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Link: Marijuana Statistics in the US: Cannabis Use & Abuse (2022 Data Update)
.. Tashkin FInds; Data Suggests Possible Protective Effect
Autumn 2005
O'Shaughnessy's
Journal of the California Cannabis Research Medical Group
Marijuana smoking —“even heavy longterm use”— does not cause cancer of the lung, upper airways, or esophagus, Donald Tashkin, MD, reported at this year’s meeting of the International Cannabinoid Research Society.
Coming from Tashkin, this conclusion had extra significance for the assembled drug-company and university-based scientists (most of whom get funding from the U.S. National Institute on Drug Abuse). Over the years, Tashkin’s lab at UCLA has produced irrefutable evidence of the damage that marijuana smoke wreaks on bronchial tissue.
With NIDA’s support, Tashkin and colleagues have identified the potent carcinogens in marijuana smoke, biopsied and made photomicrographs of pre-malignant cells, and studied the molecular changes occurring within them.
It is Tashkin’s research that the Drug Czar’s office cites in ads linking marijuana to lung cancer. Tashkin himself has long believed in a causal relationship, despite a study in which Stephen Sidney, MD, examined the files of some 64,000 Kaiser patients and found that marijuana users did not develop lung cancer at a higher rate or die earlier than non-users.
Of five smaller studies on the question, only two —involving a total of about 300 patients— concluded that marijuana smoking causes lung cancer.
Tashkin decided to settle the question by conducting a large, population-based, case-controlled study. “Our major hypothesis,” he told the ICRS, “was that heavy, longterm use of marijuana will increase the risk of lung and upper-airways cancers.”
The Los Angeles County Cancer Surveillance program provided Tashkin’s team with the names of 1,209 L.A. residents aged 59 or younger with cancer (611 lung, 403 oral/pharyngeal, 90 laryngeal, 108 esophageal).
Interviewers collected extensive lifetime histories of marijuana, tobacco, alcohol and other drug use, and data on diet, occupational exposures, family history of cancer, and various “socio-demographic factors.”
Exposure to marijuana was measured in “joint years” —average number of joints per day x years that number smoked. Thus if a person had smoked two joints a day for 15 years they’d have consumed for 30 j-yrs.
Controls were found based on age, gender and neighborhood. Among them, 46% had never used marijuana, 31% had used for less than one joint year, 12% had used for 1-10 j-yrs, 5% had used 10-30 j-yrs, 2% had used for 30-60 j-yrs, and 3% had used for more than 60 j-yrs.
Tashkin controlled for tobacco use and calculated the relative risk of marijuana use resulting in lung and upper airways cancers. A relative risk ratio of .72 means that for every 100 non-users who get lung cancer, only 72 people who smoke get lung cancer. All the odds ratios in Tashkin’s study turned out to be less than one!
Compared with subjects who had used less than one joint year, the estimated odds ratios for lung cancer were .78 for 1-10 j-yrs [according to the abstract book and .66 according to notes from the talk]; .74 for 10-30 j-yrs; .85 for 30-60 j-yrs; and 0.81 for more than 60 j-yrs.
The estimated odds ratios for oral/pharyngeal cancers were 0.92 for 1-10 j-yrs; 0.89 for 10-30 j-yrs; 0.81 for 30-60 j-yrs; and 1.0 for more than 60 j-yrs. “Similar, though less precise results were obtained for the other cancer sites,” Tashkin reported. “We found absolutely no suggestion of a dose response.”
The data on tobacco use, as expected, revealed “a very potent effect and a clear dose-response relationship —a 21-fold greater risk of developing lung cancer if you smoke more than two packs a day.” Similarly high odds obtained for oral/pharyngeal cancer, laryngeal cancer and esophageal cancer. “So, in summary” Tashkin concluded, “we failed to observe a positive association of marijuana use and other potential confounders.”
