Update on Synthetic Drug Surprises

Spicier than ever.

Four drug deaths last month in Britain have been blamed on so-called “Superman” pills being sold as Ecstasy, but actually containing PMMA, a synthetic stimulant drug with some MDMA-like effects that has been implicated in a number of deaths and hospitalizations in Europe and the U.S. The “fake Ecstasy” was also under suspicion in the September deaths of six people in Florida and another three in Chicago. An additional six deaths in Ireland have also been linked to the drug. (See Drugs.ie for more details.)

PMMA, or paramethoxymethamphetamine, causes dangerous increases in body temperature and blood pressure, is toxic at lower doses than Ecstasy, and requires up to two hours in order to take effect.

In other words, very nearly the perfect overdose drug.

Whether you call them “emerging drugs of misuse,” or “new psychoactive substances,” these synthetic highs have not gone away, and aren’t likely to. As Italian researchers have noted, “The web plays a major role in shaping this unregulated market, with users being attracted by these substances due to both their intense psychoactive effects and likely lack of detection in routine drug screenings.” Even more troubling is the fact that many of the novel compounds turning up as recreational drugs have been abandoned by legitimate chemists because of toxicity or addiction issues.

The Spice products—synthetic cannabinoids—are still the most common of the novel synthetic drugs. Hundreds of variants are now on the market. Science magazine recently reported on a UK study in which researchers discovered more than a dozen previously unknown psychoactive substances by conducting urine samples on portable toilets in Greater London. Call the mixture Spice, K2, Incense, Yucatan Fire, Black Mamba, or any other catchy, edgy name, and chances are, some kids will take it, both for the reported kick, and for the undetectability. According to NIDA, one out of nine U.S. 12th graders had used a synthetic cannabinoid product during the prior year.

“Laws just push forward the list of compounds,” Dr. Duccio Papanti, a psychiatrist at the University of Trieste who studies the new drugs, said in an interview for this article. “The market is very chaotic, bulk purchasing of pure compounds are cheaply available from China, India, Hong-Kong, but small labs are rising in Western Countries, too. Some authors point out that newer compounds are more related to harms (intoxications and deaths) than the older ones. You can clearly see from formulas that newer compounds are different from the first ones: new constituents are added, and there are structural changes, so although we have some clues about the metabolism of older, better studied compounds, we don't know anything about the newer (and currently used) ones."

The problems with synthetic cannabinoids often begin with headaches, vomiting, and hallucinations. At the Department of Medical, Surgical, and Health Sciences at the University of Trieste, researchers Samuele Naviglio, Duccio Papanti, Valentina Moressa, and Alessandro Ventura characterized the typical ER patient on synthetic cannabinoids, in a BMJ article: “On arrival at the emergency department he was conscious but drowsy and slow in answering simple questions. He reported frontal headache (8/10 on a visual analogue scale) and photophobia, and he was unable to stand unassisted. He was afebrile, his heart rate was 170 beats/min, and his blood pressure was 132/80 mm Hg.”

According to the BMJ paper, the most commonly reported adverse symptoms include: "Confusion, agitation, irritability, drowsiness, tachycardia, hypertension, diaphoresis [sweating], mydriasis [excessive pupil dilation], and hallucinations. Other neurological and psychiatric effects include seizures, suicidal ideation, aggressive behavior, and psychosis. Ischemic stroke has also been reported. Gastrointestinal toxicity may cause xerostomia [dry mouth], nausea, and vomiting. Severe cardiotoxic effects have been described, including myocardial infarction…”

In a recent article (PDF) for World Psychiatry, Papanti and a group of other associates revealed additional features of synthetic cannabimemetics (SC), as they are officially known: “For example, inhibition of γ-aminobutyric acid receptors may cause anxiety, agitation, and seizures, whereas the activation of serotonin receptors and the inhibition of monoamine oxidases may be responsible for hallucinations and the occurrence of serotonin syndrome-like signs and symptoms.”

Papanti says researchers are also seeing more fluorinated drugs. “Fluorination is the incorporation of fluorine into a drug,” he says, one effect of which is “modulating the metabolism and increasing the lipophilicity, and enhancing absorption into biological membranes, including the blood-brain barrier, so that a drug is available at higher concentrations. An increasing number of fluorinated synthetic cannabinoids are available, and fluorinated cathinones are available, too.”

