While traveling in China in 1971, two-time Pulitzer Prize-winning journalist James Reston underwent an emergency appendectomy, after which Chinese medical personnel treated his pain with acupuncture. His description of the experience in the pages of the New York Times brought the practice of traditional Chinese medicine front and center.
Two years later, Lewis Thomas, then president of Memorial Sloan-Kettering Cancer Center, delivered an address in which he said, “These are bad times for reason, all around. Suddenly, all of the major ills are being coped with by acupuncture. If not acupuncture, it is apricot pits.” Thomas was referring to laetrile, a compound extracted from the pits of apricots and bitter almonds, one of the most sought-after alternative treatments for cancer at the time, but one whose effectiveness had been the topic of bitter controversy for years. Banned since 1963 in the U.S., laetrile is reported to still be readily available in the Bahamas and Mexico and is sold online.
And the examples don’t end there. Lots of ballyhoo, head-scratching, and accusations of quackery attended growing patient demand for alternative treatments, hyped in the popular press as cures that were “natural” and based on millennia-old medical traditions practiced in places such as China and India.
In 1999, in response to a growing outcry for some kind of evidence-based scientific analysis of the safety and efficacy of this blizzard of nonconventional treatments, the National Institutes of Health, then under the direction of Harold Varmus, established the National Center for Complementary and Alternative Medicine (NCCAM). Since its founding, NCCAM has funded basic and clinical research at institutions around the world on plant and animal products such as acai, black cohosh, gingko biloba, and shark cartilage, as well as on the therapeutic value of treatments including acupuncture, yoga, massage, reiki, and meditation.
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Almost 40 percent of US adults and 12 percent of US children have used complementary or alternative therapies, according to a 2007 survey by NCCAM, and much of what was once considered “alternative,” including acupuncture, is now part of more-holistic regimens offered at 40 percent of US hospitals, including Memorial Sloan-Kettering Cancer Center. According to a 2010 survey by the American Hospital Association and the Samueli Institute, a nonprofit center for the study of wellness and healing, this trend is driven by patients demanding alternative or complementary treatment options for conditions that are difficult to manage or cure, such as diabetes, chronic pain, and cancer. Most physicians have lukewarmly embraced such therapies, often because they feel that patients will desert conventional therapy out of desperation if they are not offered a wider range of treatment options.
Researchers who study the scientific validity of nonconventional treatments rarely see them as stand-alone remedies, preferring to call the union of conventional and nonconventional “integrated therapy.”
The Scientist staff asked experts about the scientific evidence for a number of treatments that may be on the verge of becoming incorporated into integrated therapies, from acupuncture and probiotics to marijuana and psychedelics. We sought to highlight the data that either supports or contravenes the effectiveness of these alternative therapies. As with most health interventions, we uncovered both positive and negative aspects of these treatments for which patients are clamoring and physicians are demanding evidence.
—Mary Beth Aberlin
Though research is deepening our understanding of the role of microbes in our health, good clinical trials are still needed before consumers can be sure they will enjoy any benefits.
Microbes, mostly bacteria and yeast, teem throughout our bodies, setting up their own ecosystems on our skin and in our mouths and guts. As it becomes ever clearer that microbial ecosystems are intimately connected to our health, consumers look to probiotics—strains of bacteria or yeast that may have health benefits if ingested or applied externally—as gentler alternatives to current therapies. Beyond the obvious interest in developing probiotic treatments for gastrointestinal disorders, researchers hope to understand how probiotics may influence obesity, skin health, vaginal health, and even our moods. With probiotics showing up in everything from yogurt to face cream, it’s difficult to know whether these products have credible benefits. Clinical studies are beginning to support the early promise of some probiotic treatments, and scientists are rapidly expanding their knowledge of how microbes interact with our bodies and how probiotics might be rationally employed both to treat and to prevent disease.
“It’s a very exciting time to be a microbiologist,” says Maria Marco of the University of California, Davis, who studies how lactic acid bacteria, which include strains used in milk fermentation, interact with our intestines to improve health. She points to a confluence of genetic data from the Human Microbiome Project and experimental data, which together are beginning to illuminate the role of microbes in health.
