Showing posts sorted by relevance for query psychosis. Sort by date Show all posts
Showing posts sorted by relevance for query psychosis. Sort by date Show all posts

Sunday, November 23, 2008

Marijuana Panic Revisited


U.K. journal casts doubt on psychosis connection.

In May of this year, The University College of London reports that different strains of marijuana cause different types of psychological maladies. Shortly thereafter, Prime Minister Brown "publically described new strains of cannabis as 'lethal,' as if they could trigger a fatal overdose," according to an editorial in the Guardian. (See "U.K. Marijuana Panic Continues"). And in August, a mental health story run by the London Daily Mail claimed that smoking a single joint of marijuana increased the risk of developing schizophrenia by 41 per cent—an erroneous statistic that was also hotly contested by various U.K. drug experts. (See "Media Suffers Attack of Cannabis Psychosis").

Now comes a review article from the British Journal of Psychiatry, published by the Royal College of Psychiatrists, strongly suggesting that the odds of an association between cannabis and psychosis is “low.”

A group of drug experts and psychiatrists, including scientists from the University of Bristol, Imperial College London, Cambridge University, and Cardiff University undertook to “systematically review the evidence pertaining to whether cannabis affects outcome of psychotic disorders.”

The group searched relevant databases and compiled a list of more than 15,000 relevant references. A total of 13 longitudinal studies were included in the quality assessment.

The authors concluded that, despite prevailing clinical opinion, it remained “unclear” whether cannabis led to worse outcomes for people with psychosis, “or whether this impression is confounded by other factors. Specifically, the review authors noted that “few studies adjusted for baseline illness severity, and most made no adjustment for alcohol, or other potentially important confounders. Adjusting for even a few confounders often resulted in substantial attenuation of results.”

In the end, “confidence that most associations were specifically due to cannabis is low.”

Graphics Credit: COSMOS

Thursday, August 22, 2013

“Spiceophrenia”


Synthetic cannabimimetics and psychosis.

Not long ago, public health officials were obsessing over the possibility that “skunk” marijuana—loosely defined as marijuana exhibiting THC concentrations above 12%, and little or no cannabidiol (CBD), the second crucial ingredient in marijuana—caused psychosis. In some cases, strong pot was blamed for the onset of schizophrenia.

The evidence was never very solid for that contention, but now the same questions have arisen with respect to synthetic cannabimimetics—drugs that have THC-like effects, but no THC. They are sold as spice, incense, K2, Aroma, Krypton, Bonzai, and dozens of other product monikers, and have been called “probationer’s weed” for their ability to elude standard marijuana drug testing. Now a group of researchers drawn primarily from the University of Trieste Medical School in Italy analyzed a total of 223 relevant studies, and boiled them down to the 41 best investigations for systematic review,  to see what evidence exists for connecting spice drugs with clinical psychoses.

Average age of users was 23, and the most common compounds identified using biological specimen analysis were the now-familiar Huffman compounds, based on work at Clemson University by John W. Huffman, professor emeritus of organic chemistry: JWH-018, JWH-073, JWH-122, JWH-250. (The investigators also found CP-47,497, a cannabinoid receptor agonist developed in the 80s by Pfizer and used in scientific research.) The JWH family consists of very powerful drugs that are full agonists at CB-1 and CB-2 receptors, where, according to the study, “they are more powerful than THC itself.” What prompted the investigation was the continued arrival of users in hospitals and emergency rooms, presenting with symptoms of agitation, anxiety, panic, confusion, combativeness, paranoia, and suicidal ideation. Physical effects can includes elevated blood pressure and heart rate, nausea, hallucinations, and seizures.

One of the many problems for researchers and health officials is the lack of a widely available set of reference samples for precise identification of the welter of cannabis-like drugs now available. In addition, the synthetic cannabimimetics (SCs) are frequently mixed together, or mixed with other psychoactive compounds, making identification even more difficult. Add in the presence of masking agents, along with various herbal substances, and it becomes very difficult to find out which of the new drugs—none of which were intended for human use—are bad bets.

Availing themselves of toxicology tests, lab studies, and various surveys, the researchers, writing in Human Psychopharmacology’s Special Issue on Novel Psychoactive Substances, crunched the data related to a range of psychopathological issues reported with SCs—and the results were less than definitive. They found that many of the psychotic symptoms occurred in people who had been previously diagnosed with an existing form of mental disturbance, such as depression, ADHD, or PTSD. But they were able to determine that psychopathological syndromes were far less common with marijuana than with SCs. And those who experienced psychotic episodes on Spice-type drugs presented with “higher/more frequent levels of agitation and behavioral dyscontrol in comparison with those psychotic episodes described in marijuana misusers.”

In the end, the researchers can do no better than to conclude that “the exact risk of developing a psychosis following SC misuse cannot be calculated.” What would the researchers need to demonstrate solid causality between designer cannabis products and psychosis? More product consistency, for one thing, because “the polysubstance intake pattern typically described in SC misusers may act as a significant confounder” when it comes to developing toxicological screening tools. Perhaps most disheartening is “the large structural heterogeneity between the different SC compounds,” which limited the researchers’ ability to interpret the data.

This stuff matters, because the use of Spice-type drugs is reported to be increasing in the U.S. and Europe. Online suppliers are proliferating as well. And the drugs are particularly popular with teens and young adults. Young people are more likely to be drug-naïve or have limited exposure to strong drugs, and there is some evidence that children and adolescents are adversely affected by major exposure to drugs that interact with cannabinoid receptors in the brain. 




Thursday, July 31, 2014

Avoid the ‘Noid: Synthetic Cannabinoids and “Spiceophrenia”


Like PCP all over again.

Synthetic cannabis-like “Spice” drugs were first introduced in early 2004, and quickly created a global marketplace. But the drugs responsible for the psychoactive effects of Spice products weren’t widely characterized until late 2008. And only recently have researchers made significant progress toward understanding why these drugs cause so many problems, compared to organic marijuana.

Synthetic cannabinoids (SC), as a class of drugs, are generally more potent at cannabinoid receptors than marijuana itself.  As full agonists, synthetic cannabinoids show binding affinities between 5 and 10,000 times higher than THC at these receptors.