A primary problem is that physicians are still largely unacquainted with these chemicals, several years after their current popularity began. This is entirely understandable. In addition to the synthetic cathinones, several new mind-altering substances based on compounds discovered decades ago have also surfaced lately. Papanti provided a partial list of additional compounds that have led to official concern in the EU:

—Synthetic opioids (the best known are AH-7921, MT-45)

—Synthetic stimulants (the best known are MDPV, 4,4'-DMAR)

—New synthetic psychedelics (the NBOMe series)

—New dissociatives (Methoxetamine, Methoxphenidine, Diphenidine)

—New performance enhancing drugs (Melanotan, DNP)

—Gaba agonists (Phenibut, new benzodiazepines)

Most of the new and next-generation synthetics are not readily detected by standard drug screen processes. Spice drugs will not usually show up on anything but the most advanced test screening, using gas chromatography or liquid chromatography-tandem mass spectrometry—high tech tools which are rarely available for anything but serious (and costly) forensic investigations.

“Testing is a big problem,” Papanti declares. “From a clinical point of view, do you need the test to make a diagnosis of intoxication, for following up an addiction treatment, or for forensic purposes? With the new drugs, maybe taken together, with different pharmacology, we are not very sure about this yet. If I want to have confirmation of a diagnosis of SC intoxication, I need two weeks as an average, in order to obtain the result. Your patient has been discharged by that time, or in the worse case, he is dead.”

 Another major problem, according to Papanti, “is that the machines need sample libraries in order to recognize the compound, and samples mean money. Plus, they need to be continuously updated.”

In summary, there is no antidote to these drugs, but intoxication is general less than 24 hours, and the indicated medical management is primarily supportive. If you plan to take a drug marketed as Ecstasy, or indeed any of the spice or bath salt compounds, Drugs.ie notes that there are some basic rules of conduct that will help maximize the odds of a safe trip:

—If you don’t “come up” as quickly as anticipated, don’t assume you need another pill. PMMA can take two hours or more to take effect. Do not “double drop.”

—If you don’t feel like you expected to feel, and are noticing a “pins-and-needles” feeling or numbness in the limbs, consider the possibility that another drug is involved.

—Don’t mix reputed Ecstasy with other drugs, especially alcohol, as PMMA reacts very dangerously with excessive alcohol.

—Remember to hydrate, but don’t overhydrate. If you go dancing, figure on about a pint per hour.

What's in That X Pill, Ravers?

Ecstasy comes loaded with other drugs. 

 I'm not a huge fan of infographics, mostly because they tend to overpromise and are often marred by factual errors. But this one sticks to basics, and reminds kids that pure MDMA is not the play here. Familiar with dibenzylpiperazine? How about 5-MEO-DIPT? Good old methamphetamine you know—but do you want your Ecstasy, itself an amphetamine spinoff, springloaded with an extra dose of it? Scroll down for pictures of "dirty rolls."

 Via Recovery Connection
View More Addiction Related Infographics

Interview with Cognitive Neuropsychologist Keith Laws

LSD, E, CBT, and “Mind-Pops.”

Our latest participant in the “Five Question Interview” series is Dr. Keith Laws, professor of cognitive neuropsychology and head of research in the School of Psychology at the University of Hertfordshire, UK. Dr. Laws holds a Ph.D. from the Department of Experimental Psychology at the University of Cambridge, and is the author of Category-Specificity: Evidence for Modularity of Mind. He has written extensively on cognitive deficits resulting from certain types of neurological injury, and has won several awards for his research on cognitive functioning in schizophrenia. He also maintains an active interest in the challenges of functional brain imaging. Professor Laws is frequently quoted in the British media, and is the author of more than 100 peer-reviewed articles. He is a Chartered Psychologist and an Associate Fellow of the British Psychological Society. And recently, Professor Laws became a blogger, launching the LawsNeuroBlog. He maintains a web homepage, and is virtually unbeatable in the category of obscure British rock trivia.

1. LSD is back in the news, with a rehash of several old studies on acid and alcoholism. A lot of people would like to revive research interest in LSD, MDMA, magic mushrooms, and other psychedelics. What’s your view?

Keith Laws: Yes, “re-hash” is an appropriate phrase—we are witnessing a rebranding of “counter-culture” as “over-the-counter-culture.” The history of LSD research is frequently retold as if grand therapeutic advances were halted because hostile governments criminalised LSD. The bottom-line, however, is that most studies of the 50s and 60s produced little worthy of further scientific pursuit. The recent meta-analysis of 60s studies examining whether LSD reduces “alcohol misuse” is a case in point.

That meta-analysis consisted of 6 trials—none of which produced a significant effect, but their total pooled effect suggested some impact on alcohol misuse. In my recent post on this study, I highlighted a series of points, including: how it is likely that further negative studies have been gathering dust in the file drawers of researchers over the years; how some samples consisted of people with serious comorbid mental health and neurological problems (schizophrenia, epilepsy, organic brain disorder, low IQ); and crucially, how the authors made the totally unfounded assumption that anyone dropping-out of the studies had relapsed into drinking. This had a large and disproportionate impact on the control samples in those studies—as many more dropped out from control groups. Combined with the lack of significant effects in any one study, doubts exist about relying on these data as a justification for starting large-scale trials of LSD for alcoholism. We should certainly skeptically regard statements by some, such as Professor David Nutt, that LSD is “as good as anything we’ve got for treating alcoholism.”