There was time for only one question, said the moderator, and San Francisco oncologist Donald Abrams, M.D., was already at the microphone: “You don’t see any positive correlation, but in at least one category, it almost looked like there was a negative correlation, i.e., a protective effect. Could you comment on that?” (Abrams was referring to Tash-kin’s lung-cancer data for marijuana-only smokers, 1-10 j-yrs.)
“ Yes,” said Tashkin. “The odds ratios are less than one almost consistently, and in one category that relationship was significant, but I think that it would be difficult to extract from these data the conclusion that marijuana is protective against lung cancer. But that is not an unreasonable hypothesis.”
Abrams’s Favorable Results
Abrams had results of his own to report at the ICRS meeting. He and his colleagues at San Francisco General Hospital had conducted a randomized, placebo-controlled study involving 50 patients with HIV-related peripheral neuropathy. Over the course of five days, patients recorded their pain levels in a diary after smoking either NIDA-supplied marijuana cigarettes or cigarettes from which the THC had been extracted. About 25% didn’t know or guessed wrong as to whether they were smoking the placebos, which suggests that the blinding worked.
Abrams’s results show marijuana providing pain relief comparable to Gaba-pentin, the most widely used treatment for a condition that afflicts some 30% of patients with HIV.
After Abrams’s presentation, a questioner bemoaned the difficulty of “separating the high from the clinical benefits.” Abrams responded: “I’m an oncologist as well as an AIDS doctor and I don’t think that a drug that creates euphoria in patients with terminal diseases is having an adverse effect.” His study was funded by the University of California’s Center for Medicinal Cannabis Research.
Add ICRS Notes
The 15th annual meeting of the ICRS was held at the Clearwater, Florida, Hilton, June 24-27. Almost 300 scientists attended. R. Stephen Ellis, MD, of San Francisco, was the sole clinician from California. Medical student Sunil Aggarwal, Farmacy operator Mike Ommaha and therapist/cultivator Pat Humphrey audited the proceedings.
Some of the younger European scientists expressed consternation over the recent U.S. Supreme Court ruling and the vote in Congress re-enforcing the cannabis prohibition. “How can they dispute that it has medical effect?” an investigator working in Germany asked us earnestly. She had come to give a talk on “the role of different neuronal populations in the pharmacological actions of delta-9 THC.”
For most ICRS members, the holy grail is a legal synthetic drug that exerts the medicinal effects of the prohibited herb. To this end they study the mechanism of action by which the body’s own cannabinoids are assembled, function, and get broken down. A drug that encourages production or delays dissolution, they figure, might achieve the desired effect without being subject to “abuse.”
News on the scientific front included the likely identification of a third cannabinoid receptor expressed in tissues of the lung, brain, kidney, spleen and smaller branches of the mesenteric artery. Investigators from GlaxoSmith-Kline and AstraZeneca both reported finding the new receptor but had different versions of its pharmacology. It may have a role in regulating blood pressure.
Several talks and posters described the safety and efficacy of Sativex, G.W. Pharmaceuticals’ plant extract containing high levels of THC and cannabidiol (CBD) formulated to spray in the mouth. See “Dr. X’s Top Talks,” on page 11.
G.W. director Geoffrey Guy seemed upbeat despite the slide his company’s stock took this spring when UK regulators withheld permission to market Sati-vex pending another clinical trial. Canada recently granted approval for doctors to prescribe Sativex, and five sales reps from Bayer (to whom G.W. sold Canadian marketing rights) are promoting it to neurologists. Sativex was approved for treatment of neuropathic pain in multiple sclerosis, but can be prescribed for other purposes as doctors see fit.
Most of the work being done with CBD and CBN is done with materials provided by GW, and some two dozen papers and posters gave them acknowledgment. At last there is a realistic alternative to NIDA for the young researchers to look to for support (and plant cannabinoids to study). GW has contributed to a significant shift in attitude.