A recent literature study by Duccio Papanti at the University of Trieste and coworkers sheds additional light on the problematic nature of these drugs. In an article for Advances in Dual Diagnosis titled “’Noids in a nutshell: everything you (don’t) want to know about synthetic cannabimimetics,” the researchers note that “Spice products’ effects have been anecdotally described by users as intense and ‘trippy’ marijuana-like, with hallucinatory experiences being associated with higher levels of intake. In comparison with cannabis, SC compounds may be associated with quicker ‘kick off’ effects; significantly shorter duration of action; larger levels of hangover effects; and more frequent paranoid feelings.”

The study also points out a trouble spot: “Super-concentrations of synthetic cannabinoids (e.g. ‘hot-spots’) in herbal blends, originating from a non-optimal homogenization between synthetic cannabinoids and the vegetal substrate, can result in overdoses/intoxications and ‘bad trips’ in users.” In other words, the chemical powder is often so poorly mixed with the vegetable matter that potencies in the batch can be way too high, depending upon the luck of the draw, and are bound to vary from batch to batch in any event.

Nonetheless, there is a cluster of specific health effects that brings users to the emergency room. The typical set of symptoms—bearing in mind that polydrug use always complicates the picture—include elevated heart rate, elevated blood pressure, visual and auditory hallucinations, agitation, anxiety, nausea, vomiting, and seizures.

The authors note that “nausea and seizures are very uncommon in marijuana use, due to the suggested anticonvulsant/antiemetic properties of cannabis.” In fact, misusers who present doctors with vomiting as a symptom are often assumed to be free of cannabis-type drugs. Not so with synthetic cannabinoids. In an email interview, lead author Duccio Papanti told me that “many users describe the occurrence of vomiting, even with a non-recurrent and low use of these compounds. My idea is that this may be due to the smoking of hot-spotted blends, and that at high concentrations these compounds can work more on 5-HT receptors (in fact, vomit and seizures are signs of a serotonin syndrome).”

Less common, luckily, are other medical issues like heart attack, kidney injuries, and stroke. Of primary concern, the authors warn, are the reported incidents of “transient psychotic episodes,” “relapse of a primary psychosis,” and “‘ex novo’ psychosis in previous psychosis-free subjects.”

As for the mechanism behind the reported hallucinogenic effects: “A number of synthetic cannabinoids contain an indole moiety, either in their basic structure or in their substituents.” Indoles are molecular groups structurally similar to serotonin, and are active in drugs like LSD and DMT.

“According to this finding,” Papanti says, “their use could interfere with serotonin 5-HT neurotransmission more than THC. It is possible that the indole moieties incorporated in the molecules of synthetic cannabinoids can bind 5-HT2 receptors, acting as an hallucinogenic drug (in fact visual hallucinations are not uncommon in SC use).”

 One of the main problems, of course, is that physicians know almost nothing about detecting and treating acute overdoses of synthetic cannabinoid products. And even if an OD victim was lucky enough to wash up at a health facility that had access to instant chromatography detection testing, “[due to] the lack of appropriate reference samples, SC compounds are difficult to identify.”

The risk here is not evenly distributed, obviously. Young people, and anybody subject to marijuana urine testing, are the clear market for these products. This includes students, athletes, members of the Armed Forces, transportation workers, mining workers, and many others. Spice users are overwhelmingly male.

How many people are taking the risk? An estimate of student use comes from the U.S. 2013 “Monitoring the Future” survey, which shows that about 8% of 17-18 year-olds have tried Spice products. For 12th graders, Spice products are second only to marijuana itself in many districts. And yet there is a dearth of longitudinal studies in humans to evaluate the long-term impact of using synthetic cannabinoids.

Papanti and colleagues call for the creation of an international agency dedicated to “toxicovigilance” based on a “non-biased ‘real-time’ database,” including adverse drug effects, as a way of clarifying and promoting appropriate clinical guidelines for Spice drugs. “These substances are dangerous, and they have been associated with a number of deaths,” Papanti says. He would like to see a “network in which users report their adverse effects. Such an online system already exists in the Pharmacovigilance program at the Lareb Centre in the Netherlands. They collect reports of medications’ adverse effects from both patients and doctors and it works very well.”

Tolerance, dependence, and withdrawal have all been documented in several categories of Spice products. Spice withdrawal effects can be severe, the authors say, and may include craving, tremor, profuse sweating, insomnia, anxiety, irritability and depression.

Graphics Credit:  http://www.caregroupnz.org.nz/drug-prevention-education-campaign/

Friday, March 16, 2012

LSD and Alcohol: The History


Back when acid was legal.

After last week’s blitz of coverage concerning studies done in the 60s on the use of LSD for the treatment of alcoholism, I thought it would be useful to provide a bit of background; some pertinent psychedelic history to help put this information in perspective:

It may come as a surprise to many people that throughout the 60s, there were LSD clinics operating in England and Europe. European LSD therapists tended to use very low doses as an adjunct to traditional psychoanalytic techniques. But North American researchers took a different, bolder approach. When “psychedelic” therapy began to catch on in Canada and the United States, therapists typically gave patients only one or two sessions at very high doses. These early efforts were aimed at producing spontaneous breakthroughs or recoveries in alcoholics through some manner of religious epiphany or inner conversion experience. The only other quasi-medical approach of the day, the Schick Treatment Center’s brand of “aversion therapy,” was not seen to produce very compelling long-term recovery rates, and subsequently fell out of favor. In this light, the early successes with LSD therapy, sometimes claimed to be in the 50-75 per cent range, looked noteworthy indeed. However, the design and criteria of the LSD/alcoholism studies varied so widely that it has never been possible to draw definitive conclusions about the work that was done, except to say that LSD therapy seemed to be strikingly effective for certain alcoholics. Some patients were claiming that two or three trips on LSD were worth years of conventional psychotherapy—a claim not heard again until the advent of Prozac thirty years later.

 “I’ve taken lysergic acid several times, and have collected considerable information about it,” Bill Wilson, the co-founder of Alcoholics Anonymous, disclosed in a private letter written in 1958. “At the moment, it can only be used for research purposes. It would certainly be a huge misfortune if it ever got loose in the general public without a careful preparation as to what the drug is and what the meaning of its effects may be.”  Like many others, Wilson was excited by LSD’s potential as a treatment for chronic alcoholism. Even Hollywood was hip to the new therapy. Cary Grant, among others, took LSD under psychiatric supervision and pronounced it immensely helpful as a tool for psychological insight. Andre Previn, Jack Nicholson, and James Coburn agreed. (It could be argued that the human potential movement began here).