2. Tell us about your research interest in the effect of Ecstasy (MDMA) on memory.

Keith Laws: First, I think its crucial not to confuse E and MDMA. Studies of MDMA in humans are few, and mostly examine acute effects via self-report. The vast majority of studies though, including our work, examine the residual effects of street-E in abstinent users i.e. taking largely unknown compounds mixed with varying degrees of MDMA. For me, the real public health issue relates to street-E since most people outside of the lab rarely get to consume pure MDMA.

In 2007 we meta-analysed 26 studies that had examined memory on standardized tests in over 600 ecstasy users and 600 non-users and found significant long and short-term verbal memory impairments in 75% of users. Intriguingly, E was unrelated to visual memory problems; however those who also smoked cannabis did display significant visual memory impairment. A key finding of ours was that the lifetime number of E tablets consumed was unrelated to the degree of memory impairment. This led to a host of misrepresentations in the media and amongst E users who saw it as license to take as many Es as they want. I view this finding, however in a much starker light—taking E is akin to playing Russian Roulette with your memory. Some may tolerate 100s or even 1000s of E tablets, but for others far fewer may lead to memory problems—we can predict that 3 in 4 users will develop memory problems, but not which 3 or after how many tablets. Of course, ecstasy (like Cannabis) is often advocated as a safe-ish drug because it rarely kills. Indeed, metrics of drug harm developed in the UK emphasise physical and social harm, but fail to explicitly acknowledge the cognitive problems associated with E and other recreational drugs. Given that as many as 500,000 young people in the UK use E each week and 75% are affected, then that’s 375,000 young people developing significant verbal memory problems!

3. You’re not convinced by the findings of a recent study of magic mushrooms, where the researchers documented an overall decrease in brain activity. What else could account for this effect?

Keith Laws: Well, the surprising thing about the Carhart-Harris et. al. psilocybin study was the general pattern of brain deactivation, which contrasts with the findings of activation in others such as Vollenweider and colleagues in Switzerland who find increased activation. The decreased activation especially in the medial prefrontal cortex (mPFC) and the posterior cingulate cortex (PCC) were curious and reminded me of the similar deactivation in these areas linked both to anxiety and to the anticipation of unpleasant events. It occurred to me that the prospect of tripping in a scanner may be quite anxiety provoking, and several features of the study led to me to think this may have been the case. First the order of testing was always the same - participants received the placebo scan always before the psilocybin scan and so, could always anticipate the trip— potentially heightening anxious anticipation in that condition. Second, Carhart-Harris et. al. measured “anxiety” and “fear of losing one’s mind” and both multiplied many fold in the psilocybin condition. Interestingly and subsequently, Vollenweider and colleagues pooled date from 23 studies and found that experimental settings involving scanning most strongly predicted unpleasant and/or anxious reactions to psilocybin - converging directly on my suspicion. Although nobody would deny that hallucinogens such as psilocybin impact brain function - the question is which parts reflect the “trip” and which parts reflect “anxiety about the trip”?

4. You have also looked at the matter of using cognitive behavioral therapy for various kinds of mental disorders. How does CBT measure up, in your opinion? Is it useful for addiction?

Keith Laws: Yes, unlike any other country, the UK endorses using CBT to treat psychotic symptoms and to prevent relapse in schizophrenia. Indeed, “NICE” (the National Institute of Clinical Excellence), which decide which treatments are made available to UK patients, suggest that we offer CBT to “all people with schizophrenia”. Anyway, we meta-analysed the data for whether CBT reduces symptomatology or prevents relapse and came to the conclusion that the evidence supports neither. Crucially, CBT only appeared to “work” when the therapists were not blind at outcome assessment i.e. they knew to which group the patient was assigned (CBT or control)! The irony is that CBT therapists sing the mantra of evidence-based practice!

In terms of the use of CBT in people with substance abuse problems, it produces a small impact on abstinence with opiates, stimulants and cocaine, but has little or impact on alcohol use; and as one might expect, these effects disappear across time. Some evidence also suggests that women respond better to CBT than men. Perhaps the most intriguing finding in this area is that CBT has had much greater success in reducing cannabis use, with up to 80% showing significant reduction in use.

5. What else have you been investigating recently? What are you excited about?

Keith Laws: Over the past 3 years or so I have been doing more work with individuals suffering from the obsessive compulsive syndrome of disorders i.e. OCD, Body Dysmorphic Disorder, Trichotillomania, Schizo-Obsessive disorder, Tourette’s, and Perfectionism. Our work is looking at phenotypes that might be expressed through this range of disorders and in their first-degree unaffected relatives. 