On numerous occasions during the meeting a NIDA-funded researcher would describe the negative effects of THC, and immediately a scientist with a British accent would be at the mike pointing out that such a high dose injected into the stomach of a rat had nothing to do with the human experience with cannabis. It must have happened five or six times. The Brits were always very diplomatic, but they functioned like a truth squad.
Roger Pertwee of the University of Aberdeen reported intriguing results from experiments using a cannabis strain bred by GW to be high in THCV (tetrohydrocannabivarin).
It turns out that THCV strongly antagonizes anandamide while hardly antagonizing THC! It’s as if the cannabis plant contains and makes available to the body a choice of drugs and the body uses those it needs to achieve a balanced state (homeostasis). If the body is producing endocannabinoids in excess, it can use the plant cannabinoid THCV to achieve homeostasis. If the endocannabinoid system needs a boost, the THC provides it (while the THCV shuts down the EC system, giving it a rest as it were). The key to relief, apparently, is not high cannabinoid levels but proper gradients.
Guy explained, “It’s as if the plant contains a first-aid kit giving the body everything it needs to get bettter, and the body decides which components to employ... The endocannibnoid system begins to kick in in abnormality, in pathology. Perhaps it kicks in whether the pathology is an increase in something or a decrease in something. What it’s trying to do is get whatever that abnormality is back to homeostasis.
“ The antagonist may be working to restore function back to the center, and the agonist might be working to restore function back to the center, and once they’ve achieved the norm, they don’t go any further. The endocannabinoid system is the supeme modulator. Its job is done once you’re back to the norm. Most endocannabinoid modulators simply won’t drive the physiology or biochemistry —whatever they’re controlling— past the norm to a detrimental effect.”
Rimonabant Comes Closer
Which might explain the apparent benignity of Rimonabant, a drug that works by blocking the CB1 receptor system. Rimonabant is being tested by Sanofi-Aventis for weight loss and smoking cessation. Originally known as SR-141716, it was developed in the early 1990s as an antagonist drug for use by researchers. At the 2004 ICRS meeting, Sanofi researchers described favorable results from clinical trials of Rimonabant as a diet drug. They informally predicted regulatory approval in Europe and the U.S. within a year. Some observers warned that blocking the CB1 receptor system could result in unforeseen longterm side effects and noted that at least one MS patient had experienced an exacerbation after taking Rimonabant.
Although regulatory approval has not yet been granted, Sanofi reported good news at this meeting regarding side-effects: no more MS cases in a smoking-cessation study study involving more than 1,000 patients worldwide. “Both the 5mg and 20mg doses continued to show efficacy in the maintenance of abstinence from smoking,” reported Gerard Le Fur. “The 20mg dose also demonstrated efficacy in the reduction of weight gain as well as significantly increasing the HDL-Cholesterol levels.”
A Sanofi team also reported favorable results from studies using Rimonabant to treat various rodent models of “metabolic syndrome” —obesity-related high blood pressure, high insulin levels, excessive triglycerides and “bad” cholesterol and other problems increasing the risk of diabetes, heart attack and stroke. There is growing acceptance of the notion that the body can adjust to even a heavy blockade of the CB1 system. Perhaps when the CB1 receptor is blocked, the endocannabinoids are redirected to other targets. At times the layman is struck by how rudimentary the biochemists’ understanding of the body’s mechanism of action really is.
“ We’re on plateau one or two and the answer is on plateau 12,” said Guy. “ We could spend the next 30 years on receptors and still not fully understand them. When we talk about receptors and agonists and antagonists we should be talking in the same breath about functionality —real functionality, not models in non-pathological situations. We need an understanding of the clinical outcome.”
Osteopathic Manipulation Boosts Endocannabinoid System
John McPartland of GW Pharmaceuticals reported that osteopathic manipulative treatment (OMT) works via the endocannabinoid system. McPartland and co-workers conducted a randomized, placebo-controlled study involving 31 patients of a New Zealand osteopath.
“ Cannabimimetic effects” were measured by patients filling out a questionnaire before and after treatment defining levels of light-headedness, hunger, alterness, etc. Anandamide levels in the blood were also measured before and after treatments.