About 200 clinical trials have investigated the use of probiotics to treat gastrointestinal disorders, and the science is finally catching up to the hype, says Marco. A March 2011 Cochrane Review recommended the use of probiotics in premature babies to help prevent necrotizing enterocolitis, in which sections of bowel tissue die. In November 2011 another Cochrane Review of 16 studies reported efficacy in treating children with probiotics to prevent antibiotic-associated diarrhea. But the evidence is not overwhelmingly positive, notes Matthew Ciorba, a gastroenterologist at Washington University in St. Louis. “If there were super-strong results, all physicians would be prescribing [them],” Ciorba says. The Cochrane study showed that probiotic treatment reduced antibiotic-associated diarrhea from more than 220 cases per 1,000 children to fewer than 90. But the review’s lead author, Bradley Johnston at the University of Toronto’s Hospital for Sick Children, explains that due to a lack of high-quality data, he and his coauthors are not extremely confident about those numbers. About 25 percent of patients did not complete the studies, and even though they collected data from 3,000 children, there were relatively few cases of diarrhea, making it difficult to draw strong conclusions.
Another antibiotic-associated infection that is on the rise, the occasionally life-threatening Clostridium difficile, may be amenable to probiotic treatment, but again, rock-solid results are lacking. One reason for the dearth of convincing clinical trials, Johnston notes, is that it’s more difficult to conduct trials for a rare disease like C. diff, because they require larger numbers of base participants to catch the rare cases needed to power the study. A 2008 meta-analysis examining probiotic treatment of C. diff infection did not recommend the therapy, but Johnston says that an updated analysis is expected to be completed this summer. Fecal transplants of healthy-donor gut microbes—also considered a probiotic treatment—have shown promise in case studies of C. diff, but clinical trials are needed. Investigations of the probiotic potential of Saccharomyces boulardii, closely related to brewer’s yeast, and Lactobacillus rhamnosus GG have produced mixed results, but suggest that both may aid in treating recurrent C. diff infections. Johnston expects to see more strain-specific trials for this hospital-acquired infection in the future. (See “Wrestling with Recurrent Infections,” The Scientist, May 2011.)
Trials investigating probiotic treatment of chronic inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, have so far failed to demonstrate a strong effect. A 2011 Cochrane Review of four clinical trials surveying probiotic treatment of ulcerative colitis couldn’t recommend the therapy due to a lack of large, well-designed, randomized trials. The pooled studies covered only 587 participants; two trials were not completely blinded; and one had a dropout rate of nearly 50 percent.
It’s clear that larger and better-designed studies are necessary, but researchers are also contending with microbial ecosystems that aren’t easily altered. “Our microbes are fairly established,” says Mary Ellen Sanders, of Dairy and Food Culture Technologies in Colorado. “They can be perturbed [with new probiotics or pathogenic strains] but they tend to bounce back,” so eating yogurt won’t permanently colonize the gut with beneficial bacteria. Thus, chronic problems stemming from a specific spectrum of microbes—unlike antibiotic-associated diarrhea—will be unlikely to respond to a quick dose of probiotics.
Lackluster trial results may also stem from using the wrong probiotic to treat an illness. Specific probiotic strains may have drastically different effects, even if the microbes are from the same species, explains Marco. Her own work on the immunomodulatory effects of Lactobacillus plantarum on human immune cells showed that production of the pro-inflammatory cytokine IL-12 differed up to 16-fold based on the strain, and the amount of the anti-inflammatory cytokine IL-10 differed 14-fold. Immunomodulation is one key mechanism thought to underlie probiotic effects. Cell-wall components of probiotics, such as peptidoglycans and teichoic acids, can spur pro- or anti-inflammatory reactions from mucosal and immune cells, depending on modifications like glycosylation and acetylation. A strain of L. plantarum that promotes more IL-10 production has been shown to protect against colitis in a mouse model.
Although controlling inflammation is thought to be one mechanism, how, exactly, probiotics work against conditions such as antibiotic-induced diarrhea is unclear, says Gregor Reid, a microbiologist at the University of Western Ontario who helped write the World Health Organization’s definition of probiotics 10 years ago. It’s known that commensal (nonpathogenic) microbes can stimulate mucus or antimicrobial peptide production by gut epithelial cells, Reid explains, and probiotics might also compete with pathogenic bacteria for an ecological niche.