Other things we are working on include what we call “Mind-Pops”—those little thoughts, words, images, or tunes that suddenly pop into your mind at unexpected times and are totally unrelated to your current activity—described long ago by novelists such as Marcel Proust and Vladimir Nabokov.  We have just published a paper showing that verbal hallucinations, the core symptom of schizophrenia, may be related to the mind-pop phenomenon that almost everybody experiences, but just manifests itself in a different way.

MDMA Likes It Hot

X and ambient air temperature.

One of the enduring mysteries about MDMA, the popular amphetamine derivative known as Ecstasy, or X, is the relationship between the drug and ambient air temperature. Why are raves hot, sweaty, and full of loud music and flashing lights? Because “human subjects report a higher euphoric state when taking the drug in sensory rich environments,” according to researchers. So there’s a reason for all those glow sticks and speaker stacks. But is it something inherent in the mechanism of the drug—or simply the overheated party atmosphere combined with vigorous dancing—that can sometimes raise a ravers’ body temperature to dangerous levels?

Drug researchers have known for some time that Ecstasy and high temperature are somehow interlinked. Animal studies have produced strong evidence that a heated environment can cause an increase in MDMA-stimulated serotonin 5-HT response. Many ravers take steps to prevent hyperthermia, or overheating, by regularly drinking water and coming off the dance floor at regular intervals. Most people have heard of hypothermia, a condition in which body temperature drops to dangerously low levels. But hyperthermia can be just as deadly, and it is a common emergency room complaint in MDMA admissions. 

In animal models, rats on MDMA (they like it enough to self-administer) show significantly elevated responses to serotonin in the nucleus accumbens at high room temperatures. What does that mean? What goes up must come down: It opens the door to possible serotonin depletion, which can cause dysfunctions in mood and cognition. Researchers at the University of Texas in Austin have found that in rodents, “the magnitude of the hyperthermic response has been tightly correlated with MDMA-induced 5-HT depletion in various brain regions.” The question they pose is whether “elevated ambient temperatures, such as those encountered in rave venues, can exacerbate MDMA-induced temperature-increasing effects and the likelihood of adverse drug effects.” (Cocaine has temperature-related effects as well. When the ambient air temperature is higher than 75 degrees F, accidental cocaine overdoses increase.)

Ecstasy boosts dopamine as well. The Texas researchers suggest that “the combined enhancement of 5-HT and dopamine may contribute to MDMA’s unique effects on thermoregulation.” They also found that core temperature responses appeared to be “experience-dependent,” meaning that rats didn’t show significantly elevated core temperatures in warm rooms until after they had rolled with MDMA at least ten times. And the worse it gets, the worse it gets, according to the report, published in European Neuropsychopharmacology: “Our results suggest that a heated environment facilitates MDMA-induced disruption of homeostatic thermoregulatory responses, but that repeated exposure to MDMA may also disrupt thermoregulation regardless of ambient temperature.”

So, while all that sweaty dancing amps up the perceptual effects of Ecstasy, it isn’t necessarily implicated in overheating. To simulate a nightclub full of X-ed out ravers, investigators at the Scripps Research Institute tested rats on MDMA while the animals exercised on activity wheels.  Writing in Pharmacology Biochemistry and Behavior, the researchers found that “wheel activity did not modify the hyperthermia produced…. These results suggest that nightclub dancing in the human Ecstasy consumer may not be a significant factor in medical emergencies.”

Bottom line: Although we have a reasonable idea of how it works in animals, we don’t really know how much of that knowledge applies to humans in rave settings. Research aimed at teasing out the specifics of temperature-related responses to MDMA is ongoing. And it does matter. Frequent heat-induced responses could lead to prolonged 5-HT depletion, which is suspected of causing an escalation of drug intake in experienced Ecstasy users. And frequent, escalating use of MDMA is implicated in a long roster of potential cognitive impairments. 

Photo Credit: http://electricchildren.com

“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.

It is beginning to look like acute kidney injury from the newer synthetic drugs may be a genuine threat. And if that wasn’t bad enough, continuing research has implicated MDMA, better known as Ecstasy, as another potential source of kidney damage. Recreational druggies, forewarned is forearmed.

Bath salts first. In the Wyoming case, while the drug in question may have been one of the synthetic marijuana products marketed as Spice, it’s entirely possible that the drug in question was actually one or more of the new synthetic stimulants called bath salts. (Quality control and truth in packaging are not part of this industry). The American Journal of Kidney Diseases recently published a report titled “Recurrent Acute Kidney Injury Following Bath Salts Intoxication.” It features a case history that Yale researchers believe to be “the first report of recurrent acute kidney injury associated with repeated bath salts intoxication.”  The most common causes for emergency room admissions due to bath salts—primarily the drugs MDPV and mephedrone—are agitation, hallucinations, and tachycardia, the authors report. But the case report of a 26-year old man showed recurrent kidney injury after using bath salts. The authors speculate that the damage resulted from “severe renal vasospasm induced by these vasoactive substances.” (A vasoactive substance can constrict or dilate blood vessels.)

