alcohol is normal, common, healthy, and very responsible.

Message 2: The damage done by alcohol is caused by a small group of deviants who cannot handle alcohol.

Message 3: Normal adult non-drinkers do not, in fact, exist

Message 4: Ignore the fact that alcohol is a harmful and addictive chemical substance (ethanol) for the body.

Message 5: Alcohol problems can only be solved when all parties work together.

Message 6: Alcohol marketing is not harmful. It is simply intended to assist the consumer in selecting a certain product or brand.

Message 7: Education about responsible use is the best method to protect society from alcohol problems.

Recently, I ran across a great response to these same 7 myths by Dr. David Nutt, the British psychiatrist perhaps best known in the states as the scientist who got fired a few years ago from his post on the government’s Advisory Council on the Misuse of Drugs. Nutt’s primary sin was to suggest that, on a straightforward calculation of risks and harms, horseback riding was probably a more dangerous activity than taking the drug Ecstasy. The Home Secretary at the time insisted that you couldn’t compare a legal activity to an illegal one, or something like that, and Nutt compounded his sins by suggesting that marijuana was a safer drug than alcohol. British politicians took a serious dislike to him, the more so since most of the published medical science was on his side. After the dust settled, Nutt was one of the primary founders of the Independent Scientific Committee on Drugs (ISCD), formed to offer alternative views on drugs and addiction grounded in science.

Anyway, in his book, Drugs Without the Hot Air, Nutt has his own responses to the 7 Myths, which I excerpt here:

1. Consuming Alcohol is Normal: It’s normal, so long as you have the “normal” high-activity variant of the ALDH2 enzyme. If you don’t have that form of the enzyme, Nutt reminds his readers, as many Asians and Aleuts do not, then alcohol will affect you quite non-normally through the so-called alcohol flush reaction. Moreover, many cultures and societies unfamiliar with its effects “suffer hugely when new types of alcohol appear, particularly if they are aggressively marketed.”

2. Alcohol damage is caused by a small group of deviants: According to Dr. Nutt, statistics show that “millions of people, NOT a tiny minority, suffer harm from their own alcohol consumption, or cause harm to others…. It is the everyday drinking of people who have come to see alcohol as an essential part of life rather than the luxury it used to be, that has created a spike in cancers and stomach problems, and will see liver disease match heart disease as the leading cause of death in the UK by 2020.”

3. Normal adult non-drinkers do not exist: The alcohol industry is forever reminding politicians of how unpopular alcohol restrictions are to the voting populace. “The existence of non-drinkers obviously threatens this portrayal of society, so the industry tends to dismiss them as having something wrong with them. While some teetotalers are recovering alcoholics, many others have made a positive choice not to drink.” And there are others, I would add, often referred to as “sick” teetotalers, who have quit drinking for medical reasons unrelated to alcoholism.

4. Ignore alcohol’s harm to the body: Nutt reminds us that “there is no other drug which is so damaging to so many different organ systems in the body…. Most other drugs cause damage primarily in one or two areas—heart problems from cocaine, or urinary tract problems from ketamine. Alcohol is harmful almost everywhere.”

5. Alcohol problems can be solved when everybody works together: “In practice, what the industry means by ‘working together’ is bring in voluntary codes rather than statutory regulation—solving problems through rules that the industry CHOOSES to comply with, rather than laws which they MUST comply with.”

6. Alcohol marketing is intended to assist consumers in selecting products: Specifically, 800 million British pounds every year for advertising and promotion, according to Nutt. That’s just the kind of civic-minded bunch those alcohol sellers are. The reality, of course is that “marketing communications do have a marked effect on consumption…. All this further entrenches the false division between alcohol and illegal drugs, persuades people that consuming alcohol is safe, and makes realistic discussions of the harm alcohol causes very difficult.”

7. Education about responsible use is the best approach: “It is useful for the drinks industry,” Nutt explains, “to emphasize the value of education, because it takes the focus off regulation…. There is also extensive evidence gathered by the WHO from around the world, showing that merely providing information and education without bringing in other policy measures doesn’t change people’s drinking behavior.”