One future challenge will be translating promising animal studies into effective human trials, says Sanders. For example, she notes, probiotics “give really nice results” in mouse models of Crohn’s disease, but so far attempts to replicate this in humans have fallen short.
Researchers are also beginning to tackle the question of how probiotics may help in conditions seemingly unrelated to our guts, such as periodontal disease, allergic disorders, and even mental health. It’s known that our microbial ecosystems are in flux for several months after birth, and if certain strains are linked to later disease, like asthma, early manipulation of our microbiota might be a wise prophylactic strategy, says Reid. Sanders, in turn, postulates that the Human Microbiome Project may provide us with information that will help us identify the right microbes to help infants and children develop appropriately. Research linking obesity or stress responses to the gut microbiome is in tantalizing early stages. Marco points to one study in which probiotic treatment influenced mouse stress behaviors, and several which suggest that gut microbes may influence energy expenditure and abdominal fat.
In the meantime, says Ciorba, it remains difficult for the consumer to benefit from successful probiotics studies. Even if a yogurt contains a probiotic strain that is backed by scientific research, it’s difficult to know how the viability of the commercial strain compares to the doses tested in the lab or how long it should be taken for optimal effect. Touching again on the notion that our intestinal health may influence our mental health, Ciorba points to irritable bowel syndrome—a constellation of generally mild symptoms that may be difficult to measure clinically. Though probiotic treatment may not change the amount of diarrhea or timing of bowel movements, patients still report improvements in pain symptoms. When taking probiotics, Ciorba says, “they just feel better.”
Acupuncture may not work any better than its placebo, but even the placebo often improves patient outcomes.
In 1997, the National Institutes of Health convened a conference to evaluate acupuncture—the insertion of needles into the skin at points that run along so-called meridian lines outlined by Chinese traditional medicine—with the goal of determining whether the technique had a place in Western medicine. The practice is used to treat a wide range of conditions, from pain to infertility, epilepsy and schizophrenia, and the NIH consensus conference was tasked with determining if the claims were valid. “A consensus conference is more like a court of law than a scientific meeting,” explains Richard Hammerschlag, Emeritus Dean of Research at Oregon College of Oriental Medicine, who presented at the meeting. “At that point, there was relatively little good research. Most of the studies were underpowered, low-sample studies.”
Twelve professionals from fields including anthropology, psychiatry, public health, osteopathic medicine, and substance abuse evaluated the presentations, and at the end of the conference drafted a report summarizing their collective opinion.
Despite the limited data available, and the panel’s rather hedged wording, the conference report found that there was enough evidence to support the use of acupuncture for post-operative dental pain and for nausea after chemotherapy, and evidence for several other applications that seemed promising. The conference report, which was published in the Journal of the American Medical Association, lent an air of validity to the use of acupuncture. “I think it was considered a milestone in accepting acupuncture in medical practice,” says Eric Manheimer, an administrator of the Cochrane Collaboration’s Complementary Medicine Field.
5 years and some 4,000 clinical trials later, researchers are still not convinced that acupuncture is any better than the often-used placebo of sham acupuncture, which employs only superficial needle insertion into random points on the skin. The confounding issue, and the one which most researchers seem to agree on, is that both acupuncture and sham treatment appear to have benefits over the standard of care, creating what researchers call the “efficacy paradox.” It suggests that either acupuncture exerts a powerful but reproducible placebo effect in patients, or that inserting needles randomly has the same effect as inserting needles into some 400 acupuncture points that traditional Chinese practitioners believe help unblock one’s qi, or life force.
Researchers studying placebo effects have demonstrated that acupuncture can go a long way towards helping patients feel better. One recent study by placebo researcher Ted Kaptchuk at Beth Israel Deaconess Medical Center compared albuterol, an asthma medication, with sham acupuncture, no intervention, or a placebo inhaler (NEJM, 365:119-26, 2011). Patients reported feeling better after albuterol treatment, as well as after sham acupuncture and the placebo inhaler, but not if they received no treatment at all. However, when researchers took an objective measure of their asthma—the maximum forced expiratory volume in one second—it was clear that only those treated with albuterol actually improved.