No drug this powerful and strange, if American history was any guide, could remain legal for long. Unlike their colleagues in the intelligence agencies, politicians and law enforcement officers didn’t know about Mongolian shamans and their fly agaric mushrooms; about European witches and their use of psychoactive plant drugs like nightshade and henbane; about Persian sheiks with their cannabis water pipes; Latin American brujos with their magic vines.

But for the CIA, the big fish was always LSD.

What interested the Central Intelligence Agency about LSD was its apparent ability to produce the symptoms of acute psychosis. Operation ARTICHOKE was designed to ferret out LSD’s usefulness as an instrument of psychological torture, and as a possible means of destabilizing enemy forces by means of aerosol sprays or contaminated water supplies. (The drug’s overwhelming potency made such parts-per-billion fantasies a possibility.)

The agency knew where to turn for a secure American source of supply. Eli Lilly and Co., the giant drug manufacturer, was already involved in LSD research on behalf of the U.S. government. The trouble was that LSD was expensive, and all roads led to Sandoz Laboratories in Switzerland. Organic LSD had to be painstakingly extracted from ergot, a fungus that grows in kernels of rye. Eventually, Sandoz and Eli Lilly successfully synthesized LSD in their own laboratories. With the advent of a reliable domestic supplier of synthetic LSD, the CIA under Allen Dulles was assured of a steady source for experimental purposes.

When LSD did not pan out as a reliable agent of interrogation, CIA investigators turned their attention to its purported ability to mimic acute psychosis—its “psychomimetic” aspect—which researchers were praising as a new avenue toward a biological understanding of schizophrenia. The CIA funneled grant money for LSD research into the academic and commercial R&D world through a host of conduits. Various experiments with non-consenting subjects—typically military or prison personnel—showed that LSD could sometimes break down established patterns of thought, creating a “twilight zone” during which the mind was more susceptible to various forms of psychological coercion and control. Perhaps, under the influence of LSD, prisoners could be transformed into counter-espionage agents. It also occurred to the CIA that the same drug could be used on their own agents for the same purposes. Numerous CIA agents took LSD trips in order to familiarize them with acid’s Alice-in-Wonderland terrain. Some of these unusual experiments were captured on film for use in military training videos.

One place where ARTICHOKE research took place was the Addiction Research Centre at the Public Health Service Hospital in Lexington, Kentucky—the same hospital that specialized in the treatment of hardcore heroin addicts. Lexington was part hospital and part penitentiary, which made it perfect for human experimentation. The addict/inmates of Lexington were sometimes given LSD without their consent, a practice also conducted at the federal prison in Atlanta, and at the Bordentown Reformatory in New Jersey. 

In 1953, then-CIA director Allen Dulles authorized Operation MK-ULTRA, which superseded earlier clandestine drug investigations. Under the direction of Dr. Sidney Gottlieb, a chemist, the government began slipping LSD and other psychoactive drugs to unwitting military personnel. During a work retreat in Maryland that year, technicians from both the Army and the CIA were dosed without their knowledge, and were later told that they had ingested a mind-altering drug. Dr. Frank Olson, a civilian biochemist involved in research on biological warfare, wandered away from the gathering in a confused state, and committed suicide a few days later by leaping to his death from an upper floor of the Statler Hilton in New York City. The truth about Olson’s death was kept secret from his family, and from the rest of the nation, for more than twenty years. In 1966, LSD was added to the federal schedule of controlled substances, in the same category as heroin and amphetamine. Simple possession became a felony. The Feds had turned off the spigot, and the research came to a halt. Federal drug enforcement agents began showing up at the homes and offices of well-known West Coast therapists, demanding the surrender of all stockpiles of LSD-25. The original acid elite was being hounded, harassed, and threatened in a rancid atmosphere of pharmaceutical McCarthyism. Aldous Huxley, Humphrey Osmond, even father figure Albert Hoffman, all viewed these American developments with dismay. The carefully refined parameters and preparations, the attention to set and setting, the concerns over dosage, had gone out the window, replaced by a massive, uncontrolled experiment in the streets. Small wonder, then, that the circus atmosphere of the Haight-Ashbury “Summer of Love” in 1967 seemed so badly timed. Countercultural figures were extolling the virtues of LSD for the masses—not just for research, not just for therapy, not as part of some ancient religious ritual—but also just for the freewheeling American hell of it. What could be more democratic than the act of liberating the most powerful mind-altering drug known to man?

It is at least conceivable that researchers and clinicians eventually would have backed away from LSD anyway, on the grounds that the drug’s effects were simply too weird and unpredictable to conform to the rigorous dictates of clinical studies. Nonetheless, researchers had been given a glimpse down a long, strange tunnel, before federal authorities put an end to the research.


Graphics Credit: http://news.sky.com

Monday, July 21, 2014

Hunting For the Marijuana-Dopamine Connection


Why do heavy pot smokers show a blunted reaction to stimulants?

Most drugs of abuse increase dopamine transmission in the brain, and indeed, this is thought to be the basic neural mechanism underlying the rewarding effects of addictive drugs. But in the case of marijuana, the dopamine connection is not so clear-cut. Evidence has been found both for and against the notion of increases in dopamine signaling during marijuana intoxication.

Marijuana has always been the odd duck in the pond, research-wise. Partly this is due to longstanding federal intransigence toward cannabis research, and partly it is because cannabis, chemically speaking, is damnably complicated. The question of marijuana’s effect on dopamine transmission came under strong scrutiny a few years ago, when UK researchers began beating the drums for a theory that chronic consumption of strong cannabis can not only trigger episodes of psychosis, but can be viewed as the actual cause of schizophrenia in some cases.

It sounded like a new version of the old reefer madness, but this time around, the researchers raising their eyebrows had a new fact at hand: Modern marijuana is several times stronger than marijuana in use decades ago. Selective breeding for high THC content has produced some truly formidable strains of pot, even if cooler heads have slowly prevailed on the schizophrenia issue.

