An Interview with Neuroscientist Jon Simons

Brain scans, iPhone love, and state-dependent memory.

(Third post in the “Five-Question Interview” series.)

Brain scans have put cognitive neuroscience on the map. They have become a key part of addiction studies as well. In fact, brain scans have put neuroscience on the front page, due to the controversies they have engendered. Cognitive neuroscientist Jon Simons, a lecturer in the Department of Experimental Psychology at the University of Cambridge, UK, and principal investigator at the University’s Memory Laboratory, is attempting to expand our understanding of the specific regions of the brain involved in human memory. His research involves functional neuroimaging of healthy volunteers and examining the effects of neurological and psychiatric disorders, and normal aging, on memory abilities.

Dr. Simons obtained his PhD at the MRC Cognition and Brain Sciences Unit in Cambridge, and from there moved to a post-doctoral position at Harvard University. He returned to the UK and took up a research fellowship at University College London before returning to Cambridge. He was recently senior author on a thought-provoking paper published in the Journal of Neuroscience about a brain structure variation that might explain why some people in the general population are better than others at distinguishing real events from those they imagined or were told about. We asked Dr. Simons to help straighten out some of the confusion over scanning data, and to be the third guest in our “Five-Question Interview” series.

1. PET and fMRI scans have stirred up a good deal of debate and heated argument lately. While brain scans have been used to extend our understanding of crucial functions like memory and reward, they’ve also been used to “prove” that we’re addicted to our iPhones. Some scientists put almost no faith in them at all. What’s going on?

Neuroimaging methods like fMRI have certainly become quite common in the media over recent years. Unfortunately, not all the media coverage does the kind of job we might wish in explaining the methods and findings and, importantly, the limitations and caveats that need to be considered when interpreting the data. You mention the recent New York Times op-ed in which it was claimed that people “literally love their iPhones,” on the basis that viewing an iPhone was associated with fMRI activity in a brain region previously linked with “love and compassion.” Unfortunately, the same brain area has also been linked with negative emotions like disgust, as well as many other cognitive functions, seriously undermining the claims in the New York Times story. It may turn out to be true that our feelings about iPhones reflect love, or perhaps more likely a kind of dopamine-driven addiction response, but such simplistic analyses as the one the NYT gave such prominence are unlikely to help with understanding that.

However, I think it’s a mistake to confuse the media representation of fMRI research with the field itself. Many researchers design very careful fMRI experiments in which factors of interest are varied while others are controlled, and resulting patterns of brain activity are analysed with statistical caution and interpreted in the light of a broad range of previous findings. This is the kind of work that is moving the field forward, but, like most good science, it is not particularly sexy, and the researchers involved are less keen to make the kinds of extravagant claims that get you into the New York Times. In my view, it’s up to all of us—scientists and journalists—to make sure that the public get to hear more about the good fMRI work, and less about silly iPhone love stories.

2. Is there a specific role for functional neuroimaging in the diagnosis and treatment of addiction?

This isn’t really my area, but I know from talking with colleagues that neuroimaging has certainly contributed to understanding the neurobiology of addiction. For example, a great deal is known about the brain networks and neurotransmitter systems implicated in impulsivity, compulsions, reward processing and other cognitive functions that are relevant to addiction disorders. Such knowledge is obviously very important for informing clinical practice. Whether neuroimaging can also play a role in diagnosis and treatment is, as far as I can tell, less clear. Making accurate diagnoses in an individual on the basis of neuroimaging data requires characterisation of the specific patterns of brain activity exhibited by that individual, which is difficult to achieve. Similar problems afflict attempts to assess the success of different treatments. However, as imaging technology develops and statistical methods are refined, it may be that neuroimaging will be able to offer new insights that contribute to effective diagnosis and treatment.


3. Please explain the basics of state-dependent memory as it relates to alcohol, using your famous example about remembering Brad Pitt’s or Angelina Jolie’s phone number.