In another study, participants were asked to rate their belief that acupuncture would work prior to acupuncture treatment for pain. Those with high expectations showed greater pain relief than those with lower expectations, regardless of whether they received real or sham acupuncture (Pain, 128:264-71, 2007). While the research suggests that there is a strong placebo component to acupuncture, that may not be a bad thing, says acupuncture practitioner and placebo researcher Tao Liu, a visiting scholar at the University of Maryland School of Medicine. “Placebo effects can be clinically relevant and can be harnessed to improve patient care. Acupuncture is a good example,” Liu says in an e-mail.
Another possible explanation for the efficacy paradox touches on the fact that researchers still don’t have a good idea what acupuncture’s mechanism of action might be, which makes it extremely difficult to create an appropriate control. “That was the problem [in 1997] and is still the problem today,” says Hammerschlag. When drug trials are performed to test efficacy, “you know what the real drug’s mechanism is—how it’s absorbed, how it’s metabolized, and how it’s degraded,” he says. That knowledge allows researchers to design a placebo that doesn’t do any of those things, but that mimics the treatment enough to deceive the patient. Some sham acupuncture trials use methods such as poking a person with the blunt end of the needle or using placebo needles which retract into the handle of the needle, but these can be too easy for a patient to spot, rendering the placebo ineffective. Real needles superficially inserted into the skin at nonmeridian points are harder for patients to differentiate from “true” acupuncture, but some researchers think that even apart from patients’ belief that they are getting the real thing, this placebo could still activate the same mechanism of action as needles inserted into the traditional meridian points.
While there is no agreement on how acupuncture might work, a number of physiological changes do occur as a result of acupuncture needling, both in animal models and in humans, along meridian lines or not, which may or may not be related to acupuncture’s proposed medicinal effects. For example, studies in mice suggest that acupuncture’s reported effect of relieving pain may be mediated by the localized release of adenosine, which has analgesic effects (Nat Neurosci, 13:883-88, 2010). Other studies show that connective tissue in mice sticks to acupuncture needles and measurably wraps around the needle, which stretches the tissue. As a result of this stretching, nearby fibroblasts become enlarged and, over the course of 30 minutes, cause the connective tissue to relax. Simple mechanical stretching of the connective tissue appears to have the same effect on fibroblasts, but acupuncture provides a way of creating a local and sustained stretch, says Helene Langevin, a neuroscientist who studies connective tissue and mechanotransduction at the University of Vermont. But, she says, “we don’t know how that translates to changes in pain [perception]. We haven’t tested that yet.”
Although the question of whether acupuncture helps patients due to a placebo effect or an actual physiological change remains open, a number of insurance companies both in the United States and in the United Kingdom have begun to cover the practice, at least for a few conditions, such as lower back pain. Whether it works for the right reasons or the wrong ones, the treatment does appear to work for some people, says Hammerschlag. “We certainly don’t know enough yet to throw it out.”
Facts about the benefits of medical marijuana are sparse, hampered by the politics and regulatory difficulties of doing such research.
Marijuana (Cannabis sp.) has been used as a medicine for more than 4,000 years. But in the eyes of the US federal government, cannabis is an illegal drug that has no place in the clinic. Biomedical researchers who would like to study cannabis in a medical setting are frustrated by the challenges of obtaining government clearance and funding. But some data pointing to medical benefits of smoking marijuana do exist.
In 1970, the US Congress voted to classify cannabis under Schedule I of the Controlled Substances Act. Marijuana joined heroin, LSD, and peyote on Schedule I, and according to the Act, it—along with all other Schedule I drugs—has a high potential for abuse, lacks safety, and has “no currently accepted medical use in treatment in the United States.”
Since then, 16 US states and the District of Columbia have legalized the use of medicinal cannabis for a variety of indications, from chronic pain to cancer- and HIV-related appetite and weight loss, nausea, and vomiting. But despite the recent wave of state-level legalization, and the enactment of similar laws in Canada and elsewhere around the globe, the US federal government still classifies marijuana as a Schedule I drug, a designation that makes studying the medical effects of the drug in the U.S. extremely difficult (requiring approval from the Drug Enforcement Administration in addition to the Department of Health and Human Services (HHS)). Therefore, it has been far more common (and easier) to get funding and clearance to study the negative impacts of marijuana as a substance of abuse than to investigate its positive effects as a therapeutic agent.