As I wrote in my original post: Who could be against the promotion of responsible alcohol use? Irresponsible zealots and deviants, that’s who. Why should all of us happy drinkers be made to suffer for the sins of a few rotten apples?

Indeed, all of the messages, overtly or covertly, send the same signal: You should drink more. It’s good for you.

Graphics Credit: http://www.holyrood.com/2011/04/at-what-price/

What is Drug Craving?

Exploring the engine of drug relapse.


“In terms of treatment, you can’t just attack the rewarding features of the drug. In the case of alcohol, we already have a perfect drug to make alcohol aversive--and that’s Antabuse. But people don’t take it. Why don’t they take it? Because they still crave. And so they stop taking it. You have to attack the other side, and hit the craving.”
--Dr. Ting-Kai Li, 1990 interview

It causes relapses and treatment failure. It leads good people to break good promises and do harm to themselves and others. What is this thing called craving? Isn’t it just another word for lack of will power?

Scientists have gained a much deeper understanding of how and why addicts crave. For years, craving was represented by the tortured tremors and sweaty nightmares of extreme heroin and alcohol withdrawal. Significantly, however, the symptom common to all forms of withdrawal and craving is anxiety. This prominent manifestation of craving plays out along a common set of axes: depression/dysphoria, anger/irritability, and anxiety/panic. These biochemical states are the result of the “spiraling distress” (George Koob’s term) and “incomprehensible demoralization” (AA’s term) produced by the addictive cycle. The mechanism driving this distress and demoralization is the progressive dysregulation of brain reward systems, leading to biologically based craving. The chemistry of excess drives the engine of addiction, which in turn drives the body and the brain to seek more of the drug.

Whatever the neuroscientists wanted to call it, addicts knew it as “jonesing,” from the verb “to jones,” meaning to go without, to crave, to suffer the rigors of withdrawal. Most doctors don’t get it, and neither did many of the therapists, and least of all the public policy makers. Drug craving is ineffable to the outsider.

Drug craving itself is mediated by glutamate receptor activity in the hippocampus—the seat of learning and memory. A fundamental branch of what we might dub the “relapse pathway” runs through the glutamate-rich areas of the hippocampus. The puzzling matter of craving and relapse began to come into focus only when certain researchers began to rethink the matter of memory and learning as it applies to the addictive process. This led back to the role of glutamate, and it gradually became clear that the drug high and the drug craving were, in a manner of speaking, stored in separate places in the brain. Research at the National Institute for Drug Abuse (NIDA) strongly supports the hypothesis that drug memories induced by environmental triggers originate primarily in the hippocampus. And glutamate may be the substance out of which the brain fashions “trigger” memories that lead certain addicts down the road to relapse.

Glutamate is the most common neurotransmitter in the brain. (In sodium salt form, as monosodium glutamate, it is a potent food additive.) About half of the brain’s neurons are glutamate-generating neurons. Glutamate receptors are dense in the prefrontal cortex, indicating an involvement with higher thought processes like reasoning and risk assessment. The receptor for glutamate is called the N-methyl-D-aspartate (NMDA) receptor. And unfortunately, as the gifted science writer Constance Holden related in Science 292, NMDA antagonists, which might have proven to be potent anti-craving drugs, cannot be used because they induce psychosis. Dissociative drugs like PCP and ketamine are glutamate antagonists.

However, drugs that play off receptors for glutamate are already available, and more are in the pipeline. As a precursor for the synthesis of GABA, glutamate has lately become a tempting new target for drug research. Ely Lilly and others have been looking into glutamate-modulating antianxiety drugs, which might also serve as effective anti-craving medications for abstinent drug and alcohol addicts.

Photo credit: Changing Lives Foundation

Synthetic Drugs: Collected Posts

Catching up with bath salts and spice.


The Low Down on the New Highs: Not all bath salts are alike.