Ha! Glad if the example I used has proven memorable. The basic idea of state-dependent memory is that your recollection of a previous event is likely to be better if you’re in the same physiological state as you were when the event occurred. So, to use alcohol as an example, if you’re at a party and happen to drunkenly strike up conversation with Angelina Jolie (or Brad Pitt, if you prefer) and, bowled over by your charm and witty repartee, she tells you her phone number, you may well not remember it when you wake up sober the next morning. However, the evidence from many state-dependent memory studies suggests that you would have a better chance of recalling the number if you got drunk again. The effect doesn’t just apply to alcohol: any physiological state, any emotion we’re feeling, in fact any aspect of the context we’re in when we try to remember, which was also there when we previously experienced an event, will improve our memory for that event. This was described as the ‘encoding specificity principle’ by a great memory researcher, Endel Tulving.

4. Some researchers maintain that mental illness and addiction to drugs and alcohol are not, properly speaking, diseases at all. What’s your stance on the continual battles over the “disease model” of addiction and other disorders like depression?

There are both advantages and disadvantages to the “disease model” of cognitive disorders. For some people, it might be helpful to receive a clinical disease diagnosis and, perhaps, an idea of the therapeutic interventions through which they might go about “recovering” from their condition. Among the disadvantages are that labelling people as “addicts”, for example, can stigmatise those struggling with dependence and might lead to them avoiding responsibility for changing their addictive behaviour because they see diseases as requiring expert intervention. It’s a difficult area, and I can see both sides of the debate.

5. You’ve done neuroscience at Cambridge in the U.K., and at Harvard in the U.S. Is science conducted differently in the two countries?

My experience was that science in the US at that time (in 2000-2001) was different from in the UK. There seemed to be many more opportunities to get involved in interesting projects and to gain access to advanced technical equipment like fMRI scanners than was the case in the UK then. I also noted a difference in the willingness of people who were experts in techniques like fMRI, or in research involving patients with rare brain lesions, to share their expertise and resources in a collaborative way. Fortunately, I’ve found since I’ve been back in the UK a similarly friendly and collaborative environment, particularly in Cambridge now. I think this is partly a result of initiatives to bring researchers together across traditional scientific boundaries, such as Cambridge Neuroscience. However, I think the biggest US/UK difference now is the prevalent feeling that science is valued much more in the US than it is over here. Despite the best efforts of campaigns like Science is Vital, successive UK governments have failed to invest in science to the same degree as other nations, including the US. Particularly in the current financial climate, when significant cuts to science funding have been threatened, this means that morale is low, uncertainty is high, and significant numbers of scientists are deciding to move abroad. I don’t know that I’m ready to join them yet, but if the situation gets much worse, it would have to be something I’d consider.

Photo Credit: http://www.neuroscience.cam.ac.uk

Prohibition in Perspective

An essay on the Harrison Narcotic Act of 1914.

As the 20th Century began, America’s drinking habits were undergoing a thorough review. But In late 1914, five years before the prohibition of alcohol became the law of the land, the government also took aim at other drugs. The legal status of heroin and cocaine changed overnight with the passage of the Harrison Narcotic Act. The U.S. Congress, with the vociferous backing of William Jennings Bryan, the prohibitionist Secretary of State, voted to ban the “non-medical” use of opiates and derivatives of the coca plant.

Under the Harrison Act, physicians could be arrested for prescribing opiates to patients. “Honest medical men have found such handicaps and dangers to themselves and their reputation in these laws,” railed an editorial in the National Druggist, “that they have simply decided to have as little to do as possible with drug addicts...” The Harrison Act did have the effect of weeding out casual users, as opium became dangerous and expensive to procure. Housewives, merchants, salesmen, and little old ladies who had been indulging in the “harmless vice” now gave it up.

By 1919, continued pressure from the alcohol temperance movement culminated in Congressional passage of the Volstead Act, which provided for federal enforcement of alcohol prohibition. The temperance activists had pulled it off, though there is nothing very “temperant” about total prohibition. A year later, the states ratified the 18th Amendment. Within a five-year period, morphine, cocaine, and alcohol had all been banned in America. The Prohibition Era had begun. At roughly the same time, alcohol prohibition movements were sweeping across Europe, Russia, and Scandinavia, as evidenced by this 1921 news photograph of Chinese Maritime Officers with 300 lbs of smuggled morphine confiscated in cylinders shipped from Japan.

