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.”

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Addiction Doctors Pick Top Ten Journal Articles

A screen for problem gambling, medications for insomniac alcoholics, and more.

A group of addiction doctors presented a Top Ten List of peer-reviewed articles from 2011 at the American Society of Addiction Medicine’s Annual Medical-Scientific Conference in Richmond, VA. Dr. Michael Weaver presented the findings, noting that the list was “reached by consensus, and articles were selected not only for their quality but also to represent different areas of addiction medicine.” Dr. Weaver stressed that “not all published studies were done really well, and some may not apply to the patients treated by a particular clinician.”

According to Dr. Edward Nunes, with the Department of Psychiatry at Columbia University, the journal articles provide a "nice mixture on epidemiology and clinical outcome or clinical trials research,” which represent “the type of evidence most relevant to patient care."

Thanks to Catharine Zivkovic (@ccziv) for drawing attention to this list. The summaries are my own. Disclaimer: In some cases, these brief summaries are based solely on a reading of the journal abstracts.

1. 

Hsueh-Han Yeh, M.S. et al. (2011). Five-Year Trajectories of Long-Term Benzodiazepine Use by Adolescents: Patient, Provider, and Medication Factors. Psychiatric Services 62(8): 900–907.

 A Taiwanese study analyzing benzodiazepine prescription records came up with a simple solution: “Prescribers can reduce the risk of long-term use by assessing whether pediatric patients have received benzodiazepines from multiple doctors for various medical conditions.” Huh. Who’d have thought of that one, eh? But for various reasons, such checks, and the open records required to make them possible, are the exception rather than the rule in current health care systems. The study group found that for long-term users under 21, defined as anyone in receipt of a benzodiazepine prescription for 31 or more days in a calendar year, one in four patients fell into the categories of “accelerating or chronic users.” Specifically, “A history of psychosis or epilepsy, prescription by providers from multiple specialties, and receipt of benzodiazepines with a long half-life or mixed indications significantly increased one's risk of becoming a chronic or accelerating user.”

2. 

McBride, O, and Cheng, Hui G. (2011) Exploring the emergence of alcohol use disorder symptoms in the two years after onset of drinking: findings from the National Surveys on Drug Use and Health. Addiction 106(3): 555-563.

This study looked for clinical features of alcohol dependence and socially maladaptive drinking patterns during the first 24 months of alcohol use, based on stats from the 2004-2007 National Surveys on Drug Use and Health (NSDUH). Result: New alcohol users “frequently experienced problems relating to self-reported tolerance, spending a great deal of time recovering from the effects of alcohol and unsuccessful attempts at cutting down on drinking. The likelihood of experiencing the clinical features increased steadily in the first 9 months after use, but appeared to plateau or only gradually increase thereafter.” The researchers suggest there may be a window of opportunity during the 2nd year of drinking.

3.

Volberg, Rachel A., et al. (2011) A Quick and Simple Screening Method for Pathological and Problem Gamblers in Addiction Programs and Practices. The American Journal on Addictions. 20(3): 220-227.

Doctors, as these researchers point out, don’t often screen their patients for pathological gambling. To combat this, the investigators offer health professionals brief computer screenings they have developed for use in identifying problem gambling. “Given the high rates of comorbidity, routine and accurate identification of gambling-related problems among individuals seeking help for substance abuse and related disorders is important.” 

4.

Alford, Daniel. P., et al. (2011). Collaborative Care of Opioid-Addicted Patients in Primary Care Using Buprenorphine: Five-Year Experience. Archives of Internal Medicine 171(5):425-431.

Buprenorphine remains an underused but often effective treatment for opiate addiction, the authors of this study maintain. The cohort being studied was a group of addicted patients under the dual care of general physicians and nurse care managers. “Of patients remaining in treatment at 12 months, 154 of 169 (91.1%) were no longer using illicit opioids or cocaine based on urine drug test results,” the investigators report. However, dropout rates were high. The researchers did find that the nurse-doctor model was workable: “Collaborative care with nurse care managers in an urban primary care practice is an alternative and successful treatment method for most patients with opioid addiction that makes effective use of time for physicians who prescribe buprenorphine.”

5. 

Kolla, B.P., et. al. (2011) Pharmacological Treatment of Insomnia in Alcohol Recovery: A Systematic Review. Alcohol and Alcoholism 46: 578-585.

In this Mayo Clinic review of drugs used for sleep problems in alcohol recovery, the authors combed through more than 1,200 articles and reported that, of all the old and new drugs being used, an old and rarely used medication—trazadone—improved sleep measures as reliably as anything else that was tested. Gabapentin got good but equivocal marks due to questions about testing and inclusion criteria. Topiramate and carbamazepine helped in some cases. Furthermore, “in single, small, mostly open-label studies, quetiapine, triazolam, ritanserin, bright light and magnesium have shown efficacy, while chlormethiazole, scopolamine and melperone showed no difference or worsening. Conclusion: Trazodone has the most data suggesting efficacy.”