One of the reports helping to bank the fires on this notion appeared recently in the Proceedings of the National Academy of Sciences (PNAS). Joanna S. Fowler of the Biosciences Department at Brookhaven National Laboratory, Director Nora Volkow of the National Institute on Drug Abuse (NIDA), and other researchers compared brain dopamine reactivity in healthy controls and heavy marijuana users, using PET scans. For measuring dopamine reactivity, the researchers chose methylphenidate, better known as Ritalin, the psychostimulant frequently prescribed for attention-deficit hyperactivity disorder (ADHD). Ritalin basically functions as a dopamine reuptake inhibitor, meaning that the use of Ritalin leads to increased concentrations of synaptic dopamine.

In the study, heavy marijuana users showed a blunted reaction to the stimulant Ritalin due to reductions in brain dopamine release, according to the research. “The potency of methylphenidate (MP) was also reported to be stronger by the controls than by the marijuana abusers." And in marijuana abusers, Ritalin caused an increase in craving for marijuana and cigarettes.

 “We found that marijuana abusers display attenuated dopamine responses to MP including reduced decreases in striatal distribution volumes,” according to the study’s conclusion. “The significantly attenuated behavioral and striatal distribution volumes response to MP in marijuana abusers compared to controls, indicates reduced brain reactivity to dopamine stimulation that in the ventral striatum might contribute to negative emotionality and drug craving.”

Down-regulation from extended abuse is another complicated aspect of this: “Although, to our knowledge, this is the first clinical report of an attenuation of the effects of MP in marijuana abusers, a preclinical study had reported that rats treated chronically with THC exhibited attenuated locomotor responses to amphetamine. Such blunted responses to MP could reflect neuroadaptations from repeated marijuana abuse, such as downregulation of DA transporters.”

 Animal studies have suggested that these dopamine alterations are reversible over time.

Another recent study came to essentially the same conclusions. Writing in Biological Psychiatry, a group of British researchers led by Michael A.P. Bloomfield and Oliver D. Howes analyzed dope smokers who experienced psychotic symptoms when they were intoxicated. They looked for evidence of a link between cannabis use and psychosis and concluded: “These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.” And again, the higher the level of current cannabis use, the lower the level of striatal dopamine synthesis capacity.  As for mechanisms, the investigators ran up against similar causation problems: “One explanation for our findings is that chronic cannabis use is associated with dopaminergic down-regulation. This might underlie amotivation and reduced reward sensitivity in chronic cannabis users. Alternatively, preclinical evidence suggests that low dopamine neurotransmission may predispose an individual to substance use.”

The findings of diminished responses to Ritalin in heavy marijuana users may have clinical implications, suggesting that marijuana abusers with ADHD may experience reduced benefits from stimulant medications.

Photo Credit: http://www.biologicalpsychiatryjournal.com/

Sunday, May 20, 2012

Energy Drinks: What’s the Big Deal?


The sons of Red Bull are sporting record concentrations of caffeine.

Are energy drinks capable of pushing some people into caffeine-induced psychotic states? Some medical researchers think so, under the right set of conditions.

Red Bull, for all its iconic ferocity, is pretty tame, weighing in at approximately half a cup of coffee. Drinks like Monster Energy and Full Throttle push it up to 100-150, or the equivalent of a full cuppa joe, according to USDA figures at Talk About Coffee. That doesn’t sound so bad—unless you’re ten years old. A little caffeine might put you on task, but an overdose can leave you scattered and anxious—or worse. If you cut your teeth on Coke and Pepsi, then two or three energy drinks can deliver an order-of-magnitude overdose by comparison.

Readers are entitled to ask: Are you serious? Can’t we just ignore the inevitable view-this-with-alarm development in normal kid culture, and move on? 

My interest began when I ran across a 2009 case report in CNS Spectrums, describing an apparent example of “caffeine-induced delusions and paranoia” in a very heavy coffee drinking farmer. “Convinced of a plot against him,” the psychologists write, “he installed surveillance cameras in his house and on his farm…. He became so preoccupied with the alleged plot that he neglected the business of the farm…. and he had his children taken from him because of unsanitary living conditions.”

The patient was not known to be a drinker, reporting less than a case of beer annually. He had shown no prior history of psychotic behaviors. But for the past This post was chosen as an Editor's Selection for ResearchBlogging.orgseven years, he had been consuming about 36 cups of coffee per day, according to his account. Take that number of cups times 125 milligrams, let’s say, for a daily total of 4500 milligrams. At that level, he should be suffering from panic and anxiety disorders, according to caffeine toxicity reports, and he would be advised to call the Poison Control Center. And that certainly seems to have been the case. “At presentation,” the authors write, “the patient reported drinking 1 gallon of coffee/day.”

On the one hand, the idea of caffeine causing a state resembling chronic psychosis is the stuff of sitcoms. On the other hand, metabolisms do vary, and the precise manner in which coffee stimulates adenosine receptors can lead to anxiety, aggression, agitation, and other conditions. Could caffeine, in an aberrant metabolism, break over into full-blown psychosis? At the Caffeine Web, where psychiatrists and toxicologists duke it out over all things caffeinated, Sidney Kay of the Institute of Legal Medicine writes: “Coffee overindulgence is overlooked many times because the bizarre symptoms may resemble and masquerade as an organic or mental disease.” Symptoms, he explains, can include "restlessness, silliness, elation, euphoria, confusion, disorientation, excitation, and even violent behavior with wild, manic screaming, kicking and biting, progressing to semi-stupor.”

That doesn’t sound so good. In “Energy drinks: What is all the hype?” Mandy Rath examines the question in a recent issue of the Journal of the American Academy of Health Practitioners.

Selling energy drinks to kids from 6 to 19 years old is a $3.5 billion annual industry,Rath asserts. And while “most energy drinks consumed in moderation do not pose a huge health risk,” more and more youngsters are putting away higher and higher doses of caffeine. At the level of several cans of Coke, or a few cups of strong coffee or, an energy drink or three, students can expect to experience improved reaction times, increased aerobic endurance, and less sleepiness behind the wheel. Most people can handle up to 300 mg of caffeine in a concentrated blast. Certainly a better bargain, overall, than three or four beers.