Prohibition and the passage of the Harrison Narcotics Act coincided, as well, with a short-lived effort to prohibit cigarettes. Leaving no stone unturned in the battle to eliminate drugs and alcohol from American life, Henry Ford and Thomas Edison joined forces to wage a public campaign against the “little white slavers.” Edison had shown an earlier fondness for Vin Mariani, a French wine laced with prodigious amounts of cocaine, but he and Ford wanted to stamp out cigarette smoking in the office and the factory. Although that effort would have to wait another 75 years or so, and may yet become the next large-scale test of federal prohibition, New York City did manage to pass an ordinance prohibiting women from smoking in public.  Fourteen states eventually enacted various laws prohibiting or restricting cigarettes. By 1927, all such laws had been repealed.

As Prohibition continued, police and federal law enforcement budgets soared, and arrest rates skyrocketed, but no legal maneuvers served to make alcohol prohibition effective, once “respectable” citizens had chosen not to give up drinking. The experience was so repellent that even today, when drug legalization is considered a legitimate topic of debate, most American reformers are unwilling to argue the case for neo-prohibitionism. (America’s ambivalence over alcohol is still evident in some states, where “dry” counties have made the sale of liquor illegal from time to time.)

As the temperance crusaders faded away, politicians and the public turned their attention back to heroin addiction, as the opiates became the official villains again. However, one practice that remained quietly popular with an older generation of physicians well into the 1940s was the conversion of alcoholics into morphine addicts. The advantages of alcohol-to-morphine conversion were spelled out  by Lawrence Kolb, the Assistant Surgeon General of the U.S. Public Health Service at the time:  “...Drunkards are likely to be benefited in their social relations by becoming addicts. When they give up alcohol and start using opium, they are able to secure the effect for which they are striving without becoming drunk or violent.” Perhaps so, but there were plenty of doctors who did not believe that addiction of any kind fell within the scope of medical practice in the first place.

Subsequent laws tightened up the strictures of the Harrison Act. Mandatory life sentences were imposed in several states for simple possession of heroin. The first addict sentenced to life imprisonment under the new laws was a twenty-one year-old Mexican-American epileptic with an I.Q. of 69, who sold a small amount of heroin to a seventeen year-old informer for the FBI. (In 1962, the U.S. Supreme Court ruled that imprisonment for the crime of simply being an addict, in cases where the arrest involved no possession of narcotics, was cruel and unusual punishment in violation of the Bill of Rights.) 

The Prohibition Years also sparked a rise in marijuana use and marijuana black marketeering. To checkmate the migration toward that drug, Congress passed the Marihuana Tax Act of 1937, modeled closely after the Harrison Act. The American Medical Association opposed this law, as it had opposed the Harrison Act, but to no avail. The assault on marijuana was led by Harry J. Anslinger, the indefatigable U.S. Commissioner of Narcotics who served a Hoover-like stretch from 1930 to 1962. At one point, Anslinger announced that marijuana was being taken by professional musicians. “And I’m not speaking about good musicians,” he clarified, “but the jazz type.” Due in no small part to Anslinger’s tireless public crusade against “reefer madness,” additional state and federal legislation made marijuana penalties as severe as heroin penalties. The most famous early victim of Anslinger’s efforts was screen actor (and reputed jazz fan) Robert Mitchum, who was busted in 1948 and briefly imprisoned on marijuana charges.

One highly addictive drug that did not immediately fall under the proscriptions of the Harrison Act was a cocaine-like stimulant called amphetamine. Originally intended as a prescription drug for upper respiratory ailments and the treatment of narcolepsy (sleeping sickness), the drug was first synthesized in 1887 by a German pharmacologist. It was a British chemist named Gordon Alles, however, who showed everyone just what amphetamine could really do. There was no direct analog in the plant kingdom for this one. Alles, who also worked at UCLA and Caltech, documented the remarkable stimulatory effect of “speed” on the human nervous system—research that led directly to the commercial introduction of amphetamines in the late 1930s under the trade name Benzedrine. Once it became widely available over the counter in the form of Benzedrine inhalers for asthma and allergies, it quickly became one of the nation’s most commonly abused drugs, and remained so throughout the late 1950s and 1960s—with periodic comebacks.