A possible secondary mechanism of action for kidney damage among bath salt users is rhabdomyolysis—a breakdown of muscle fibers that releases muscle fiber contents into the bloodstream, causing severe kidney damage. Heavy alcohol and drug use, especially cocaine, are also known risk factors for this condition. The complicating factor here is that rhabdomyolysis has also been described in cases of MDMA intoxication, and here we arrived at the second part of the story.

In 2008, the Clinical Journal of the American Society of Nephrology published “The Agony of Ecstasy: MDMA and the Kidney.” In this study, Garland A. Campbell and Mitchell H. Rosner of the University of Virginia Department of Medicine found that “Ecstasy has been associated with acute kidney injury that is most commonly secondary to nontraumatic rhabdomyolysis but also has been reported in the setting of drug-induced liver failure and drug-induced vasculitis.”

Chemically, MDMA is another amphetamine spinoff, like mephedrone and other bath salts. Many people take this club drug regularly without apparent harm, whereas others seem to be acutely sensitive and can experience serious toxicity, possibly due to genetic variance in the breakdown enzyme CYP2D6. The authors trace the first case report of acute kidney injury due to Ecstasy back to 1992, but “because most of these data are accrued from case reports, the absolute incidence of this complication cannot be determined.” 

 Campbell and Rosner believe that nontraumatic rhabdomyolysis is a likely culprit in many cases, and speculate that the condition is “greatly compounded by the ambient temperature, which in crowded rave parties is usually elevated.” If a physician suspects rhabdomyolysis in an Ecstasy user, “aggressive cooling measures should be undertaken to lower the patient’s core temperature to levels that will lessen further muscle and end-organ injury.” This complication can have far-reaching effects: The authors note the case history of “transplant graft loss of both kidneys obtained from a donor with a history of recent Ecstasy use.”

In addition, there may be undocumented risks to the liver as well. An earlier study by Andreu et. al. claims that “up to 31% of all drug toxicity-related acute hepatic failure is due to MDMA… Patients with severe acute hepatic failure secondary to ecstasy use often survive with supportive care and have successfully undergone liver transplantation.” 

But the picture is far from clear: “Unfortunately, no case reports of acute kidney injury secondary to ecstasy have had renal biopsies performed to allow for further elucidation…” And attributing firm causation is difficult, due to the fact that MDMA users often use other drugs in combination, some of which, like cocaine, can cause kidney problem all by themselves.

A study by Harold Kalant of the University of Toronto’s Addiction Research Foundation, published in the Canadian Medical Association Journal, proposed that “dantrolene, which is a drug used to stop the intense muscle contractures in malignant hyperthermia, should also be useful in the hyperthermic type of MDMA toxicity. Numerous cases have now been treated in this way, some with rapid and dramatic results even when the clinical picture suggested the likelihood of a fatal outcome.”

Adebamiro, A., and Perazella, M. (2012). Recurrent Acute Kidney Injury Following Bath Salts Intoxication American Journal of Kidney Diseases, 59 (2), 273-275 DOI: 10.1053/j.ajkd.2011.10.012

Graphics Credit:  http://trialx.com  

Marijuana Use Up, Up, Up

NIDA releases annual survey of teen drug use.

Research compiled from an annual survey of 8th, 10th and 12th graders by the National Institute on Drug Abuse (NIDA) shows that “marijuana use increased among eighth-graders, and daily marijuana use increased significantly among all three grades. The 2010 use rates were 6.1 percent of high school seniors, 3.3 percent of 10th -graders, and 1.2 percent of eighth-graders compared to 2009 rates of 5.2 percent, 2.8 percent, and 1.0 percent, respectively.”

At a news conference held to announce the results of the study, NIDA director Dr. Nora Volkow said that “high rates of marijuana use during the teen and pre-teen years, when the brain continues to develop, place our young people at particular risk. Not only does marijuana affect learning, judgment, and motor skills, but research tells us that about 1 in 6 people who start using it as adolescents become addicted.”

The annual report, called “Monitoring the Future,” takes the temperature of current teen drug use through interviews with more than 50,000 students across the country. The research is conducted at the Survey Research Center in the Institute for Social Research at the University of Michigan.