Nonetheless, some researchers have braved the bureaucratic obstacles to conduct a handful of randomized, placebo-controlled trials that point to benefits of smoking cannabis, though they acknowledge that smoking the plant comes with its own risks and drawbacks. A more extensive body of literature involves molecular components, extracts, or synthetic forms of marijuana, simply because studying these non-Schedule I substances is less fraught with regulatory obstacles than is studying the whole plant.
The strongest evidence of smoked marijuana’s benefit exists in patients who experience chronic pain. With funding from the University of California Center for Medicinal Cannabis Research (CMCR), researchers published studies in 2007, 2008, and 2009 that all suggested smoked cannabis possessed analgesic properties. A study published in 2007, for example, noted that HIV patients experiencing neurological pain, or neuropathy—a general name for burning pain, hypersensitivity to light touch, and other uncomfortable symptoms—experienced a dulling of that pain when they smoked a cannabis cigarette three times a day for 5 days.
Psychiatrist Igor Grant, director of the center and an HIV/AIDS researcher at the University of California, San Diego, says that patients suffering from neuropathy in particular seem to find relief in cannabis. “We don’t have terrific agents to treat it. There are agents [such as antiepileptics and antidepressants] and they are modestly effective in many people,” Grant says. “The bottom line is that [cannabis] seems to work, and the effects are comparable in strength to traditional agents.”
Other studies from the CMCR have probed new conditions the plant might be used to treat. For example, UC San Diego researchers reported in 2008 that smoked marijuana has the potential to reduce muscle spasticity in multiple sclerosis (MS) patients. That finding was bolstered by a randomized, double-blind, placebo-controlled study published last year on the liquid marijuana extract Sativex, which is approved for use in some European countries, Canada, and New Zealand. The results of that trial, conducted by European researchers, indicated that a 4-week course of Sativex, an oral spray that contains the cannabinoids cannabidiol (CBD) and delta-9 tetrahydrocannabinol (THC), was safe and effective at reducing spasticity in many MS patients.
US researchers are completing Phase III trials of Sativex for the treatment of pain associated with cancer, and Otsuka Pharmaceutical, the US licensing partner of UK drugmaker GW Pharmaceuticals, hopes to gain FDA approval soon.
Aside from the relative logistical ease of studying constituents, extracts, or synthetics due to the fact that they do not run afoul of the Controlled Substances Act, these compounds stimulate the endocannabinoid system, the body’s homegrown constellation of receptors that interact with the active components of cannabis in a more tractable way than does smoked cannabis. “Harnessing that system with medications is a potentially new avenue for therapeutics,” says Mark Ware, McGill University neurologist and pain physician.
For example, Marinol is a synthetic THC drug that is used by chemotherapy patients experiencing nausea and vomiting or AIDS patients who are rapidly losing weight. It is the only FDA-approved synthetic cannabinoid, and offers an alternative to conventional therapies for these patients, though results have been mixed when comparing its effects to those of smoked cannabis, with the herbal version usually outperforming the synthetic.
This highlights one problem with going the synthetic route in the eyes of some cannabis researchers. “We shouldn’t forget that the herbal product contains multiple other constituents which may add to the effects of any one single agent,” says Ware. Also problematic are isolated cannabinoids’ tendency to be rapidly broken down in the liver and the difficulty in determining optimal doses.
As the political and social storm around medical cannabis continues to brew, most researchers who have seriously tested the drug’s therapeutic properties lament their inability to freely study it in a medical context. “The [cannabis] laws date to a time when what we knew about marijuana was voodoo,” says Mayo Clinic psychiatrist Michael Bostwick. “[The drug] can’t be applied to humans and to therapeutics because the laws don’t permit it to be done. The whole attitude towards medical marijuana is just irrational.”