Photo Credit: www.newworldencyclopedia.org

Feds Go “Passive-Aggressive” in Fight Against Medical Marijuana

Sending in the IRS instead of knocking down doors.

It’s official: The Obama administration has thrown off the gloves, repudiating Attorney General Eric Holder’s vow of two years ago that the federal government was not interested in prosecuting “state-legal” cannabis activity. Instead, a flurry of action is underway, intended to signal that the DOE and DEA are out to put a stake through the heart of the medical marijuana industry as a whole. Marijuana, however it is used, remains wholly illegal under federal statutes, and federal law enforcement officials insist such laws trump any state laws aimed at allowing the sale and use of cannabis.

During the last 30 days:

-- The DEA raided medical marijuana clinics in Tempe, Arizona.

--The Rhode Island governor reneged on an earlier pledge to okay medical marijuana in his state, saying that any such activity would make the state a target for federal prosecution. 

-- Federal prosecutors seized the bank accounts of medical marijuana shops in Sacramento, claiming a series of “irregular deposits.”

--The IRS decreed that the biggest marijuana dispensary in California cannot deduct ordinary business expenses on its taxes.

--A study of marijuana for posttraumatic stress disordered descended into “regulatory limbo,” as Brian Vastag reported for the Washington Post, after the National Institute on Drug Abuse (NIDA), the only legal source of cannabis for researchers, refused to hand over government marijuana to the study authors because of “a number of concerns” about research protocol.

--A California Appellate Court ruled that the statute allowing  marijuana dispensaries in Long Beach is in violation of federal law, which will force a long and arduous rewrite of the permitting laws for that city, and presumably other cities as well.

 The irony is that California’s medical marijuana industry, the first in the nation, may have survived the SWAT team attacks of the Bush years, only to fall victim to renewed regulatory fervor under President Obama’s watch. And, as I reported earlier at The Fix: “Britain’s giant GW Pharmaceuticals received U.S. patent approval for the use of Sativex, its nasal spray for treatment of advanced cancer pain composed of—yes, that’s right—a combination of the two primary chemicals found in cannabis. Since then, Sativex has made it all the way to Phase III clinical testing in a bid for FDA approval. At the moment, the company’s chances of producing a cannabis based pill are looking very good.” Meanwhile, so-called “whole-plant” marijuana research is getting squeezed out.

And now comes word that federal prosecutors are following up with a giant crackdown on all California dispensaries. Associated Press reports that U.S. attorneys sent letters this week to at least 16 pot dispensaries, “warning the stores they must shut down in 45 days or face criminal charges and confiscation of their property even if they are operating legally under the state’s 15-year-old medical-marijuana law.”

Sources say that cease-and-desist letters from U.S. Attorney Melinda Haag in California had been received by some dispensaries, stating the “violations of the federal law referenced…. is a federal crime,” and further stipulating that the penalties could include property forfeitures and 40 years of prison time, reports Chris Roberts at SF Weekly.

And the Associated Press obtained copies of letters sent to San Diego dispensaries, in which federal prosecutors claim that marijuana shops are illegal and subject to criminal prosecution and civil enforcement actions. “Real and personal property involved in such operations are subject to seizure by and forfeiture to the United States… regardless of the purported purpose of the dispensary.”

The action follows warning letters that were sent to dispensary owners and state officials by federal prosecutors in June, which strongly hinted that state employees might be liable for prosecution as well. A California attorney told SF Weekly that the feds were now embarking on a more effective “passive-aggressive” approach to shutting down the medical marijuana industry. “They’ve systematically changed their approach,” said the attorney. “Probably after talking to a PR professional.”

Graphics Credit:  http://www.shouselaw.com/

Bath Salts, Graphically

What you need to know about mephedrone.

The Pat Moore Foundation has put together this nifty chart as a primer on mephedrone, the amphetamine-type stimulant marketed as "bath salts." Thanks PMF! 