“You’re 16 hours into your 24-hour shift on the medic unit, and you find yourself responding to an “unknown problem” call.... Walking up to the patient, you note a slender male sitting wide-eyed on the sidewalk. His skin is noticeably flushed and diaphoretic, and he appears extremely tense. You notice slight tremors in his upper body, a clenched jaw and a vacant look in his eyes.... As you begin to apply the blood pressure cuff, the patient begins violently resisting and thrashing about on the sidewalk—still handcuffed. Nothing seems to calm him, and he simultaneously bangs his head on the sidewalk and tries to kick you...” [Go here]


The New Highs: Are Bath Salts Addictive? What we know and don’t know about synthetic speed.

Call bath salts a new trend, if you insist. Do they cause psychosis? Are they “super-LSD?” The truth is, they are a continuation of a 70-year old trend: speed. Lately, we’ve been fretting about the Adderall Generation, but every population cohort has had its own confrontation with the pleasures and perils of speed: Ritalin, ice, Methedrine, crystal meth, IV meth, amphetamine, Dexedrine, Benzedrine… and so it goes. For addicts: Speed kills. Those two words were found all over posters in the Haight Ashbury district of San Francisco, a few years too late to do the residents much good…. [Go here]


“Bath Salts” and Ecstasy Implicated in Kidney Injuries: “A potentially life-threatening situation.”

Earlier this month, state officials became alarmed by a cluster of puzzling health problems that had suddenly popped up in Casper, Wyoming, population 55,000. Three young people had been hospitalized with kidney injuries, and dozens of others were allegedly suffering from vomiting and back pain after smoking or snorting an herbal product sold as “blueberry spice.” The Poison Review reported that the outbreak was presently under investigation by state medical officials.  “At this point we are viewing use of this drug as a potentially life-threatening situation,” said Tracy Murphy, Wyoming state epidemiologist…. [Go here]


The Triumph of Synthetics: Designer stimulants surpass heroin and cocaine.

A troubling report by the United Nations Office on Drugs and Crime (UNODC) shows that amphetamine-type stimulants (ATS) have, for the first time, become more popular around the world than heroin and cocaine. Marijuana remains the most popular illegal drug in the world, and the use of amphetamines has fallen sharply in the U.S., but the world trend represents the worldwide triumph of synthetic drug design over the plant-based “hard drugs” of the past…. [Go here]

Marijuana: The New Generation: What’s in that “Spice” packet?

They first turned up in Europe and the U.K.; those neon-colored foil packets labeled “Spice,” sold in small stores and novelty shops, next to the 2 oz. power drinks and the caffeine pills. Unlike the stimulants known as mephedrone or M-Cat, or the several variations on the formula for MDMA—both of which have also been marketed as Spice and “bath salts”—the bulk of the new products in the Spice line were synthetic versions of cannabis…. [Go here]


An Interview with Pharmacologist David Kroll: On synthetic marijuana, organic medicines, and drugs of the future.

Herewith, a 5-question interview with pharmacologist David Kroll, Ph.D., Professor and Chair of Pharmaceutical Science at North Carolina Central University in Durham, and a well-known blogger in the online science community. A cancer pharmacologist whose field is natural products—he’s currently involved in a project to explore the potential anticancer action of chemicals found in milk thistle and various sorts of fungi—Dr. Kroll received his Ph.D. from the University of Florida, and completed his postdoctoral fellowship in Medical Oncology and Molecular Endocrinology at the University of Colorado School of Medicine. He went on to spend the first nine years of his independent research and teaching career at the University of Colorado School of Pharmacy, where he taught all aspects of pharmacology, from central nervous system-active drugs, to anticancer and antiviral medications…. [Go here]


Mephedrone, the New Drug in Town: Bull market for quasi-legal designer highs.

Most people in the United States have never heard of it. Very few have ever tried it. But if Europe is any kind of leading indicator for synthetic drugs (and it is), then America will shortly have a chance to get acquainted with mephedrone, a.k.a. Drone, MCAT, 4-methylmethcathinone (4-MMC), and Meow Meow--the latter nickname presumably in honor of its membership in the cathinone family, making it chemically similar in some ways to amphetamine and ephedrine. But its users often refer to effects more commonly associated with Ecstasy (MDMA), both the good (euphoria, empathy, talkativeness) and the bad (blood pressure spikes, delusions, drastic changes in body temperature)…. [Go here]


Tracking Synthetic Highs: UN office monitors designer drug trade.