The survey showed that teen use of Ecstasy is on the increase as well. According to NIDA, “The MTF survey also showed a significant increase in the reported use of MDMA, or Ecstasy, with 2.4 percent of eighth-graders citing past-year use, compared to 1.3 percent in 2009. Similarly, past-year MDMA use among 10th-graders increased from 3.7 percent to 4.7 percent in 2010.”

As for cigarettes, the recent downward trend has “stalled” after several years of steady improvement, said NIDA. “Greater marketing of other forms of tobacco prompted the 2010 survey to add measures for 12th-graders’ use of small cigars (23.1 percent) and of tobacco with a smoking pipe known as a hookah (17.1 percent).”

For the first time, according to the survey, “declines in cigarette use accompanied by recent increases in marijuana use have put marijuana ahead of cigarette smoking by some measures. In 2010, 21.4 percent of high school seniors used marijuana in the past 30 days, while 19.2 percent smoked cigarettes.”

The survey detected a downward trend in binge drinking across the board. Prescription drug abuse remained fairly steady.

The survey also tracks students’ perception of drugs and their risks, and the degree to which drug are viewed as harmful. The report concludes: “Related to its increased use, the perception that regular marijuana smoking is harmful decreased for 10th- graders (down from 59.5 percent in 2009 to 57.2 percent in 2010) and 12th-graders (from 52.4 percent in 2009 to 46.8 percent in 2010). Moreover, disapproval of smoking marijuana decreased significantly among eighth-graders.”

The survey at the University of Michigan is led by Dr. Lloyd Johnston, operating under a NIDA grant. Additional information on the MTF Survey, as well as comments from Dr. Volkow can be found at http://www.drugabuse.gov/drugpages/MTF.html.

X-ed Out.

Another look at MDMA and serotonin.

A study by Canada’s Centre for Addiction and Mental Health (CAMH) has confirmed earlier findings that chronic users of ecstasy (MDMA) have abnormally low levels of serotonin transporter molecules in the cerebral cortex.

While a decade of research on the effects of ecstasy on brain serotonin has been controversial and largely inconclusive, the latest study used drug hair analysis to confirm levels of MDMA in 49 users and 50 controls. An additional division was made between chronic X users who also tested positive for methamphetamine, and those who did not. Regular usage of MDMA was defined as two tablets twice a month.

The Canadian study, funded by the U.S. National Institute on Drug Abuse (NIDA) and published in the journal Brain, suggests that the serotonin surge responsible for ecstasy’s effects results in a net depletion in regular X users. That is not a new finding--but the Canadian study goes further, suggesting that the serotonin depletion is localized in one area of the brain.

“We were surprised to discover that SERT was decreased only in the cerebral cortex and not throughout the brain,” said study leader Stephen Kish in a press release, “perhaps because serotonin nerves to the cortex are longer and more susceptible to changes.”

Low serotonin transporter (SERT) levels in the cerebral cortex were found in all X users, with or without amphetamine. Dr. Kish noted that the CAMH findings replicate what Kish referred to as “newer data” from Johns Hopkins University. In 1999, a controversial serotonin study of ecstasy users at Johns Hopkins laboratory was criticized for overestimating the level of danger posed by ecstasy-induced serotonin impairments.

Okay, the finding is becoming more robust. But what does it mean? According to co-author Isabelle Boileau, a low SERT level does “not necessarily” indicate structural brain damage. “There is no way to prove whether low SERT is explained by physical loss of the entire serotonin nerve cell, or by a loss of SERT protein within an intact nerve cell.”

For his part, Dr. Kish indicated that his concerns centered on the connection between lower serotonin measurements and MDMA tolerance levels. “Most of the ecstasy users of our study complained that the first dose is always the best, but then the effects begin to decline and higher doses are needed,” he said. “The need for higher doses, possibly caused by low SERT, could well increase the risk of harm caused by this stimulant drug.” The published study concluded that “behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions.”

However, in addition to the confounding variable of methamphetamine (see my post, “How Pure is Ecstasy?”), it remains unclear whether the SERT alterations detected in the study are transient or permanent. Moreover, the nature of the link that “might” exist between lower SERT levels and cognitive impairment in the brains of regular ecstasy users remains a subject of dispute in the drug research community, as in this earlier post.  (And just to emphasize that drugs are complicated things, a spate of promising recent research has suggested that ecstasy might be an effective option for treating people with post-traumatic stress disorder).

The CAMH, affiliated with the University of Toronto, is Canada’s largest mental health and addiction teaching hospital.

Kish, S., Lerch, J., Furukawa, Y., Tong, J., McCluskey, T., Wilkins, D., Houle, S., Meyer, J., Mundo, E., Wilson, A., Rusjan, P., Saint-Cyr, J., Guttman, M., Collins, D., Shapiro, C., Warsh, J., & Boileau, I. (2010). Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C]DASB and structural brain imaging study Brain DOI: 10.1093/brain/awq103

Graphics Credit: pubs/teaching/teaching4/Teaching3.html

Some Background on the Psychedelic Renaissance

Ecstasy, MAPS, and Post-Traumatic Stress Disorder.