The “sham” manipulation mimicked a new technique called “biodynamic osteopathy in the cranial field.” The sham practitioner sabotaged her own concentration and mental healing intention by silently reciting “backwards serial sevens” while she applied light manual contact to the patient’s head.
Subjects receiving OMT indeed reported feeling cannabi-mimetic effects (more creativity, less coherence, for example) and their serum anandamide levels increased 168% over pre-treatment levels. Subjects receiving sham manipulation reported no changes in the questionnaire and there was no change in their serum anandamide levels.
McPartland et al noted that patients receiving OMT often experience an improved sense of well-being, sedation and euphoria —effects similar to those brought on by cannabis consumption. Previous studies indicated these psychotropic effects are not elicited by endorphins (as once had been assumed).
A recent study by Andrea Giuffrida, who contributed to the OMT study, showed that “runner’s high” correlated with elevated anandamide and not endorphins. Patients receiving chiropractic, massage, acupuncture, and energy healing also experience parallel psychotropic effects. The authors conclude that the endocannabinoid system may be mediating a widespread but heretofore unrecognized therapeutic phenomenon.
.. Tashkin FInds; Data Suggests Possible Protective Effect
Autumn 2005
O'Shaughnessy's
Journal of the California Cannabis Research Medical Group
Marijuana smoking —“even heavy longterm use”— does not cause cancer of the lung, upper airways, or esophagus, Donald Tashkin, MD, reported at this year’s meeting of the International Cannabinoid Research Society.
Coming from Tashkin, this conclusion had extra significance for the assembled drug-company and university-based scientists (most of whom get funding from the U.S. National Institute on Drug Abuse). Over the years, Tashkin’s lab at UCLA has produced irrefutable evidence of the damage that marijuana smoke wreaks on bronchial tissue.
With NIDA’s support, Tashkin and colleagues have identified the potent carcinogens in marijuana smoke, biopsied and made photomicrographs of pre-malignant cells, and studied the molecular changes occurring within them.
It is Tashkin’s research that the Drug Czar’s office cites in ads linking marijuana to lung cancer. Tashkin himself has long believed in a causal relationship, despite a study in which Stephen Sidney, MD, examined the files of some 64,000 Kaiser patients and found that marijuana users did not develop lung cancer at a higher rate or die earlier than non-users.
Of five smaller studies on the question, only two —involving a total of about 300 patients— concluded that marijuana smoking causes lung cancer.
Tashkin decided to settle the question by conducting a large, population-based, case-controlled study. “Our major hypothesis,” he told the ICRS, “was that heavy, longterm use of marijuana will increase the risk of lung and upper-airways cancers.”
The Los Angeles County Cancer Surveillance program provided Tashkin’s team with the names of 1,209 L.A. residents aged 59 or younger with cancer (611 lung, 403 oral/pharyngeal, 90 laryngeal, 108 esophageal).
Interviewers collected extensive lifetime histories of marijuana, tobacco, alcohol and other drug use, and data on diet, occupational exposures, family history of cancer, and various “socio-demographic factors.”
Exposure to marijuana was measured in “joint years” —average number of joints per day x years that number smoked. Thus if a person had smoked two joints a day for 15 years they’d have consumed for 30 j-yrs.
Controls were found based on age, gender and neighborhood. Among them, 46% had never used marijuana, 31% had used for less than one joint year, 12% had used for 1-10 j-yrs, 5% had used 10-30 j-yrs, 2% had used for 30-60 j-yrs, and 3% had used for more than 60 j-yrs.
Tashkin controlled for tobacco use and calculated the relative risk of marijuana use resulting in lung and upper airways cancers. A relative risk ratio of .72 means that for every 100 non-users who get lung cancer, only 72 people who smoke get lung cancer. All the odds ratios in Tashkin’s study turned out to be less than one!