Produced by the United Nations Office on Drugs and Crime (UNODC), the Global SMART Update  (PDF) for October provides interim reports of emerging trends in synthetic drug use. The report does not concern itself with cocaine, heroin, marijuana, alcohol, or tobacco. “Unlike plant-based drugs,” says the report, “synthetic drugs are quickly evolving with new designer drugs appearing on the market each year.” The update deals primarily with amphetamine-type stimulants, but also includes newer designer drugs such as mephedrone, atypical synthetics like ketamine, synthetic opioids like fentanyl, and old standbys like LSD…. [Go here]


The New Cannabinoids: Army fears influx of synthetic marijuana.

It’s a common rumor: Spice, as the new synthetic cannabis-like products are usually called, will get you high--but will allow you to pass a drug urinalysis. And for this reason, rumor has it, Spice is becoming very popular in exactly the places it might be least welcomed: Police stations, fire departments—and army bases. What the hell is this stuff? [Go here]

Photo credit: http://gizmodo.com/

photo credit 2: http://www.clemson.edu/

Army Doctor Sees Victory, and a Dangerous Drug Bites the Dust—Almost.

An interview with the man who blew the whistle on the neurotoxic malaria drug in the U.S. Army’s kit bag.

A dangerous malaria drug invented by the Army and commonly used by soldiers and civilians alike causes everything from episodes of psychotic violence to nightmares more real than reality, and is finally being withdrawn as the first-line treatment for troops in malarial zones.

Lariam, known medically as mefloquine, has also been a licensed treatment for civilians abroad for more than 25 years. Yet it has only been in the recent past that common knowledge of Lariam’s dangers has surfaced publically.

The development of Lariam was a prime example of military-industrial cooperation. Discovered at the Walter Reed Army Institute of Research during the Vietnam war, initially tested on prisoners at the Joliet Correctional Center in Illinois, and marketed worldwide by Hoffmann-La Roche, mefloquine was an urgent response to high malaria rates in U.S. combat troops overseas. Unfortunately, such close cooperation also led to a lack of adequate clinical testing—the practice that underpins the notion of drug safety. Ashley M. Croft of the Royal Army Medical Corps in Britain has written that in the case of Lariam, “the first randomized controlled trial of the drug in a mixed population of general travellers was not reported until 2001.” Croft believes the FDA was influenced by “the powerful military-industrial-governmental lobby into over-hasty decisions.”

In addition, “travel medicine experts in most countries were slow to recognize the danger signals associated with Lariam…. As late as 2005 a reviewer in the New England Journal of Medicine, also an employee of the US military for over 20 years, continued to maintain… that Lariam was a ‘well tolerated’ drug,” according to Croft. The victims of all this pharmacological hoodoo, Croft maintains, “have been those many business travellers, embassy staff, tourists, aid workers, missionaries, soldiers and others who were well at the start of their journeys into malaria-endemic areas…”

Largely due to the efforts of Dr. Remington Nevin, a medical epidemiologist and a physician in the U.S. Army, who went public about Lariam’s potential for causing psychological illness, military officials announced in December that the Army was done with Lariam as a first-line malaria preventative except for “special circumstances.” In the past, such special circumstances have allegedly included its use as an interrogation drug at Guantanemo.

As far back as 2004, an alarming number of suicides among troops in Iraq prompted calls for an investigation of Lariam. “The military is ignoring this drug’s known side effects,” Steve Robinson of the National Gulf War Resource Center told UPI. In October of 2004, Sen. Dianne Feinstein (D-Calif) urged then-Secretary of Defense Donald Rumsfeld to investigate the drug: “Given the mounting concerns about Lariam as expressed by civilians, service members and medical experts about its known serious side effects, I strongly urge you to reassess,” she wrote to Rumsfeld. Meanwhile, Mark Benjamin and Dan Olmsted of UPI were reporting that “mounting evidence suggests Lariam has triggered mental problems so severe that in a small percentage of users it has led to suicide. UPI also reported that soldiers involved in a string of murder-suicides at Fort Bragg, N.C., in the summer of 2002 after returning from Afghanistan had taken the drug.”