For its part, the NIH claims that studying smoked marijuana is fair game. “Research projects seeking to determine the therapeutic potential of smoked marijuana are considered under the same criteria as any other project submitted for NIH funding,” the agency wrote in an e-mail to The Scientist. “Investigator-initiated applications for NIH funding are evaluated by peer-review groups composed of scientists from outside the NIH. The peer-review group evaluates the scientific and technical merit of the proposed research.” That said, the NIH’s Research Portfolio online Reporting Tools (RePORT) database lists many more active projects focusing on molecular components of cannabis or marijuana as a harmful drug than it does projects seeking to probe the potential medical benefits of smoking cannabis. Still, officials at the HHS also claim that the US government is game to fund studies of medical marijuana. “We’re very open to people submitting applications and trying to make [evaluating medical marijuana study proposals] a transparent and efficient process,” says Sarah Wattenberg, senior advisor for substance abuse policy at HHS. “In order for us to move this forward at all, we have to take the politics and stigma away, deal with it as a therapeutic class, and give people what science there is,” says Ware.
Particularly vexing to Ware is that so many people all over the world are using marijuana either recreationally or for the treatment of some ailment, legally or more often illegally, while science is forced to sit idly by and miss out on all that potential data. “We have so many people who are already doing the drug in one form or another in some sort of legal framework, but they’re not being involved in any type of research,” he says. “There’s kind of a huge natural experiment going on right now, and we’re not learning from it.”
While research on LSD and other hallucinogenic drugs slowed dramatically after their illegalization in the 1960s, the little research that continued has touted their promise in treating a wide range of disorders.
In the late 1940s, researchers began experimenting with the controlled use of psychedelic drugs, such as lysergic acid diethylamide (LSD), as possible therapeutics to supplement psychotherapy. The drugs’ psycholytic or “mind-loosening” effects, they realized, made it easier for patients to explore repressed memories. Over the next few decades, research on psychedelics expanded to include their potential application to anxiety disorders, obsessive-compulsive tendencies, depression, drug and alcohol dependence, pain, bereavement reactions, sexual dysfunction, and more. By 1965, more than 2,000 published articles—most of them, admittedly, anecdotal case reports—touted the effectiveness of psychedelic drugs in helping to safely treat some 40,000 patients, with few negative side effects reported.
But rampant, uncontrolled recreational use and reports of adverse reactions during the 1960s led to the illegalization of LSD and other such drugs in the United States—cutting off the supply to research labs around the country and slowing psychedelics research to a trickle. Like marijuana, the drugs are now listed as Schedule I drugs, and researchers hoping to study their medical benefits must get approval from several different agencies and boards. In the last 10 years or so, however, new research on their therapeutic benefits has warranted the drugs’ entry into clinical studies, and today, a handful of trials are bringing psychedelics closer to use in the clinic.
“Psychedelic drugs, from a scientific viewpoint, shouldn’t even be a controversial subject,” says Ben Sessa, a child and adolescent psychiatrist working in South West England. “They are effective and safe treatments for mental illness, and there’s very good evidence for that.”
Psychedelics act on various neuro-transmitter and hormone systems in the brain. LSD and psilocybin, the psychedelic component of “magic” mushrooms, for example, affect serotonin and dopamine signaling, while MDMA, or “ecstasy,” increases output of oxytocin, among other changes. Although these neural pathways are known to regulate mood, learning and memory, bonding, and more, and their dysregulation is implicated in psychosis, exactly how the drugs’ actions in the brain translate into a therapeutic effect (or a bad trip) is still unclear. “We know what receptors they’re targeting, we know basically what kind of second messenger signals inside the cells they get started, but beyond that we don’t know how they work,” says Emmanuelle Schindler, a physician scientist and neurology resident at Yale School of Medicine. Of course, “that is not known for any psychiatric drug,” adds South Carolina–based psychiatrist and researcher Michael Mithoefer.
Uncertainties aside, several psychedelic drugs have started to show real promise in recent clinical trials. In 2010, a phase II trial of MDMA conducted by Mithoefer and colleagues successfully “cured” 10 of 12 posttraumatic stress disorder (PTSD) patients—who no longer exhibited symptoms typical of the disorder after participating in just two 8-hour psychotherapy sessions while on MDMA. The three subjects who had had to leave their jobs as a result of their PTSD were all able to return to work.