But first of all, you don’t need high-priced, caffeine-packed superdrinks to achieve that effect. A milligram of caffeine is a milligram of caffeine. But wait, what about the nifty additives in Full Throttle and Monster and Rockstar? The taurine and… stuff. Taurine is an amino acid found in lots of foods. Good for you in the abstract. Manufacturers also commonly add sugar (excess calories), ginseng (at very low levels), and bitter orange (structurally similar to norepinephrine). However, the truly interesting addition is guarana, a botanical product from South America. When guarana breaks down, it’s principal byproduct is, yes, caffeine. Guarana seeds contain twice the caffeine found in coffee beans. Three to five grams of guarana provide 250 mg of caffeine. Energy drink manufacturers don’t add that caffeine to the total on the label because—oh wait, that’s right, because makers of energy drinks, unlike makers of soft drinks, don’t have to print the amount of caffeine as dietary information. And on an ounce-for-pound basis, kids are getting a lot more caffeine with the new drinks than the older, labeled ones.

All of this increases the chances of caffeine intoxication. Rath writes that researchers have identified caffeine-related increases among children in hypertension, insomnia, motor tics, irritability, and headaches. Chronic caffeine intoxication results in “anxiety, emotional disturbances, and chronic abdominal pain.” Not to mention cardiac arrhythmia, seizures, and mania.

So what have we learned, kids? Energy drinks are safe—if you don’t guzzle several of them in a row, or substitute them for dinner, or have diabetes, or an ulcer, or happen to be pregnant, or are suffering from heart disease or hypertension. And if you do OD on high-caffeine drinks, it will not be pleasant: Severe palpitations, panic, mania, muscle spasms, etc. Somebody might even want to take you to the emergency room. Coaches and teachers need to keep a better eye out for caffeine intoxication.

Note: There is a “caffeine calculator” available at the Caffeine Awareness website, designed to determined whether you are a coffee addict. I can by no means swear to its scientific accuracy, but, based on my own, distinctly non-young person daily intake, the test told me that my consumption was likely to manifest itself as “high irritability, moodiness & personality disorders.” Can I blame it all on those endless cokes we had as kids? Growing up in the Baby Boom suburbs, we all drank carbonated caffeine beverages instead of water. Nothing much has changed except the caffeine levels.

Rath, M. (2012). Energy drinks: What is all the hype? The dangers of energy drink consumption Journal of the American Academy of Nurse Practitioners, 24 (2), 70-76 DOI: 10.1111/j.1745-7599.2011.00689.x

Graphics Credit: http://urlybits.com/

Friday, May 4, 2012

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.”


Monday, October 7, 2013

Spiced: Synthetic Cannabis Keeps Getting Stronger


Case reports of seizures in Germany from 2008 to 2011.

I wish I could stop writing blog posts about Spice, as the family of synthetic cannabinoids has become known. I wish young people would stop taking these drugs, and stick to genuine marijuana, which is far safer. I wish that politicians and proponents of the Drug War would lean in a bit and help, by knocking off the testing for marijuana in most circumstances, so the difficulty of detecting Spice products isn’t a significant factor in their favor. I wish synthetic cannabinoids weren’t research chemicals, untested for safety in humans, so that I could avoid having to sound like an alarmist geek on the topic.  I wish I didn’t have to discuss the clinical toxicity of more powerful synthetic cannabinoids like JWH-122 and JWH-210. I wish talented chemists didn’t have to spend precious time and lab resources laboriously characterizing the various metabolic pathways of these drugs, in an effort to understand their clinical consequences. I wish Spice drugs didn’t make regular cannabis look so good by comparison, and serve as an argument in favor of more widespread legalization of organic marijuana.

A German study, published in Addiction, seems to demonstrate that “from 2008 to 2011 a shift to the extremely potent synthetic cannabinoids JWH-122 and JWH-210 occurred…. Symptoms were mostly similar to adverse effects after high-dose cannabis. However, agitation, seizures, hypertension, emesis, and hypokalemia  [low blood potassium] also occurred—symptoms which are usually not seen even after high doses of cannabis.”

The German patients in the study were located through the Poison Information Center, and toxicological analysis was performed in the Institute of Forensic Medicine at the University Medical Center Freiburg. Only two study subjects had appreciable levels of actual THC in their blood. Alcohol and other confounders were factored out. First-time consumers were at elevated risk for unintended overdose consequences, since tolerance to Spice drug side effects does develop, as it does with marijuana.

Clinically, the common symptom was tachycardia, with hearts rates as high as 170 beats per minute. Blurred vision, hallucinations and agitation were also reported, but this cluster of symptoms is also seen in high-dose THC cases that turn up in emergency rooms. The same with nausea, the most common gastrointestinal complaint logged by the researchers.

But in 29 patients in whom the presence of synthetic cannabinoids was verified, some of the symptoms seem unique to the Spice drugs. The synthetic cannabinoids caused, in at least one case, an epileptic seizure. Hypertension and low potassium were also seen more often with the synthetics. After the introduction of the more potent forms, JWH-122 and JWH-210, the symptom set expanded to include “generalized seizures, myocloni [muscle spasms] and muscle pain, elevation of creatine kinase and hypokalemia.” The researchers note that seizures induced by marijuana are almost unheard of. In fact, studies have shown that marijuana has anticonvulsive properties, one of the reason it is popular with cancer patients being treated with radiation therapy.

And there are literally hundreds of other synthetic cannabinoid chemicals waiting in the wings. What is going on? Two things. First, synthetic cannabinoids, unlike THC itself, are full agonists at CB1 receptors. THC is only a partial agonist. What this means is that, because of the greater affinity for cannabinoid receptors, synthetic cannabinoids are, in general, stronger than marijuana—strong enough, in fact, to be toxic, possibly even lethal. Secondly, CB1 receptors are everywhere in the brain and body. The human cannabinoid type-1 receptor is one of the most abundant receptors in the central nervous system and is found in particularly high density in brain areas involving cognition and memory.

The Addiction paper by Maren Hermanns-Clausen and colleagues at the Freiburg University Medical Center in Germany is titled “Acute toxicity due to the confirmed consumption of synthetic cannabinoids,” and is worth quoting at some length:

The central nervous excitation with the symptoms agitation, panic attack, aggressiveness and seizure in our case series is remarkable, and may be typical for these novel synthetic cannabinoids. It is somewhat unlikely that co-consumption of amphetamine-like drugs was responsible for the excitation, because such co-consumption occurred in only two of our cases. The appearance of myocloni and generalized tonic-clonic seizures is worrying. These effects are also unexpected because phytocannabinoids [marijuana] show anticonvulsive actions in humans and in animal models of epilepsy.

The reason for all this may be related to the fact that low potassium was observed “in about one-third of the patients of our case series.” Low potassium levels in the blood can cause muscle spasms, abnormal heart rhythms, and other unpleasant side effects.

One happier possibility that arises from the research is that the fierce affinity of synthetic cannabinoids for CB1 receptors could be used against them. “A selective CB1 receptor antagonist,” Hermanns-Clausen and colleagues write, “for example rimonabant, would immediately reverse the acute toxic effects of the synthetic cannabinoids.”

The total number of cases in the study was low, and we can’t assume that everyone who smokes a Spice joint will suffer from epileptic seizures. But we can say that synthetic cannabinoids in the recreational drug market are becoming stronger, are appearing in ever more baffling combinations, and have made the matter of not taking too much a central issue, unlike marijuana, where taking too much leads to nausea, overeating, and sleep.

(See my post “Spiceophrenia” for a discussion of the less-compelling evidence for synthetic cannabinoids and psychosis).

Hermanns-Clausen M., Kneisel S., Hutter M., Szabo B. & Auwärter V. (2013). Acute intoxication by synthetic cannabinoids - Four case reports, Drug Testing and Analysis,   n/a-n/a. DOI:

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

Monday, July 2, 2012

Screen Time is Melting Our Children’s Brains—Or Something


An ad hoc symposium.

Earlier this week, a post  at Psychology Today—“Computer, Video Games and Psychosis: Cause for Concern"—by child psychiatrist Victoria-Dunckley stirred up a bit of social media traffic with her contention that an excess exposure to video screens is responsible for the spread of hallucinations and other psychotic symptoms in our nation’s young. She is not calling this behavior an addiction as such, but maintains that it only happens in cases where 15-22-year olds, were “plugged in” for six or more hours each day. 

Her theory: “Electronic screens, particularly interactive ones (as opposed to passive ones, like television), increase dopamine in the reward center of the brain. Dopamine is known as the brain's 'feel good' chemical, but is also related to stress, addiction, anxiety, mood, and attention.  Dopamine in excess can lead to psychotic symptoms--voices, delusions, paranoia, or confusion.”

So there you have it. Feel free to comment on this assertion. All contributions welcome.

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

Monday, April 19, 2010

Three Drug-Related Posts (Good Ones)


And a plea for your vote.

The DrugMonkey blog, written by an anonymous NIH-funded biomedical researcher,  takes on the question of why doctors dislike narcotics abusers but tolerate drinkers and smokers, and investigates whether there is something about opiates that “turns you into a jerk" in a post titled “Does one drug cause the user to be more annoying?”

Also at DrugMonkey this month, “UK Bans Mephedrone” is  a succinct summation of the dizzy panic going on in the UK over a new party drug that has similarities to the African drug khat. Did Britain institute a hasty and ill-considered ban on the substance based on political rather than scientific concerns?

Over at the Neuroskeptic blog, a British neuroscientist presents some intelligent background to the renewed interest in psychedelic research in his post, “Serotonin, Hallucinations & Psychosis.”

And lastly--although this couldn't possibly be any more off topic--my favorite tourist village--Ely, Minnesota--is currently leading the contest for "American's Coolest Small Town" at Budget Travel magazine's online site HERE.

If you are at all familiar with Ely (Gateway to the Boundary Waters Canoe Area Wilderness, Land of Sky Blue Waters, Canoe Capital of America, Summer Home to Ten Thousand Paddling Boy Scouts) vote early and vote often! Contest closes May 9.

Tuesday, July 19, 2011

An Interview With Research Psychologist Vaughan Bell


An expert on abnormal brain function talks about drugs, hallucinations, and addiction.

Vaughan Bell gets around. The multifaceted clinical and research psychologist, currently a Senior Research Fellow at the Institute of Psychiatry, King’s College, London, is, in fact, down in Colombia right now. He arrived in the country to teach clinical psychiatry at Hospital Universitario San Vicente de Paúl and the Universidad de Antioquia in Medellín, Colombia, where he remains an honorary professor, but right now he works for Médecins sans Frontières (Doctors Without Borders) as mental health coordinator for Colombia, which means he is quite frequently off in the jungle, doing good work under very bad conditions. Bell has written for numerous scientific journals, including Cognitive Neuropsychiatry, Psychiatry Research, and Cortex. He has also written for Slate, The Guardian, Scientific American, and is a contributing editor at Wired. The New York Times ran a fascinating profile of Bell’s work on debunking theories about the Internet as a cause of addiction and psychosis. He is well known online for his contributions to the Mind Hacks blog, which covers unusual and intriguing findings in neuroscience and psychology. He is also working on The Enchanted Window: How Hallucinations Reveal the Hidden Workings of the Mind and Brain, a book for Penguin UK.


Q. You’ve been looking into abnormal brain states of late: delusions, hallucinations, and dissociative disorders.  Do drugs, madness, brain injuries, and religious experiences have anything in common? Is there an underlying cause for seeing or experiencing things that aren’t there?

Vaughan Bell: Apart from involving the brain, often not. Unusual perceptions occur because the normal processes that allow us to generate sensory impressions of the world become distorted. For example, the idea that we see the world as it is, is a bit of a myth, because we experience things that aren’t there all the time. The eye allows light to fall on the retina, two flat areas of photoreceptor cells which provide only patchy and poor resolution coverage of the visual field, and yet we have a very rich visual experience. The brain is filling in the rest. In your blind spots, you receive no visual information and yet we don’t have two black spots in our vision because we ‘hallucinate’ the best guess visual experience.

These are not usually considered hallucinations because the experience remains stable and predictable but these same processes, with just slight instabilities, can lead to spectacular hallucinatory states – such as Charles Bonnet syndrome –where damage to the retina leads to visions of monkeys, rabbits and little men. In other words, there are as many causes for hallucinations as there are causes for our perception of reality. If the same processes are affected through drugs, brain damage, trance states, stress or simply expectation, we can say that a particular experience has a similar basis but we have to think of the interaction to understand them fully. Trying to explain experiences solely by the brain, mind or environment makes little sense.

Q: You’ve experimented with “the vine”—ayahuasca, a powerful South American hallucinogenic plant that contains DMT. You obviously lived to tell about it. Did you see any transdimensional machine elves?

Bell: There were no transdimensional machine elves, although the whole experience was quite striking. I was kindly invited to take part in the ceremony by a chap called Romualdo, a Uitito taita (shaman), who I happened to meet in a conference about indigenous culture and I was very grateful for the opportunity.

I suspect the experience of meeting what McKenna called the "machine elves" is more prominent when pure DMT is smoked which gives a more concentrated acute dose. The traditional process of taking ayahuasca, known as yagé in Colombia, involves drinking a potion made from the vine until you start puking. To get a fair dose you need to repeat this process several times, so the absorption is much slower. I managed three or four drink – puke cycles and the psychedelic effects were prominent although I never lost track of reality. I was, however, very struck by the appearance of classic Kluver form constants, geometric patterns that are probably caused by the drug affecting the visual neurons that deal with basic perceptual process (e.g. line detection).

Q. As a research psychologist, you have been critical of the disease model of addiction for being both too simplistic about mind and behavior, and too all-encompassing to be credible. In an article for Slate, you wrote: "Despite the scientific implausibility of the same disease—addiction—underlying both damaging heroin use and overenthusiasm for World of Warcraft, the concept has run wild in the popular imagination. Our enthusiasm for labeling new forms of addictions seems to have arisen from a perfect storm of pop medicine, pseudo-neuroscience, and misplaced sympathy for the miserable." How should we view addiction, and how should we be dealing with it?

Bell: I think we should view addiction as an over-applied label that is distracting us from the fact that not everyone’s difficulties with unhelpful repetitive behavior can be understood and treated in the same way. Often compulsive behaviors do have shared factors. Obsessive-compulsive disorder, impulse control disorders (like pathological gambling or compulsive stealing) and drug addictions are all known to have shared similar behavioral, neurological and genetic features but that does not mean that each disorder is essentially the same.

The idea that playing too many computer games or compulsive use of the Internet is an addiction like any other is really obscuring the fact that different compulsive behaviors also have many different components. It would be like saying that all "mood disorders" are essentially the same—it would neither be scientifically nor clinically helpful and would cause more confusion than insight. This is the situation we have with addiction at the moment.

Q. You’ve been living and working in South America for some time now. How has the drug trade and the drug war changed that part of the world, in your own experience?

Bell: If you don’t mind, I’m going to skip this question. The drug trade is interwoven with the conflict in Colombia and myself and my colleagues in Médecins sans Frontières (Doctors Without Borders) work in areas where the fighting is live and ongoing. One of the things that allows us to do our work in areas controlled by armed groups is that we are a neutral organization solely concerned with providing medical care without getting involved in the politics behind the conflict. Of course, like everyone else, I have a view, but in case it affects either our access to the people we’re trying to treat or the security of our teams in the field, I’ll keep it to myself when I’m mentioned alongside the organization.

Graphics Credit:  http://news.softpedia.com/

Tuesday, September 3, 2013

A Chemical Peek at Modern Marijuana


Researchers ponder whether ditch weed is better for you than sinsemilla.

Australia has one of the highest rates of marijuana use in the world, but until recently, nobody could say for certain what, exactly, Australians were smoking. Researchers at the University of Sydney and the University of New South Wales recently analyzed hundreds of cannabis samples seized by Australian police, and put together comprehensive data on street-level marijuana potency across the country. They sampled police seizures and plants from crop eradication operations. The mean THC content of the samples was 14.88%, while absolute levels varied from less than 1% THC to almost 40%.  Writing in PLoS one, Wendy Swift and colleagues found that roughly ¾ of the samples contained at least 10% total THC. Half the samples contained levels of 15% or higher—“the level recommended by the Garretsen Commission as warranting classification of cannabis as a ‘hard’ drug in the Netherlands.”

In the U.S., recent studies have shown that THC levels in cannabis from 1993 averaged 3.4%, and then soared to THC levels in 2008 of almost 9%. THC loads more than doubled in 15 years, but that is still a far cry from news reports erroneously referring to organic THC increases of 10 times or more.

CBD, or cannabidiol, another constituent of cannabis, has garnered considerable attention in the research community as well as the medical marijuana constituency due to its anti-emetic properties. Like many other cannabinoids, CBD is non-psychoactive, and acts as a muscle relaxant as well. CBD levels in the U.S. have remained consistently low over the past 20 years, at 0.3-0.4%. In the Australian study, about 90% of cannabis samples contained less than 0.1% total CBD, based on chromatographic analysis, although some of the samples had levels as high as 6%.

The Australian samples also showed relatively high amounts of CBG, another common cannabinoid. CBG, known as cannabigerol, has been investigated for its pharmacological properties by biotech labs. It is non-psychoactive but useful for inducing sleep and lowering intra-ocular pressure in cases of glaucoma.

CBC, yet another cannabinoid, also acts as a sedative, and is reported to relieve pain, while also moderating the effects of THC. The Australian investigators believe that, as with CBD, “the trend for maximizing THC production may have led to marginalization of CBC as historically, CBC has sometimes been reported to be the second or third most abundant cannabinoid.”

Is today’s potent, very high-THC marijuana a different drug entirely, compared to the marijuana consumed up until the 21st Century? And does super-grass have an adverse effect on the mental health of users? The most obvious answer is, probably not. Recent attempts to link strong pot to the emergence of psychosis have not been definitive, or even terribly convincing. (However, the evidence for adverse cognitive effects in smokers who start young is more convincing).

It’s not terribly difficult to track how ditch weed evolved into sinsemilla. It is the historical result of several trends: 1) Selective breeding of cannabis strains with high THC/low CBD profiles, 2) near-universal preference for female plants (sinsemilla), 3) the rise of controlled-environment indoor cultivation, and 4) global availability of high-end hybrid seeds for commercial growing operations. And in the Australian sample, much of the marijuana came from areas like Byron Bay, Lismore, and Tweed Heads, where the concentration of specialist cultivators is similar to that of Humboldt County, California.

The investigators admit that “there is little research systematically addressing the public health impacts of use of different strengths and types of cannabis,” such as increases in cannabis addiction and mental health problems. The strongest evidence consistent with lab research is that “CBD may prevent or inhibit the psychotogenic and memory-impairing effects of THC. While the evidence for the ameliorating effects of CBD is not universal, it is thought that consumption of high THC/low CBD cannabis may predispose users towards adverse psychiatric effects….”

The THC rates in Australia are in line with or slightly higher than average values in several other countries. Can an increase in THC potency and corresponding reduction in other key cannabinoids be the reason for a concomitant increase in users seeking treatment for marijuana dependency? Not necessarily, say the investigators. Drug courts, coupled with greater treatment opportunities, might account for the rise. And schizophrenia? “Modelling research does not indicate increases in levels of schizophrenia commensurate with increases in cannabis use.”

One significant problem with surveys of this nature is the matter of determining marijuana’s effective potency—the amount of THC actually ingested by smokers. This may vary considerably, depending upon such factors as “natural variations in the cannabinoid content of plants, the part of the plant consumed, route of administration, and user titration of dose to compensate for differing levels of THC in different smoked material.”

Wendy Swift and her coworkers call for more research on cannabis users’ preferences, “which might shed light on whether cannabis containing a more balanced mix of THC and CBD would have value in the market, as well as potentially conferring reduced risks to mental wellbeing.”

Swift W., Wong A., Li K.M., Arnold J.C. & McGregor I.S. (2013). Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile., PloS one, PMID:

Graphics Credit: http://420tribune.com

Thursday, February 5, 2015

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.

Wednesday, December 19, 2007

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

Wednesday, August 1, 2007

Media Suffers Attack of Cannabis Psychosis


Bad Science Makes for Bad Science Journalism

According to the London Daily Mail, smoking a single joint of marijuana increases your risk of developing schizophrenia by 41 per cent. The Mail quoted Professor Robin Murray of the Institute of Psychiatry in London, who dutifully warned that the risk was perhaps even higher than that, due to the increasing use of what the newspaper termed “powerful skunk cannabis.” The skunk effect, said Murray, meant that the study’s estimate that “14 per cent of cases of schizophrenia in the UK are due to cannabis is now probably an understatement.”

Marjorie Wallace of the mental health charity SANE told BBC News: “The headlines are not scaremongering, but reflect a daily, and preventable, tragedy.”

Wow. As Gertrude Stein once put it, “Interesting if true.”

But it’s not true at all, of course. Or, to put it more accurately: If it were true, there is no way in hell the meta study under question could be used to prove it.

Speaking as a science journalist, this is the sort of thing than can really ruin your day.

As always, it helps to start with the original published article, a meta-analysis published in the British medical journal Lancet under the title, “Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.” 2007 370: 319-28. Mark Hoofnagle, a MD/PhD Candidate in the Department of Molecular Physiology and Biological Physics at the University of Virginia, discussed the paper in depth on his Denialism Blog:

“First of all, the statement that ‘just one joint’ increases risk by 41% is absurd. The study here is of those who have tried marijuana once or more, not of people who have only tried it once. So already, the Daily Mail and every other news organization is way off. Second, I think we're ultimately seeing a post-hoc ergo propter hoc argument, and a dose-response that's more characteristic of the population studied than a real pharmacologic effect.”

Here’s why:

--People who suffer from a mental illness do more drugs than “normal” people. They are a high-risk population when it comes to addiction. There are people who have a propensity for addiction, and people who do not. Many of those who do will get hooked, but this does not mean that everything which follows is a result of the drugs.

--Latent schizophrenics often suffer their first break while under the influence of psychoactive drugs. Pot, along with LSD, physical trauma, the death of a loved one, and other intense emotional events can all trigger a schizophrenic break in late adolescence. So naturally there would be a correlation.

--The assumption that pot causes susceptibility to mental illness, rather than the other way around, can’t be proven. Hoofnagle uses the example of cigarette smoking. Anyone who has researched schizophrenia, or been around schizophrenics, knows that almost all schizophrenics smoke. (It helps quell hallucinations). Most of them began to smoke before the onset of their illness. Using the assumptions of the current study, we could say that cigarette smoking is almost certain to cause schizophrenia. Correlation, as Hoofnagle reminds us, is not causation.

--Daily pot smokers confound such a study. Are some of them exhibiting symptoms of schizophrenia, or are they exhibiting the symptoms of chronic marijuana intoxication? If they quit smoking so much, would they stop acting so crazy?

--Comorbidity is exceedingly common in drug addicts and users. There is a well-documented causal connection between depression and the use of psychoactive drugs. People suffering from depression often resort to cannabis and other drugs as a form of self-medication. Again, the mental condition leads to the drug use, and not the other way around.

--Finally, where is the epidemic of schizophrenia caused by millions of people smoking marijuana for years? What field evidence can be drawn upon to support this remarkable conclusion?

To be fair to the authors, bets are hedged. In their conclusion, Moore, et.al. state: “The possibility that this association results from confounding factors or bias cannot be ruled out, and these uncertainties are unlikely to be resolved in the near future.”

Nevertheless, the authors go on to conclude that “We believe that there is now enough evidence to inform people that using cannabis could increase their risk of developing a psychotic illness later in life.”

At www.badscience.net, Ben Goldacre wryly notes that “You know when cannabis hits the news you’re in for a bit of fun…” Of 175 studies identified as potentially relevant, Goldacre maintains that only 11 papers, describing 7 discrete data sets, actually turned to be relevant for purposes of the study. If every assumption in the paper is taken to be correct, and causality is accepted, Goldacre calculated, about 800 cases of schizophrenia per year could be attributed to marijuana in the U.K. “But what’s really important,” Goldacre writes, “is what you do with this data. Firstly you can misrepresent it….not least of all with the ridiculous ‘modern cannabis is 25 times stronger’ fabrication so beloved by the media and politicians.”

As it happens, all of this comes at a time in Britain when efforts to reclassify cannabis are being hotly debated in the government. As propaganda, the report is useful, but as a means of clarifying the debate, it will only produce confusion and demagoguery.

Sources:

--Moore, Theresa H.M., et. Al. “Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.” Lancet. 2007 370: 319-28 http://www.thelancet.com/

--MacCrae, Fiona and Andrews, Emily. “Smoking just one cannabis joint raises danger of mental illness by 40%.” London Daily Mail. 26/07/07

--“Cannabis ‘raises psychosis risk.’” BBC News. 2007/07/27 http://news.bbc.co.uk/2/hi/health/6917003.stm

--Cressey, Daniel. “Medical opinion comes full circle on cannabis dangers.” Nature. 27 July 2007.

--Hoofnagle, Mark. “Does Smoking Cannabis Cause Schizophrenia?” Denialism Blog. July 30, 2007. http://scienceblogs.com/denialism/2007/07/does_smoking_cannabis_cause_sc.php

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