Almost ten years later, Sen. Feinstein wrote another letter, this one to Secretary of Defense Leon Panetta, complaining that a 2009 policy limiting the use of mefloquine among U.S. troops was not being followed. Although parent company Roche discontinued Lariam in the U.S., generic versions remain available, and the company continues to sell Lariam in other countries. “My office has been contacted recently by servicemembers who were prescribed mefloquine when one of the other medications would have been appropriate and were not given the FDA information card. These servicemembers are now suffering from preventable neurological side effects,” including  balance problems, vertigo, and psychotic behavior,” she wrote.

In addition, as a military medical instructor told Addiction Inbox: “Some service members might ‘double up’ on their weekly dose, or increase the frequency of dosing, intentionally for recreational purposes. There is no evidence that the military educates service members to avoid this temptation or that it is unsafe. Users might even justify it by believing it could enhance the drug's anti-malarial activity. In the military, it is frequently a tenet of our culture that ‘if one is good, two is better.’"

In November,  military officials overseas stopped almost all use of mefloquine in malaria-prone areas in Africa and the Middle East. Army Col. Carol Labadie, the service’s pharmacy program manager, commented on the long overdue change: “If that means changing from one drug to another because now this original drug has shown to be potentially harmful… it is in our interests to make that change.”

As Croft wrote, it was not a case of inconvenient research being deliberately witheld. Rather, “the necessary pre-licensing research was simply never carried out.”

Questions still remain about the use of mefloquine at Guantanamo as an “enhanced interrogation technique.” Last year, Stars and Stripes ran an investigation of the matter and concluded: “Medical experts say the Defense Department policy of giving detainees large doses of mefloquine is poor medical practice at best and torture at worst.”

INTERVIEW WITH DR. REMINGTON NEVIN

—Is there any good science behind the notion that mefloquine might be addictive?

Dr. Remington Nevin: I am speaking to you in an individual capacity, and my opinions are my own and in no way reflect those of the U.S. Army or the Defense Department. There is no evidence that mefloquine is addictive per se, but the drug is well-known to produce vivid, technicolor dreams, and as a result it is frequently viewed as an incidental and convenient form of recreation among people, including Peace Corps volunteers and military service members, who find themselves already required to take the drug, and otherwise typically without access to alternative drugs of abuse, such as alcohol. The vivid "rock star" fantasies frequently reported are often perceived as consolation for the isolation and loneliness that typical accompany travel to remote areas where mefloquine is prescribed.

Ann Patchett, a prize-winning author, recently wrote a book called State of Wonder in which mefloquine features prominently, and her writing was likely based to a good degree on her and her acquaintances' experiences with the drug. Patchett herself actually refers to the drug's "recreational" properties and alludes in a recent interview to her having wanted to "take the drug out for a spin" (see http://thedianerehmshow.org/)

REHM: Did you take Lariam when you went to the Amazon?
PATCHETT: I did, I did. And actually, if I hadn't gone to the Amazon, I probably would've just taken it recreationally at home because I really wanted to take it out...
REHM: Experience it.
PATCHETT:...for a spin, right.
REHM: Yeah.
PATCHETT: And the side effects of Lariam listed on the package, psychotic dreams, terrible nightmares, paranoia, suicide is a possible side effect and I've known a lot of people who have had true psychosis on Lariam.

—Can you lay out what you know about mefloquine causing hallucinatory and dissociative effects in travelers who take it for malaria?