Another treatment advancing through clinical trials is the use of LSD and psilocybin to manage anxiety in patients with terminal illness. Just last year, advanced-stage cancer patients participating in a Phase II study of psilocybin responded positively after a single treatment. “We found fairly strong and consistent evidence that it did reduce anxiety and also improve mood, not simply for the hours and day of that experience but even in the weeks and months that followed,” says Charles Grob, a professor of psychiatry at the University of California, Los Angeles.
Because therapy with psychedelics involves only one or a handful of treatments over several weeks or months, there is little risk of side effects or dependence. “You just have to take them once or twice, and they can cause long-lasting changes that we don’t really see with other types of medication,” says Schindler.
However, the fact that so few doses are necessary makes it hard to find funding, notes Mithoefer. “That’s not a very profitable business model,” he says, particularly for pharmaceutical companies looking to cash in on future drug sales. Currently, researchers rely heavily on foundations such as the Multidisciplinary Association for Psychedelic Studies (MAPS) and the Heffter Research Institute, as well as a hodgepodge of other sources, to fund their work.
The illicit drugs’ unsavory history and continued recreational use also complicate the funding and clearance processes. “We have to jump through a lot of hoops . . . [to ensure that] our studies are fully sanctioned and approved,” says Grob.
Despite the hurdles, psychedelics researchers are hopeful that the next decade will see some of these therapies gain FDA approval—at least for use in patients who are not responding to traditional therapies. “What I’m seeing in the last couple of years is a real shift away from prejudice to actual interest and healthy skepticism,” says Mithoefer. “Certainly there are some detractors still out there, but for the most part it’s turned into more of a real scientific discussion.”
Natural doesn’t always mean safe: the scary consequences of taking understudied herbal supplements.
In the early 1990s, dozens of women, most under the age of 50, were being admitted to hospitals in Belgium with renal failure. About half of the women who had surgery to remove their nonfunctioning kidneys also had tumors in the upper urinary tract. The cases clustered around a medical clinic that had been prescribing Chinese herbs, which for more than 15 years had appeared to safely help women lose weight.
It turned out that aristolochic acid, a nephrotoxic chemical derived from Aristolochia vines, had mistakenly made it into in the slimming pill’s mix of ingredients. And while the Belgian tragedy was considered an accident, people around the world have taken the herb intentionally to aid wound healing, soothe arthritis, expel the placenta after childbirth, and repel snakes. “Every culture in the world has used Aristolochia in their traditional medicines,” says Arthur Grollman, a professor at Stony Brook University School of Medicine. “Don’t they know this is one of the most potent carcinogens that’s ever been recorded, and it’s renotoxic?”
In Taiwan, for example, one study found that one out of three people had received a prescription that included Aristolochia before the country banned the herb, and that prescriptions continued even after the ban. Interestingly, Taiwan also has one of the highest rates of upper urinary tract cancers in the world. Grollman and colleagues recently decided to test whether this coincidence has any backing in biology, and found that of 151 Taiwanese patients with upper urinary tract cancer, 83 percent had taken Aristolochia (PNAS, 109: 8241-46, 2012). The evidence was right there in the tissue: aristolochic acid metabolites actually bound to DNA in the kidneys, and were associated with specific mutations in the p53 tumor suppressor gene.
Despite the dangers uncovered by Grollman and others, such complementary and alternative therapies, referred to now as integrative medicine, aren’t regulated as drugs in the United States. “There are thousands and thousands of products being sold through all different kinds of channels,” says Stephen Bent, a professor at the University of California, San Francisco. ”And there isn’t the safety framework to capture and monitor how often people are having side effects or problems.”
In August of last year, Ranit Mishori, a family physician at Georgetown University School of Medicine, published case reports of two patients who ended up hospitalized after a seemingly innocuous colon cleanse (Journal of Family Practice, 60: 454-57, 2011). Sometimes taken orally, sometimes given enema-style, colon cleanses are intended to flush the system, but they can also cause a “tremendous amount of harm,” Mishori says. In one case, a patient was left severely dehydrated and with pancreatitis and an inflamed colon. In another case, a woman’s Crohn’s disease flared up shortly after a cleanse, causing days of cramping, diarrhea, and dehydration. “Since the publication of this article, I’ve heard about a lot more cases that haven’t made it into the medical literature,” Mishori adds.