 Created by Pat Moore Foundation

An Insite-ful Decision

Canadian Supreme Court clears the way for Vancouver’s safe-injection facility.

Insite, the controversial supervised injection site for addicts in Vancouver, has won its case before the Supreme Court of Canada for a permanent exemption from the nation's drug laws. CBC News reports that, in a unanimous decision, “The court ordered the federal minister of health to grant an immediate exemption to allow Insite to operate.”

Written by chief justice Beverley McLachlin, the ruling said in part: "Insite saves lives. Its benefits have been proven. There has been no discernable negative impact on the public safety and health objectives of Canada during its eight years of operation." A member of Parliament told the CBD: "The Conservative government has been relentless in their opposition so today's decision by the court just feels like an incredible victory. It feels like a great day."

The Supreme Court of Canada was forced to determine the fate of Insite, where addicts use clean needles with a nurse on the premises, after numerous governmental attempts to shutter the facility led to lawsuits. Numerous studies have demonstrated the benefits of such programs, but Insite remains the only long-term injection facility in North America. The eight-year old clinic has increasingly won both professional and popular support as a workable method of harm reduction in high-risk drug areas. As the Vancouver Sun sensibly notes: “It is increasingly mainstream thinking in Canadian health care as reflected by other interveners in the Supreme Court case--Canadian Nurses Association, Association of Registered Nurses of British Columbia, Registered Nurses Association of Ontario, Canadian Medical Association, and Canadian Public Health Association.” You can’t get much more mainstream than that. 

As The Fix recently reported, Insite has reduced drug overdose deaths by 35% in its notorious Downtown Eastside headquarters in a neighborhood housing the highest population of needle addicts in Canada. A recent study found  that drug overdoses do occur at Insite—but among its recorded 2,000 ODs, there has not been a single fatality (doctors are on hand with a ready supply of the anti-OD drug Naloxone). Injection centers offer other public health benefits, including steering addicts into treatment and reducing hepatitis C and HIV infections. Opposition in the U.S. has centered on the notion that safe injection facilities will encourage the use of injectable narcotics by somehow sanctioning the activity.

The Globe and Mail editorialized that when the Supreme Court of Canada convened in May to take evidence on Vancouver’s supervised injection site, it heard “detailed arguments that hinge on the fine print of the Canadian Constitution. But besides being a landmark showdown between federal and provincial powers, the hearing also sets the stage for a ruling expected to affect not only the daily lives of injection drug users on Vancouver’s Downtown Eastside but drug policy across the country and potentially farther afield.”

This was a big one, a verdict much awaited, because it will be widely seen as playing a crucial role in determining whether facilities like Insite will be allowed to operate in North America. Technically, a court ruling against Insite would not have automatically put the operation out of business, but would have left it in the twilight zone of operating under a federal government exemption that could be pulled at any time—and the current Canadian government has broadly hinted that it would do so.

The Supreme Court victory means that Insite can operate without benefit of any kind of federal government legal exemption from drug laws, a situation that has always put Insite at the mercy of political posturing.

Photo Credit:
http://www.canada.com/story_print.html?id=af132f6b-2099-407d-af87-13c12016af5a&sponsor=

The Biology of Stimulants, or Why You Can’t Stay High Forever

An essay on the losing battle for perpetual reward.

The amphetamine high, like the cocaine high, is a marvel of biochemical efficiency. Stimulants work primarily by blocking the reuptake of dopamine molecules in the synaptic gap between nerve cells. Dopamine remains stalled in the gap, stimulating the receptors, resulting in higher dopamine concentrations and greater sensitivity to dopamine in general. Since dopamine is involved in moods and activities such as pleasure, alertness and movement, the primary results of using cocaine or speed—euphoria, a sense of well being, physical alertness, and increased energy—are easily understood. Even a layperson can tell when lab rats have been on a meth binge. The rapid movements, sniffing, and sudden rearing at minor stimuli are not that much different in principle from the outward signs of meth intoxication among higher primates.