Dr. Nevin: [The symptoms] closely mimic those of a condition known as anti-NMDA receptor encephalitis, which an expert in the field, Dr. Dalmau, describes as including "anxiety, fear, bizarre or stereotypical behaviour, insomnia, and memory deficits". It is thought that rising levels of antibody to the NMDA receptor induces… widespread downstream dysregulation of  limbic dopaminergic and noradrenergic tone, which ultimately are responsible for producing the syndrome's psychotic effects… This limbic dysregulation may also be similar to what is seen with the chemical NMDA receptor antagonists, including ketamine and phencyclidine, which share with mefloquine a particular propensity towards impulsivity and dissociation. For these reasons I conclude that mefloquine should be characterized as a dissociative hallucinogen.

—What is a dissociative hallucinogen?

Dr. Nevin: It is this property that also likely explains the drug's association with suicidality and acts of violence. Mefloquine is the only non-psychotropic drug listed among the top ten associated with acts of violence, and there is a growing literature linking it causally to suicide.  It may be that the combination of mefloquine-induced amnesia, dissociation, and hallucinations (many with vivid religious or persecutory themes) creates a perfect storm that can trigger impulsive acts of violence. It is not uncommon for those recovering from (and surviving) mefloquine psychosis to report engaging in suicidal gestures that in retrospect were devoid of any fear of consequences…. Just within the past year, in a paper in the journal Science, Bissiere and colleagues demonstrated mefloquine interfering with context fear response in the hippocampus.


—Could you expand on the notion of "vivid rock star fantasies" experienced by some users?

Dr. Nevin: Extremely vivid dreams are among the most widely reported "adverse effect" of the drug. Users can frequently describe their dreams in great detail even well into the next day and, in some cases, the dreams seem to take on an almost lucid quality. Many experience gratifying and deeply pleasurable dreams that they almost don't wish to awaken from; conversely, for some others, the effect seems to be quite the opposite, with the reported nightmares being particularly haunting the next day.

—You have referred to Lariam as a "zombie" drug. Could you expand on that?

Dr. Nevin: If you must know, the reporter for AP caught me on Halloween, but I believe the term is quite apropos. The drug is the pharmaceutical equivalent of the living dead; it is somehow able to survive controversies that would have quickly killed other drugs. Interestingly, Lariam has been quietly delisted although generics remain widely available. To further stretch the metaphor, the drug is also decidedly neurotoxic and kills brain cells; one can say it "eats brains", and lastly, I would argue that a "zombie-like" state is not an unreasonable description of the most extreme adverse effects of the drug.

—I'm shocked to discover mefloquine on the list of top 10 drugs associated with acts of violence. Could you comment on a non-psychoactive drug making that list?

Dr. Nevin: It is quite shocking. Mefloquine isn't typically considered a psychotropic drug, but it probably should be recharacterized as a psychotropic medication with incidental anti-malarial properties. Of the drug contained in a 250mg tablet, only about 1-2mg, less than 1%, is ultimately found at the site of its intended anti-malarial activity, in the circulation. And although the neuropharmacokinetics are still somewhat unclear, arguably a far greater percentage of the drug is ultimately found in brain tissue than in the circulation. Incredibly, when the drug was undergoing FDA licensing, this brain penetration wasn't even well-characterized. Transcripts from the licensing meetings clearly show committee members skipping over this fact without much consideration. Certainly there seems to have been no requirement to submit the drug to neurotoxicity testing, despite many related quinoline compounds having demonstrated well-characterized, permanent neurotoxicity at least 40 years earlier.


—How common is the use of mefloquine in the U.S. as a whole?

Dr. Nevin: There has been a fairly rapid decline in the use the drug, correlating with rising appreciation of mefloquine's dangers and awareness of contraindications to its safe use. Malarone is now the predominant anti-malarial prescribed within a large network of U.S. travel clinics. The U.S. military, which developed the drug just over 40 years ago, recently prohibited the use of mefloquine as first-line agent, and has dramatically curtailed its use after research revealed the drug had been widely prescribed to service members with mental health contraindications. Recently, the U.S. Centers for Disease Control further clarified guidance against routine use of mefloquine in service members, conceding that use of mefloquine may "confound the diagnosis and management of posttraumatic stress disorder and traumatic brain injury".

—What are the consequences of mixing Lariam with alcohol?