Compared with subjects who had used less than one joint year, the estimated odds ratios for lung cancer were .78 for 1-10 j-yrs [according to the abstract book and .66 according to notes from the talk]; .74 for 10-30 j-yrs; .85 for 30-60 j-yrs; and 0.81 for more than 60 j-yrs.
The estimated odds ratios for oral/pharyngeal cancers were 0.92 for 1-10 j-yrs; 0.89 for 10-30 j-yrs; 0.81 for 30-60 j-yrs; and 1.0 for more than 60 j-yrs. “Similar, though less precise results were obtained for the other cancer sites,” Tashkin reported. “We found absolutely no suggestion of a dose response.”
The data on tobacco use, as expected, revealed “a very potent effect and a clear dose-response relationship —a 21-fold greater risk of developing lung cancer if you smoke more than two packs a day.” Similarly high odds obtained for oral/pharyngeal cancer, laryngeal cancer and esophageal cancer. “So, in summary” Tashkin concluded, “we failed to observe a positive association of marijuana use and other potential confounders.”
There was time for only one question, said the moderator, and San Francisco oncologist Donald Abrams, M.D., was already at the microphone: “You don’t see any positive correlation, but in at least one category, it almost looked like there was a negative correlation, i.e., a protective effect. Could you comment on that?” (Abrams was referring to Tash-kin’s lung-cancer data for marijuana-only smokers, 1-10 j-yrs.)
“ Yes,” said Tashkin. “The odds ratios are less than one almost consistently, and in one category that relationship was significant, but I think that it would be difficult to extract from these data the conclusion that marijuana is protective against lung cancer. But that is not an unreasonable hypothesis.”
Abrams’s Favorable Results
Abrams had results of his own to report at the ICRS meeting. He and his colleagues at San Francisco General Hospital had conducted a randomized, placebo-controlled study involving 50 patients with HIV-related peripheral neuropathy. Over the course of five days, patients recorded their pain levels in a diary after smoking either NIDA-supplied marijuana cigarettes or cigarettes from which the THC had been extracted. About 25% didn’t know or guessed wrong as to whether they were smoking the placebos, which suggests that the blinding worked.
Abrams’s results show marijuana providing pain relief comparable to Gaba-pentin, the most widely used treatment for a condition that afflicts some 30% of patients with HIV.
After Abrams’s presentation, a questioner bemoaned the difficulty of “separating the high from the clinical benefits.” Abrams responded: “I’m an oncologist as well as an AIDS doctor and I don’t think that a drug that creates euphoria in patients with terminal diseases is having an adverse effect.” His study was funded by the University of California’s Center for Medicinal Cannabis Research.
Add ICRS Notes
The 15th annual meeting of the ICRS was held at the Clearwater, Florida, Hilton, June 24-27. Almost 300 scientists attended. R. Stephen Ellis, MD, of San Francisco, was the sole clinician from California. Medical student Sunil Aggarwal, Farmacy operator Mike Ommaha and therapist/cultivator Pat Humphrey audited the proceedings.
Some of the younger European scientists expressed consternation over the recent U.S. Supreme Court ruling and the vote in Congress re-enforcing the cannabis prohibition. “How can they dispute that it has medical effect?” an investigator working in Germany asked us earnestly. She had come to give a talk on “the role of different neuronal populations in the pharmacological actions of delta-9 THC.”
For most ICRS members, the holy grail is a legal synthetic drug that exerts the medicinal effects of the prohibited herb. To this end they study the mechanism of action by which the body’s own cannabinoids are assembled, function, and get broken down. A drug that encourages production or delays dissolution, they figure, might achieve the desired effect without being subject to “abuse.”
News on the scientific front included the likely identification of a third cannabinoid receptor expressed in tissues of the lung, brain, kidney, spleen and smaller branches of the mesenteric artery. Investigators from GlaxoSmith-Kline and AstraZeneca both reported finding the new receptor but had different versions of its pharmacology. It may have a role in regulating blood pressure.