Other herbal medicines that have been implicated in causing health problems include St. John’s wort, whose leaves and yellow flowers are used to treat depression, but can interfere with HIV medications; the roots of the kava-kava plant, the improper preparation of which has been linked with liver damage; and ephedra, a short evergreen bush that goes by the name ma huang, and has been tied to high blood pressure and heart attacks.
The Dietary Supplement Health and Education Act requires that manufacturers follow quality-assurance guidelines and report adverse events. But Grollman says it does not protect consumers as well as the US Food and Drug Administration’s regulations for drugs. “If herb A is such a potent carcinogen and neophrotoxin, how do you know that herbs B, C, and D are not? They’ve never been tested. . . . Natural is definitely not safe,” says Grollman. At least, as his work shows, not always.
As demand for traditional medicines booms, conservationists worry about the toll it takes on the animals and plants that serve as ingredients.
Traditional folk remedies and the modern alternative medicines that harken back to such treatments rake in annual revenues of $80 billion to $200 billion worldwide. The market for such products is expected to grow exponentially in the coming years, and this has conservationists worried about unsustainable hunting and gathering of the world’s fauna and flora for medicinal uses.
The past decade has witnessed the extinction of several high-profile species hunted, in part, for their use in traditional medicines. Late last year, the International Union for Conservation of Nature (IUCN) officially declared the western black rhinoceros (Diceros bicornis longipes) of central-west Africa to be extinct due to widespread poaching and listed the northern white rhinoceros (Ceratotherium simum cottoni) as “possibly extinct in the wild.” Both species were hunted mercilessly for their horns, which have been highly valued in East Asian medicine for more than a millennium, and can sometimes approach the price of gold.
The use of wild fauna and flora in traditional Chinese medicine (TCM), in particular, is a concern for worldwide wildlife conservation efforts. TCM is practiced by more than a quarter of the world’s population and represents a $60 billion global market. More than 10,000 plants and animals, including endangered species such as rhinos, saiga antelopes, musk deer, Asiatic Black bears, Yangtze River dolphins, pangolins, turtles, and certain species of monkeys, orchids, and sea horses, are used in TCM.
Despite the implementation of policies banning the international trade of endangered wildlife species such as tigers and rhinos in the 1980s and ‘90s, poaching and illegal trafficking of both species has seen a dramatic rise in the last decade, largely due to increasing demand from the burgeoning economies of Southeast and East Asia.
But the problem extends beyond Asia. “When rural communities were harvesting medicinal animals for their own uses, overexploitation was seldom a problem,” explains Rômulo R.N. Alves, an expert in animal-based Latin American remedies at the Universidade Estadual da Paraíba in Brazil. “However, the growing market demands and the promise of quick returns have encouraged hunters to concentrate on species with higher economic value.”
The problem is compounded by the fact that ingredients for traditional medicines are almost always collected from the wild and seldom farmed. “The medicinal fauna in Latin America is largely based on wild animals, including many endangered species,” Alves says. And it’s not just animals. In the United States, overharvesting of American ginseng (Panax quinquefolius), which has been found to lower blood-sugar levels, boost the immune system, and have anticancer properties, have rendered it endangered in the wild.
Monitoring illegally traded natural products destined for the traditional medicine market is also notoriously hard due to lack of regulation, poor quality control, and often-nonexistent labeling. Yet there is hope that by employing sophisticated technologies, such as next-generation sequencing and genetic barcoding, customs agents will be better able to confiscate traditional medicines that incorporate illegal ingredients, says Mike Bunce, a geneticist at Murdoch University in Australia who helped sequence mitochondrial and chloroplast DNA in 15 TCM products confiscated by Australian border protection officials earlier this year.
A major focus for the IUCN, the World Wildlife Fund, and other such organizations, however, has been to raise awareness among traditional medicine practitioners and patients in China about the origin of the products they use. “It’s important that users of these products take responsibility for the use and help the [bordering] countries concerned to effectively conserve these species,” says David Morgan, Chief of Scientific Support in the secretariat of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES).