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/

Getting Spiced

Synthetic cannabis is stronger than it used to be.

First published 10/07/2013

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: 10.1002/dta.1483

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

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/

Drugs and Disease: A Look Forward

First published 2/18/2014.

Former National Institute on Drug Abuse (NIDA) director Alan Leshner has been vilified by many for referring to addiction as a chronic, relapsing “brain disease.” What often goes unmentioned is Leshner’s far more interesting characterization of addiction as the “quintessential biobehavioral disorder.”

Multifactorial illnesses present special challenges to our way of thinking about disease. Addiction and other biopsychosocial disorders often show symptoms at odds with disease, as people generally understand it. For patients and medical professionals alike, questions about the disease aspect of addiction tie into larger fears about the medicalization of human behavior.

These confusions are mostly understandable. Everybody knows what cancer is—a disease of the cells. Schizophrenia? Some kind of brain illness. But addiction? Addiction strikes many people as too much a part of the world, impacted too strongly by environment, culture, behavior, psychology, to qualify. But many diseases have these additional components. In the end, the meaning of addiction matters less than the physiological facts of addiction.

One of the attractions of medical models of addiction is that there is such an extensive set of data supporting that alignment. Specifically, as set down in a famous paper by National Institute of Drug Abuse director Nora Volkow and co-author Joanna Fowler: “Understanding the changes in the brain which occur in the transition from normal to addictive behavior has major implications in public health…. We postulate that intermittent dopaminergic activation of reward circuits secondary to drug self-administration leads to dysfunction of the orbitofrontal cortex via the striato-thalamo-orbitofrontal circuit.” This cascade of events is often referred to as the “hijacking” of the brain by addictive drugs, but nothing is really being hijacked. Rather, the abusive use of drugs changes the brain, and that should come as no surprise, since almost everything we do in the world has the potential of changing the brain in some way. “Why are we so surprised that when you take a poison a thousand times, it makes some changes in your head?” said the former director of a chemical dependency treatment program at the University of Minnesota. “It makes sense that [addictive drugs] change things.”

Critics like Fernando Vidal object to a perceived shift from “having a brain” to “being a brain.” He is saying that he cannot see the point of “privileging” the brain as a locus for the study of human behavior. In “Addiction and the Brain-Disease Fallacy,” which appeared in Frontiers in Psychiatry, Sally Satel and Scott Lillienfeld write that “the brain disease model obscures the dimension of choice in addiction, the capacity to respond to incentives, and also the essential fact people use drugs for reasons (as consistent with a self-medication hypothesis).”

An excellent example of the excesses of the anti-brain discussions is an article by Rachel Hammer of Mayo Clinic and colleagues, in the American Journal of Bioethics-Neuroscience. “Many believed that a disease diagnosis diminishes moral judgment while reinforcing the imperative that the sick persons take responsibility for their condition and seek treatment.” But only a few paragraphs later, the authors admit: “Scholars have theorized that addiction-as-disease finds favor among recovering addicts because it provides a narrative that allows the person simultaneously to own and yet disown deviant acts while addicted.” Furthermore: “Addiction reframed as a pathology of the weak-brained (or weak-gened) bears just as must potential for wielding stigma and creating marginalized populations." But again, the risk of this potentially damaging new form of stigma “was not a view held by the majority of our addicted participants…”

And so on. The anti-disease model authors seem not to care that addicted individuals are often immensely helped by, and hugely grateful for, disease conceptions of their disorder, even though Hammer is willing to admit that the disease conception has “benefits for addicts’ internal climates.” In fact, it often helps addicts establish a healthier internal mental climate, in which they can more reasonably contemplate treatment. Historian David Courtwright, writing in BioSocieties, says that the most obvious reason for this conundrum is that “the brain disease model has so far failed to yield much practical therapeutic value.” The disease paradigm has not greatly increased the amount of “actionable etiology” available to medical and public health practitioners. “Clinicians have acquired some drugs, such as Wellbutrin and Chantix for smokers, Campral for alcoholics or buprenorphine for heroin addicts, but no magic bullets.” Physicians and health workers are “stuck in therapeutic limbo,” Courtwright believes.

“If the brain disease model ever yields a pharmacotherapy that curbs craving, or a vaccine that blocks drug euphoria, as some researchers hope,” Courtwright says, “we should expect the rapid medicalization of the field. Under those dramatically cost-effective circumstances, politicians and police would be more willing to surrender authority to physicians.” The drug-abuse field is characterized by, “at best, incomplete and contested medicalization.” That certainly seems to be true. If we are still contesting whether the brain has anything essential to do with addiction, then yes, almost everything about the field remains “incomplete and contested.”

Sociologists Nikolas Rose and Joelle M. Abi-Rached, in their book Neuro, take the field of sociology to task for its “often unarticulated conception of human beings as sense making creatures, shaped by webs of signification that are culturally and historically variable and embedded in social institutions that owe nothing substantial to biology.”

And for those worried about problems with addicts in the legal system, specifically, over issues of free will, genetic determinism, criminal culpability, and the “diseasing” of everything, Rose and Abi-Rached bring good news: “Probabilistic arguments, to the effect that persons of type A, or with condition B, are in general more likely to commit act X, or fail to commit act Y, hold little or no sway in the process of determining guilt.” And this seems unlikely to change in the likely future, despite the growing numbers of books and magazine articles saying that it will.

Opponents of the disease model of addiction and other mental disorders are shocked, absolutely shocked, at the proliferation of “neuro” this and “neuro” that, particularly in the fields of advertising and self-improvement, where neurotrainers and neuroenhancing potions are the talk of the moment. Sociologists claim to see some new and sinister configuration of personhood, where a journalist might just see a pile of cheesy advertising and a bunch of fast-talking science hucksters maneuvering for another shot at the main chance. When has selling snake oil ever been out of fashion?

For harm reductionists, addiction is sometimes viewed as a learning disorder. This semantic construction seems to hold out the possibility of learning to drink or use drugs moderately after using them addictively. The fact that some non-alcoholics drink too much and ought to cut back, just as some recreational drug users need to ease up, is certainly a public health issue—but one that is distinct in almost every way from the issue of biochemical addiction. By concentrating on the fuzziest part of the spectrum, where problem drinking merges into alcoholism, we’ve introduced fuzzy thinking with regard to at least some of the existing addiction research base. And that doesn’t help anybody find common ground.

Graphics Credit: http://www.docslide.com/disease-model/