Dr. Nevin: There is fairly good evidence from case reports that alcohol may potentiate the deleterious effects of mefloquine, but the mechanism remains controversial. It had been suspected that alcohol simply exerted an inhibitory effect on mefloquine metabolism, but now… it seems likely that alcohol exerts a direct pharmacodynamic effect.


—Lariam is still sometimes prescribed for children traveling in malaria zones. Are there special dangers for kids?

Dr. Nevin: As the popularity of the drug is declining among adults, some experts with ties to industry have been peddling the drug for niche pediatric use, ostensibly because it is well tolerated. Unfortunately, such claims are based on studies which in many cases are deeply flawed and…. even verbally fluent but younger children may not have the experience or perspective to properly describe these symptoms. Apart from these considerations, I would argue that I don't think enough is understood about the neurophysiological effects of the drug to justify its use even in older children and adolescents.  Mefloquine is a psychotropic drug. Given what we are learning of mefloquine's effects on the limbic system, even at relatively low doses, it seems at least plausible that the developing brain might in some way be adversely affected by the drug, particularly during long-term dosing.

—Why was the Army so slow to move on mefloquine?

Dr. Nevin: To put things in perspective, understand that mefloquine is the sole product of an aggressive 20-year, multi-million dollar effort by the U.S. Army. Mefloquine was identified only in the early 1970s after tens of thousands of other quinoline compounds had failed toxicity and efficacy tests. By the time of mefloquine's U.S. licensure in 1989, it was essentially DoD's last and only hope. So, if I could rephrase your question, if mefloquine is as safe as the Army once claimed, then why is it no longer the drug of choice? If we assume that this quiet policy change was made in tacit acknowledge of safety concerns, then the question is, precisely what new information has informed this decision, why has this change taken so long to occur, and most importantly, what harm might this policy change now be seeking to avoid, which may already have accrued among those in whom the drug had been previously used?  

The reasons for the Army's silence on these questions are likely quite banal. Admitting mefloquine is a dangerous drug would be a bitter pill for any Army medical leader to swallow. Many of today's senior medical leaders were intimately involved in the studies that saw the drug rise to prominence, and many are on record over the previous decades publicly defending the drug against the increasingly validated claims of its earlier critics. Absent external pressure to do so, it is likely of little benefit for these senior medical leaders to suffer the humiliation that would come from admitting what they might now otherwise privately concede. Saying nothing is the path of least resistance on their journey to a comfortable retirement.

—Could you comment on allegations of Lariam use as an interrogation drug at Guantanamo?

Dr. Nevin: The use of mefloquine at Guantanamo represents either medical malpractice with culpability at some of the highest levels of military medical leadership, or it suggests something far more intentional and sinister. I typically believe that one should never ascribe to malice what can be attributed to simple incompetence, but in this case, I am not so certain. There are too many inconsistencies and unanswered questions. The issue will ultimately require the release of medical records, open hearings, and testimony to resolve. I am confident this will happen.

Addiction Inbox (D)Evolves Into Paperback

A curated collection of blog posts in print.

Online is where journalism is happening now, but it is a truism that most of the world’s repository of knowledge is still found in books. It is also true that Addiction Inbox now comes in paperback, from Amazon. For cheap. Also available in Kindle, for unbelievably cheap.

 I have selected and arranged a “best of the blog” collection,  meant to serve as a handy off-the-shelf compendium of science-based information on drugs and addiction. Is shoplifting the opiate of the masses? Does menthol really matter? Can ketamine and other party drugs cause permanent bladder damage? The posts are arranged in four sections: Research, The New Synthetics, Treatment, and Interviews/Book Reviews. This 330-page anthology of articles is designed to bring multiple perspectives to bear on questions of drugs, addiction, and treatment. For just ridiculously cheap.

Cassie Rodenberg at Scientific American’s White Noise blog was kind enough to review Addiction Inbox, the book: “The author relates the real life to the scientific, noting his own struggles with addiction, yet doesn’t get bogged down in personal tales. Rather, the writings use life tidbits as jumping off points for scientific explanation and an overarching discussion of addiction’s media landscape.”