The psychedelic drugs, new and old, are not only among the most powerful ever discovered, but are also tremendously difficult to study and utilize responsibly. By the mid-1990s, rumors about Ecstasy (MDMA) toxicity were everywhere. Unlike Prozac, but very much like LSD, Ecstasy not only blocks serotonin uptake, but also causes the release of additional serotonin, much the way cocaine and amphetamine cause the release of extra dopamine.

A study conducted by neurologist George Ricaurte at John Hopkins University under NIDA sponsorship seemed to show conclusive evidence of neurotoxic damage to the serotonin 5-HT receptors in the brains of monkeys given large doses of MDMA. A follow-up study of 30 MDMA users (existing users, since researchers didn’t have government permission to give MDMA to test subjects) showed 30 per cent less cerebrospinal serotonin, compared to a control group. However, the Johns Hopkins team did not have any baseline measurements for the MDMA users, and other neurologists raised technical objections about various aspects of the study, including dosage levels. As was often the case in such studies, the monkeys had been given a whopping dose, compared to the typical raver’s dose. Ricaurte insisted that the amount of MDMA consumed by a typical user in one night of raving was possibly enough to cause permanent brain damage. The government estimates that 10 million Americans have taken Ecstasy.

That would seem to be the end of the story, and a sobering lesson for today’s youth—but that is not how it turned out. A few years later, Dr. Charles Grob, psychiatry professor at the UCLA School of Medicine, received the first FDA approval ever given for the administration of MDMA to human volunteers. The result of Grob’s testing was that none of the volunteers showed any evidence of neuropsychological damage of any kind. In testimony before the U.S. Sentencing Commission, which was considering harsher penalties for MDMA possession in 2001, Dr. Grob seriously questioned the methodology of the Ricaurte studies: “It is very unfortunate that the lavishly funded NIDA-promoted position on so-called MDMA neurotoxicity has inhibited alternative research models which would better delineate the true range of effects of MDMA, including its potential application as a therapeutic medicine.” Science retracted its coverage of the Ricaurte findings.

It was eventually discovered that Dr. Ricaurte’s monkeys had been injected with amphetamine, not with MDMA—a discovery that also nullified four other published papers. Dr. Ricaurte explained that some labels had been switched, and a Johns Hopkins spokesperson called the whole thing “an honest mistake.” The basic questions about Ecstasy remain unanswered. Is there a line that separates a conceivably therapeutic dose of Ecstasy for mental ills or addictive ills from a possibly brain-damaging run of several dozen high-dosage trips? Perhaps the permanently altered receptor arrays, if they exist, don’t affect cognition or emotions in any significant way over the long run. Still, the risks of overindulgence appear to be at least potentially higher than the risks of overindulging in LSD or Ibogaine. All of the psychedelics tend to be more self-limiting than other categories of psychoactive drugs, anyway. After two or three days, even the most die-hard raver or LSD head is usually ready to take a break.

Rick Doblin and others at  the Multidisciplinary Association for Psychedelic Studies (MAPS) are now working with government investigators to pursue MDMA for the treatment of post-traumatic stress disorder. There are reports that very low doses of LSD sometimes have an antidepressant effect. One thing we know for certain is that people on SSRI medications or MAO inhibitors report that their experiences on LSD or Ecstasy are shorter and far less powerful than is typically the case.  There appears to be some competition for receptor sites when Zoloft meets LSD. In contrast to the diminished psychedelic experience while on SSRIs, the older norepinephrine-active tricyclics like Tofranil and Norpramine reportedly serve to potentiate the LSD or MDMA experience. None of these combinations is a wise idea, due to uncertainties about the interactions.

Even DMT, which experienced trippers compared to being shot out of a cannon, has returned as a legitimate study subject. Dr. Rick Strassman, then with the University of New Mexico’s School of Medicine, received approval for clinical testing of DMT. Strassman was drawn to the subject because of the molecule’s natural occurrence in the brain (which makes every man, woman, and child in America a drug criminal, chemically speaking). He gave DMT to 60 human volunteers over a study period of five years. Strassman was primarily interested in near-death experiences and mystical experiences. None of the supervised DMT sessions evidently resulted in any detectable harm to the participants. Strassman presents his views on the medical use of DMT in his book, DMT: The Spirit Molecule.

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008, 2009.

Graphics Credit: http://hightimes.com/

How Pure Is Ecstasy?

Dutch study of street MDMA.