Chemically, cocaine and amphetamine are very different compounds. Psychoactively, however, they are very much alike. Of all the addictive drugs, smoked cocaine and speed have the most direct and most devastatingly euphoric effect on the dopamine systems of the brain. Cocaine and amphetamine produce rapid classical conditioning in addicts, demonstrated by the intense cravings touched off by such stimuli as the sight of a building where the user used to buy or sell. Environmental impacts of this nature can produce marked blood flow increases to key limbic structures in abstinent addicts.

In clinical settings, cocaine users have a hard time distinguishing between equal doses of cocaine and Dexedrine, administered intravenously. As we know, it is the shape of the molecule that counts. The amphetamines are shaped like dopamine and norepinephrine, two of the three reward chemicals. Speed, then, is well suited to the task of artificially stimulating the limbic reward pathway. Molecules of amphetamine displace dopamine and norepinephrine in the storage vesicles, squeezing those two neurotransmitters into the synaptic gap and keeping them there. By mechanisms less well identified, cocaine accomplishes the same feat. Both drugs also interfere with the return of dopamine, norepinephrine, and serotonin molecules to their storage sacs, a procedure known as reuptake blocking. Cocaine works its effects primarily by blocking the reuptake of dopamine.

Amphetamine was once one of the most widely prescribed drugs in the pharmacological cornucopia. It exists in large part now as a recreational drug of choice, abuse, and addiction. The same is true of cocaine. It was replaced as a dental anesthetic long ago, in favor of non-addictive variants like Novocain. The same tragic list of statistical side effects that apply to abusers of alcohol, heroin and nicotine also apply to stimulant abusers: Increased risk of car accidents, homicides, heart attack, and strokes.

In the late 1990s, scientists at Johns Hopkins and NIDA showed that opiate receptors play a role in cocaine addiction as well. PET scans demonstrated that cocaine addicts showed increased binding activity at mu opiate receptors sites in the brain during active cocaine addiction. Take away the cocaine, and the brain must cope with too many empty dopamine and endorphin receptors. It is also easy to understand the typical symptoms of cocaine and amphetamine withdrawal: lethargy, depression, anger, and a heightened perception of pain. Both the cocaine high and the amphetamine high are easily augmented with cigarettes or heroin. These combinations result in “nucleus accumbens dopamine overflow,” a state of neurochemical super saturation similar to the results obtained with the notorious “speedball”—heroin plus cocaine.

With the arrival of smokable forms of cocaine and amphetamine, the race to pin down the biology of stimulation became even more urgent. Stimulants in smokable form—crack and ice—are even more rapidly addictive for addiction-prone users. “The reason has to do with the hydraulics of the blood supply,” a researcher at the University of Minnesota explained to me. “High concentrations are achieved with each inhalation, and sent right upstairs to the brain—but not all of the brain simultaneously. The target of the flow of blood is the limbic system, whereas the remainder of the brain is exposed to much milder concentrations.”

This extraordinarily concentrated jolt to the reward center is the reason why smokable cocaine and speed are able to pack such a wallop. The entire range of stimulative effects hits the ventral tegmental area and associated reward regions of the brain in seconds, and the focused nature of the impact yields an astonishingly pleasurable high.

But the long-term result is exactly the opposite. It may sound dour and religious, but the scientific fact of the matter is that continuous chemical pleasure extracts its fee in the end: The body’s natural stock of these neurotransmitters starts to fall as the brain, striving to compensate for the artificial flooding of the reward center, orders a general cutback in production. At the same time, the receptors for these neurotransmitters become excessively sensitive due to the frequent, often unremitting nature of the stimulation.

“It’s clear that cocaine causes depletion of dopamine, norepinephrine, serotonin—it is a general neurotransmitter depleter,” said my research source. “That may account for many of the effects we see after someone has stopped using cocaine. They’re tired, they’re lethargic, they sleep; they may be depressed, moody, and so on.” Continued abuse of stimulant drugs only makes the problem worse. One reason why cocaine and amphetamine addicts will continue to use, even in the face of rapidly diminishing returns, is simply to avoid the crushing onset of withdrawal. Even though the drugs may no longer be working as well as they once did, the alternative—the psychological cost of withdrawal—is even worse. In the jargon used by Alcoholics Anonymous, addicts generally have to get worse before they can get better.