6.

Bohnert, A.S., et. al. (2011). Association between opioid prescribing patterns and opioid overdose-related deaths. Journal of the American Medical Association 305: 1315-1321.

Accidental prescription overdose deaths are on the rise, and this group of university researchers in Ann Arbor and Indianapolis thinks it may have something to do with how the dosing instructions are usually worded.  They set out to investigate “the association of maximum prescribed daily opioid dose and dosing schedule (“as needed,” regularly scheduled, or both) with risk of opioid overdose death among patients with cancer, chronic pain, acute pain, and substance use disorders.” They found from VHA hospital records that “the frequency of fatal overdose over the study period among individuals treated with opioids was estimated to be 0.04%.” The risk for overdose was directly related to the “maximum prescribed daily dose of opioid medication.” And patients who stuck with regular dosages, or took opioids “as needed,” were not at any elevated risk for overdose. Another obvious but frequently overlooked conclusion: “Among patients receiving opioid prescriptions for pain, higher opioid doses were associated with increased risk of opioid overdose death.”

7. 

Allsop, D.J. et al. (2011). The Cannabis Withdrawal Scale development: patterns and predictors of cannabis withdrawal and distress. Drug and Alcohol Dependence 19(1-2):123-9.

Rates of treatment for marijuana abuse and addiction are increasing, say these Australian authors, along with relapse rates. They have devised a Cannabis Withdrawal Scale that measures such withdrawal effects as associated distress, strange dreams, trouble sleeping, and angry outbursts—common manifestations of withdrawal from weed. The scientists maintain that their “Cannabis Withdrawal Scale can be used as a diagnostic instrument in clinical and research settings where regular monitoring of withdrawal symptoms is required.”

8.

West, R., et al. (2011) Placebo-Controlled Trial of Cytisine for Smoking Cessation. New England Journal of Medicine 365: 1193-1200.

This important study assessed the effectiveness of the drug cytisine in smoking cessation programs, and a potential star was born. In a single-center, randomized, double-blind, placebo-controlled trial, the journal paper concluded that “cytisine was more effective than placebo for smoking cessation. The lower price of cytisine as compared with that of other pharmacotherapies for smoking cessation may make it an affordable treatment to advance smoking cessation globally.”

9. 

Elkashef A., et al. (2011) Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial. Addiction Published online 12/16.

Conducted at eight medical centers across the U.S., this study found that for most of the 140 methamphetamine-dependent adults under scrutiny, use of topiramate produced “abstinence from methamphetamine during weeks 6-12.” That’s the good news. Unfortunately,  “secondary outcomes included use reduction versus baseline, as well as psychosocial variables… topiramate did not increase abstinence from methamphetamine during weeks 6-12.” That’s the bad news. And here’s the silver lining, as far as the investigators are concerned: “Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent.”

10.

Levina. A., et al. (2011). Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine. Science Translation Medicine 3(107) 107-109.

There really is s a gateway drug. In fact, there are two of them in our culture. Almost every potential addict starts out with alcohol or cigarettes or both. Because they are legal and easily available. So is cocaine and marijuana, once you get the hang of it, but in the beginning, and all around us, it’s booze and cigs. The amazing premise of this final study is this: “Pretreatment of mice with nicotine increased the response to cocaine, as assessed by addiction-related behaviors and synaptic plasticity in the striatum, a brain region critical for addiction-related reward.” Nicotine primes subjects for cocaine addiction, in effect. “These results from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking and while actively still smoking, and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine, consistent with our data from mice. If our findings in mice apply to humans, a decrease in smoking rates in young people would be expected to lead to a decrease in cocaine addiction.”

Photo Credit: www.flickr.com/

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.

—Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction

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

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

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

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

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

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

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

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

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

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

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

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

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

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

INTERVIEW WITH DR. REMINGTON NEVIN

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

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

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

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

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

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

—What is a dissociative hallucinogen?

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


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

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

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

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

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

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


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

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

—What are the consequences of mixing Lariam with alcohol?

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


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

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

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

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

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

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

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

A Few Words About Glutamate

Meet another major player in the biology of addiction.

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

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

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

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

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


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

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

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

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

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


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

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/

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.

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

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

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U.K. Marijuana Panic Continues

British Prime Minister plans to stiffen pot penalties.

The national hysteria over "skunk" marijuana shows no signs of abating in Great Britain, as Prime Minister Gordon Brown is poised to overrule his advisors and reclassify cannabis as a more dangerous drug. Lost in the debate is any semblance of reasonable discussion about scientific research on marijuana.