Which was pretty much what I was hoping to do when I started this blog….

What We Talk About When We Talk About Drugs

Some number crunching at bluelight.ru.

A fantastic set of interactive graphics tracking conversational trends in drugs at the chat board bluelight.ru reveals some surprises, to the delight of data journalists everywhere. Virostatiq, a software package authored by Marko Plahuta, was put to the task of analyzing traffic at the drug discussion site. Various kinds of plots are available, with endless variables to permutate. Bear in mind that the data that got crunched dealt with the subject of messages, and cannot be directly correlated with drug use, trends, distributions, etc. But it is a fascinating glimpse at what illegal drug users are talking about, and from that, some inferences can be hazarded.

Plahuta writes:

I thought it would be nice to visualize these drug groups based on what users of harm-reduction forums say, so I analyzed around 1.2 million posts on bluelight.ru and constructed a simple diagram that tells a lot…. My whole database contains posts from 2010 until March 2013. Here’s an analytical tool to better understand what’s going on in the recreational drug community. Time is on horizontal axis, while the proportion of posts mentioning specific drug relative to all posts in that month is on the vertical axis. Play around with interactive chart to discover emerging trends, or simply to behold the wax and wane of specific chemicals as they compete for users’ neurological apparatuses, while their manufacturers are temporarily evading ever stricter analog laws.

The chart above represents a graphic created for Addiction Inbox using the visual data provided by Virostatiq. I have singled out six drugs of abuse for discussion. Bear in mind that the trend lines for common drugs like LSD, Ecstasy, marijuana, and methamphetamine all show much higher usage than the ones I have chosen to chart.

—Mephedrone, arguably the most common “bath salt” stimulant, was mentioned at bluelight.ru a lot during 2010, when it came to the U.S. in a major way. But comments have been tailing off pretty steeply ever since. This suggests that mephedrone was sampled and found wanting by those who knew what drug they were taking. Or it could simply be old news by now, and less of a topic for discussion. But if the graph is suggestive of interest levels in the drug-using community, mephedrone seems to have a PR problem.

—Surprisingly, at least to me, a hallucinogen name 2c-e was one of the most talked-about designer drugs of all. 2c-e is a research chemical similar to mescaline but with a spotty track record. Linked to deaths and hospitalizations in Oklahoma and Minnesota, it isn’t known for certain whether the medical problems were due to the pure drug or contaminants. 2c-e is one of the drugs to come out of Alexander Shulgin’s infamous laboratories, and has been around for 20 years. As Tony O’Neill wrote at The Fix: “All in all, it doesn’t sound like the best bet for a recreational Saturday night at the dance club.” As with mephedrone, 2c-e was less talked bout in the last year of the graph.

—Kratom retained a steady popularity over the full 3-year period. Kratom has always been hovering in the background of the opiate family, but seems to have undergone an unprecedented surge in underground popularity of late. From a tree native to Southeast Asia, and often used as a tea, Kratom is powered by an active ingredient called mitragynine—a substance capable of partially activating the mu- and delta-opioid receptors. Kratom serves as a weak opium, and some opiate enthusiasts swear by it for use as a withdrawal aid.

—One of the popular synthetic cannabis products to come out of the Huffman labs at Clemson University, jwh-018 seems to have pretty much cratered as a topic of discussion among drug cognoscenti. Perhaps some of the news about synthetic cannabis and correlations with serious liver problems has taken the shine off that apple. Or simply the fact that, over the few years that synthetic cannabis has been available, users have learned that they prefer the real thing, drug tests notwithstanding.

—Hydrocodone, otherwise known as Vicodin, may have lost some popularity lately due to the popularity of oxycontin and other new synthetic opiate formulations. This is the drug that may have cost Rush Limbaugh his hearing. As a legitimate pain drug, it suffers in comparison with oxycontin, aka Percodan.

—Ketamine is a major topic of discussion, which makes sense. Lately it has rebounded as a party drug, and also scored highly in clinical testing of its efficacy as a short-acting treatment for depression. Unfortunately, use of the drug has been linked to bladder problems  lately.