When addicts talk about “chasing a high,” the metaphor can be extended to the losing battle of neurotransmitter levels.

Photo Credit: http://etinkata.blogspot.com

An Interview with Pharmacologist David Kroll

On synthetic marijuana, organic medicines, and drugs of the future.

(Second post in the “Five-Question Interview” series.)

Back in July, Addiction Inbox ran a fascinating 5-question interview with clinical and research psychologist Vaughan Bell. The post touched on abnormal brain function, drugs, hallucinations, and addiction. It was a blast.

The huge and multi-talented staff here at Addiction Inbox has hopes of making this a semi-regular feature, since there is no shortage of interesting and accomplished people out there who can sometimes be successfully pestered into answering broad-ranging questions about drugs and addiction for an obscure science blog.

Herewith, a 5-question interview with pharmacologist David Kroll, Ph.D., Professor and Chair of Pharmaceutical Science at North Carolina Central University in Durham, and a well-known blogger in the online science community.

A cancer pharmacologist whose field is natural products—he’s currently involved in a project to explore the potential anticancer action of chemicals found in milk thistle and various sorts of fungi—Dr. Kroll received his Ph.D. from the University of Florida, and completed his postdoctoral fellowship in Medical Oncology and Molecular Endocrinology at the University of Colorado School of Medicine. He went on to spend the first nine years of his independent research and teaching career at the University of Colorado School of Pharmacy, where he taught all aspects of pharmacology, from central nervous system-active drugs, to anticancer and antiviral medications. He has also worked as a research pharmacologist for the Research Triangle Institute, and for SmithKline and French Laboratories. He’s responsible for Terra Sigillata—a natural products pharmacology and chemistry blog—and Take As Directed, his personal blog. He is also co-author of Breast Cancer Recurrence and Advanced Disease: Comprehensive Expert Guidance.


1. You’ve been writing about the new synthetic marijuana products on your blog, Terra Sigillata, since they first leaked into the drug underground. Can you briefly explain the origin of these “fake” cannabis chemicals, and the work done by the Huffman lab?

Every area of CNS pharmacology has chemists who try to figure out the smallest possible chemical structure that can have a biological effect. In fact, this is a longstanding practice of any area of pharmacology. Huffman was an excellent chemist who in the 1990s was trying to figure out the most important part of the active component of marijuana that might have psychotropic effects. These compounds made by him and his students, surprisingly simple ones, I prefer to call cannabimimetics since they mimic the effect of the more complex cannabinoids in marijuana. These basic chemistry and pharmacology studies are what ultimately lead to new drugs in every field - a facet of chemistry called "structure-activity relationships" or SAR.

But since they are simple, they are relatively easy to make - some of Huffman's work at Clemson was actually done by undergraduate chemistry majors. So, it was no surprise that they would be picked up by clandestine drug marketers, even though cannabis (UK) and marijuana (US) are freely available. The attraction to users was, until recently, that Huffman compounds (prefixed with "JWH-" for his initials) could not be detected in urine by routine drug testing. Hence, incense products containing these compounds have been called “probationer's weed.”

2. In a recent guest blog post for Scientific American titled “Drugs from the Crucible of Nature,” you remind us that several hundred common drugs are modified natural products. What stands in the way of discovering, isolating, and testing more of these plant drugs?

Fully 25% of all pharmaceuticals can trace their roots to natural products: chemicals made by plants, bacteria, fungi, and marine creatures that possess biological effects in mammals. The first ones we recognized as humans were those which altered our perception of reality or our ability to adapt to the strenuous, pre-modern life: hallucinogens for religious purposes and stimulants to support physical activity and suppress hunger. Over time, we found other drugs that treated pain (opiates), heart failure or "dropsy" (digitalis), or cancerous lesions (podophyllin from the Penobscot Native Americans).

We know today that natural products have much greater chemical diversity than drugs made by man and are useful additions to the study of new drug targets. However, naturally-occurring drugs sometimes have major drawbacks: they are difficult to make in the laboratory or require large amounts of their natural source to be commercially viable, they can have undesired effects that may not be apparent from traditional uses, or they require chemical modifications to be safer, more resistant to metabolism, and to become patentable intellectual property.