British health authorities continue to find the basics of cannabis to be an inscrutable mystery. Some months ago, they declared that "skunk" cannabis was linked to the onset of schizophrenia. Since no one knows what, exactly, causes schizophrenia, and recent findings continue to point toward genetic causes, this was a doubly astonishing claim.

Now, continuing in the same vein of misinformation, The University College of London reports that different strains of marijuana cause different types of psychological maladies. Recently, 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. The Guardian went on to note that "Whitehall's own panel of experts has concluded that increased marijuana use has not been matched by a corresponding rise in mental illness."

The move to shift marijuana to Class B status from its current Class C designation has been fueled by these dubious reports. As long as British politicians continue to believe that something called "skunk" is a new and lethal derivative of marijuana, and that it causes psychosis, schizophrenia and suicide, no substantive debate on cannabis regulation can possibly take place. Colin Blakemore, a prominent professor of neuroscience at the Universities of Oxford and Warwick, tackled the issue in an article for the Guardian:

And what of the alarming stories of horrifying powerful "skunk"? Some newspapers have told us that the level of THC, the active ingredient, in street cannabis today is 20 or 30 times higher than 10 years ago. That would be rather surprising, given that THC content was 7 per cent on average in 1995. In reality, two studies, due to be published later this year, concluded that the average THC content has doubled.

Professor David Clark, a British psychologist who maintains a substance abuse information service called Wired In, writes on his blog: " I have to confess that I really cannot see what reclassifying the drug will do, other than criminalise and alienate more of our young people. It won't reduce harms that the drug can cause to some people. In saying this, I am not arguing that cannabis is safe - but nor are alcohol, tobacco and a wide range of prescription drugs which are all legal. "

addiction drugs

LSD and Serotonin

Early psychedelic research on alcoholism.

What did LSD do to the brain, exactly, in order to set off the fireworks that so fascinated brain scientists, hippies, and government spies? And why, after years of massive, unauthorized field-testing, so to speak, was there so little evidence implicating LSD as an addictive drug? Powerful as it was, LSD did not show any of the classic attributes of addiction, such as withdrawal or craving, although it was possible to build up a tolerance to its effects with repeated dosings.

Another novel brain chemical, discovered less than a year after Albert Hofmann's discovery of LSD, proved to be a crucial piece of the puzzle.

According to an early theory, the aberrant mental functioning produced by the tiniest dose of LSD was due to interference with normal levels of serotonin in the brain. In 1954, chemists D.W. Woolley and E. Shaw had published an article in Science strongly arguing that serotonin was the likely biochemical basis for major mental disorders. Wooley and Shaw confirmed that the most acutely serotonin-active substance known to man was the ergot derivative known as LSD. LSD’s chemical architecture looked eerily similar to that of serotonin.

While the idea of LSD as a “model” of psychosis did not hold up, the link between serotonin and mental disorders was there all along. The strongly serotonin-mediated mental disorders, researchers ultimately discovered, were depression, drug addiction, and alcoholism.

The psychedelic drugs, new and old, are not only among the most powerful ever discovered, but are also tremendously difficult to study and utilize responsibly. Nonetheless, these drugs have always played an important part of the story, even though they are not addictive. LSD, mescaline, DMT, psilocybin, Ibogaine, ayahuasca—none of these appeal to lab rats as a drug of abuse.

Psychedelics have been exhorted, and occasionally deployed, as specific anti-craving medications for more than 50 years now. The psychedelic experience seems to assist some addicts in their efforts to remain sober and abstinent. However, the risks of casual experimentation with these substances should be obvious. Recent research on Ecstasy only makes this point more emphatically.

In the 1950s, along with Aldous Huxley and others, Al Hubbard came to believe that the more mystical or “transpersonal” experiences LSD sometimes afforded might hold considerable psychotherapeutic potential. With LSD provided by Hubbard, Canadians Abram Hoffer, Ross Mclean, and Humphrey Osmond pursued the idea of LSD as a treatment for alcoholism. In the U.S, Oscar Janiger, Sanford Unger, and others undertook research on LSD and alcoholism on the West Coast.

Throughout this period, 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).

But the early addiction research was stuck in an impossible situation. Some of the best tools available to scientists for studying the workings of the human brain were the very drugs that were increasingly prohibited under state and federal law--drugs like heroin, cocaine, PCP, LSD, and marijuana.

By the early 1970s, meaningful research involving any of these substances had virtually ground to a halt, and grants for clinical work had dried up completely.

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


Photo Credit: Albert Hofmann Foundation

Related posts: Ibogaine and Addiction

Serotonin and Dopamine: A Primer




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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

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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