For 16 years, the Drugs Information Monitoring System (DIMS) in The Netherlands has gathered and analyzed tablets of purported MDMA sold on the street as Ecstasy. In a research report published in Addiction, Neeltje Vogels and others at the Netherlands Institute for Mental Health and Addiction in Utrecht found that between 70 to 90 % of the samples submitted as MDMA were pure. The most common non-MDMA adulterant was found to be caffeine.

The study covered the years from 1993 to 2008. In the mid to late 1990s, researchers saw an increase in ephedra and methamphetamine in the samples, and sample purity hit an all-time low of 60% in 1997. The years from 2000 to 2004 were the golden era, so to speak, for MDMA purity. “After 2004,” the study authors write, “the purity of ecstasy tables decreased again, caused mainly by a growing proportion of tablets containing meta-chlorophenylpiperazine (mCPP).” mCPP belongs to a class of stimulants, the so-called piperazines, that have been banned in several countries (See my post).

As noted on the DrugMonkey science blog, a lack of consistent published data has hampered efforts at studying street MDMA. Tablets for analysis are obtained either from law enforcement—which seizes drugs that may or may not be for sale at the club level--or drug analysis and harm reduction sites. The problem, DrugMonkey writes, is that “perhaps Ecstasy found to result in suspicious subjective effects on the user are submitted to harm reduction sites preferentially.” In other words, people only submit the brown acid.

The Dutch study, on the other hand, obtained samples for testing from capsules seized by club owners and given to the police, who then passed them on to DIMS for analysis. This system helped eliminate the possible bias effect of voluntary submissions.

The study also found that larger tablets, containing 100 mgs or more of MDMA, became increasingly popular starting in 2001.

DrugMonkey, an anonymous NIH-funded biomedical researcher, calls the study “an impressive longitudinal dataset.” The data, he wrote, give us “a good picture of the percentages of MDMA-only across time (higher than certain MDMA fans seem to acknowledge when it comes time to assess medical emergency cases) and the relative proportions of specific contaminants (certain baddies are quite rare.)”

Specifically missing in action most years is the baddy known as PMA, or para-methoxy-amphetamine, which has been implicated in many of the alleged Ecstasy deaths by overheating--a condition known as hyperthermia.

Graphics Credit: National Institute on Drug Abuse


addiction drugs

Arguing About Ecstasy

U.K. professor says “E” no riskier than horseback riding.

Professor David Nutt of Bristol University and Imperial College, London, stirred up a hornet’s nest of controversy last week when he compared the dangers of the club drug Ecstasy (MDMA) to people’s addiction to horse riding. In an article titled "Equasy: An overlooked addiction with implications for the current debate on drug harms,” published in the Journal of Psychopharmacology, Professor Nutt wrote: "Drug harm can be equal to harms in other parts of life. There is not much difference between horse-riding and ecstasy."

What makes all of this interesting is that Professor Nutt serves as the chairperson of the Home Office's Advisory Council on the Misuse of Drugs (ACMD), which will rule next week on whether ecstasy should be downgraded to a Class B drug in the British drug classification system. Drug treatment activists and government ministers immediately called for his resignation, saying Nutt was on a "personal crusade" to decriminalize the drug.

The BBC News Service reported that a Home Office spokesperson said recently that the government believed ecstasy should remain a Class A drug. "Ecstasy can and does kill unpredictably. There is no such thing as a 'safe dose'," he said.

Horse-riding accounts for 100 deaths or serious accidents a year in the U.K., according to Nutt. “Making riding illegal would completely prevent all these harms and would be, in practice, very easy to do.” In contrast, recent figures indicate about 30 deaths attributed to ecstasy use in the U.K. last year. “This attitude raises the critical question of why society tolerates - indeed encourages - certain forms of potentially harmful behaviour but not others such as drug use," Nutt wrote.

In an article by Christopher Hope in the Daily Telegraph, Nutt said: "The point was to get people to understand that drug harm can be equal to harms in other parts of life.” He cited other risky activities such as “base jumping, climbing, bungee jumping, hang-gliding, motorcycling," which, he said, were more dangerous than illicit drugs.

An ACMD spokesperson said: "Prof Nutt's academic research does not prejudice the work that he conducts as chair of the ACMD."

According to the Telegraph article, there are 500,000 regular users and between 30 million and 60 million ecstasy pills in circulation in the U.K.

In a letter published by the Journal of Psychopharmacology two years earlier, Professor Nutt used a more apt comparison to make the same point:

“The fact that alcohol is legal and ecstasy not is merely an historical accident, not a science-based decision. Alcohol undoubtedly kills thousands more people each year than ecstasy.... Many relatively ill-informed and indeed innocent young people will continue to die and many more will end up with the destructive consequences of alcohol dependence or physical damage. If the same effort currently used to deter ecstasy use was put toward reducing alcohol misuse the situation might improve.”


Photo Credit: Foundation Antidote