Over the last 10-15 years, the short-term, investor- and market-driven view of pharmaceutical companies has led the big firms to eliminate their natural product research programs. Today, much of the discovery of naturally occurring drugs has been left to academic researchers and small companies where many former pharma researchers reside. Once we get compounds that may be viewed as "druggable" by the pharmaceutical industry or the National Cancer Institute (in the US), they can then move to clinical trials.

3. Psychoactive plant drugs like the poppy played a major role in the development of modern pharmacology and neurology. One school of thought says that psychoactive drugs are overprescribed, addictive, and ineffective panaceas. The other side views such drugs as targeted, effective, and increasingly sophisticated treatments for diseases once thought to be untreatable. Have we become a nation of crazed pill heads, or is this simply pharmaceutical medicine on the march?

I have a middle-of-the-road view on this topic. As you know (and my blog readers will know) my father suffered from alcoholism that was comorbid with clinical depression. Real, biochemically-based depression has been undertreated in Western societies, in part due to the stigma that admitting mental disorders is somehow viewed as compromising one's intellect. Nothing could be farther from the truth, of course. Some of the most brilliant and creative minds in all fields have suffered from depression, mania, and, sadly, ended their lives early by suicide.

So, drugs certainly have their place for those unfairly dealt a hand of bad brain biochemistry. We should not view this as any worse than getting the bad genes for hypertension or diabetes. The problem seems to be those with mild-to-moderate psychiatric disorders, many of which can be managed without drugs but that require personal effort in the form of psychotherapy, cognitive behavioral therapy, or other flavors of hard, personal work. As Americans, what do we want? The hard work or the pill? If we want to lose weight, do we want exercise, caloric restriction, or a pill? Hence, we are the ones who are complicit with pharmaceutical companies. We want the pill rather than the hard work and the companies supply that demand. Anyone who doesn't realize that we as a society facilitate what we demonize in pharmaceutical companies is just simply in denial.

4. It’s increasingly obvious that our legal and cultural approaches to addictive drugs have not been successful. What’s your take on the drug war, and on the problematic distinction between “legal” and “illegal” drugs of abuse?

My primary research field is cancer drugs, but my teaching brings me into the realm of drugs of abuse, simply because so many of those drugs are naturally-occurring. So, my views must be taken in that perspective. In the US, I think that it is morally difficult to justify the legality of addictive drugs like alcohol and tobacco while restricting other psychoactive compounds. I do not advocate for other drugs to be used recreationally. I just feel that US laws need to be consistent. Our experiment with criminalizing alcohol was an abysmal failure that fostered organized crime. Our continued experiment with criminalizing other drugs has been equally a failure. However, I am very much against a libertarian argument that society should be free to determine what they want because, frankly, many drugs impair one's decision-making ability.

But I like your question: many drugs declared illegal for recreational use are among the most useful therapeutics for pain, especially the pain associated with surgery and cancer. My greater humanistic concern is that our society's zero tolerance approach to drugs that "could" be illegal is that people who need them for their desired effect often go without. Undermanagement of pain is the major casualty of the war on drugs. No, let me fix that. People who suffer unnecessarily from pain when useful drugs could be used are the major casualties of the war on drugs.

5. What’s going on in pharmaceutical research these days that has you excited?

When I was graduating with my toxicology degree in 1985 from the Philadelphia College of Pharmacy and Science, I asked my chairman Dr. Gary Lage where I should expect new drugs to come from. His words of wisdom were that I should pay close attention—not to drug companies, but rather to major advances in physiology. Learning that the kidney played a role in red blood cell count led to the use of erythropoeitin for anemia caused by renal failure and chemotherapy.

Today, I see major drug targets in the epigenome—the part of genetics that is affected by environmental influences. We are all stuck with the static part of our inherited DNA—the exact base sequences and their polymorphisms and mutations. However, we're learning that those things can be modified by diet, environmental exposures, and, yes, drugs. The epigenome is a broad target for a multitude of diseases, never more complicated but never more promising.