Several talks and posters described the safety and efficacy of Sativex, G.W. Pharmaceuticals’ plant extract containing high levels of THC and cannabidiol (CBD) formulated to spray in the mouth. See “Dr. X’s Top Talks,” on page 11.
G.W. director Geoffrey Guy seemed upbeat despite the slide his company’s stock took this spring when UK regulators withheld permission to market Sati-vex pending another clinical trial. Canada recently granted approval for doctors to prescribe Sativex, and five sales reps from Bayer (to whom G.W. sold Canadian marketing rights) are promoting it to neurologists. Sativex was approved for treatment of neuropathic pain in multiple sclerosis, but can be prescribed for other purposes as doctors see fit.
Most of the work being done with CBD and CBN is done with materials provided by GW, and some two dozen papers and posters gave them acknowledgment. At last there is a realistic alternative to NIDA for the young researchers to look to for support (and plant cannabinoids to study). GW has contributed to a significant shift in attitude.
On numerous occasions during the meeting a NIDA-funded researcher would describe the negative effects of THC, and immediately a scientist with a British accent would be at the mike pointing out that such a high dose injected into the stomach of a rat had nothing to do with the human experience with cannabis. It must have happened five or six times. The Brits were always very diplomatic, but they functioned like a truth squad.
Roger Pertwee of the University of Aberdeen reported intriguing results from experiments using a cannabis strain bred by GW to be high in THCV (tetrohydrocannabivarin).
It turns out that THCV strongly antagonizes anandamide while hardly antagonizing THC! It’s as if the cannabis plant contains and makes available to the body a choice of drugs and the body uses those it needs to achieve a balanced state (homeostasis). If the body is producing endocannabinoids in excess, it can use the plant cannabinoid THCV to achieve homeostasis. If the endocannabinoid system needs a boost, the THC provides it (while the THCV shuts down the EC system, giving it a rest as it were). The key to relief, apparently, is not high cannabinoid levels but proper gradients.
Guy explained, “It’s as if the plant contains a first-aid kit giving the body everything it needs to get bettter, and the body decides which components to employ... The endocannibnoid system begins to kick in in abnormality, in pathology. Perhaps it kicks in whether the pathology is an increase in something or a decrease in something. What it’s trying to do is get whatever that abnormality is back to homeostasis.
“ The antagonist may be working to restore function back to the center, and the agonist might be working to restore function back to the center, and once they’ve achieved the norm, they don’t go any further. The endocannabinoid system is the supeme modulator. Its job is done once you’re back to the norm. Most endocannabinoid modulators simply won’t drive the physiology or biochemistry —whatever they’re controlling— past the norm to a detrimental effect.”
Rimonabant Comes Closer
Which might explain the apparent benignity of Rimonabant, a drug that works by blocking the CB1 receptor system. Rimonabant is being tested by Sanofi-Aventis for weight loss and smoking cessation. Originally known as SR-141716, it was developed in the early 1990s as an antagonist drug for use by researchers. At the 2004 ICRS meeting, Sanofi researchers described favorable results from clinical trials of Rimonabant as a diet drug. They informally predicted regulatory approval in Europe and the U.S. within a year. Some observers warned that blocking the CB1 receptor system could result in unforeseen longterm side effects and noted that at least one MS patient had experienced an exacerbation after taking Rimonabant.
Although regulatory approval has not yet been granted, Sanofi reported good news at this meeting regarding side-effects: no more MS cases in a smoking-cessation study study involving more than 1,000 patients worldwide. “Both the 5mg and 20mg doses continued to show efficacy in the maintenance of abstinence from smoking,” reported Gerard Le Fur. “The 20mg dose also demonstrated efficacy in the reduction of weight gain as well as significantly increasing the HDL-Cholesterol levels.”
A Sanofi team also reported favorable results from studies using Rimonabant to treat various rodent models of “metabolic syndrome” —obesity-related high blood pressure, high insulin levels, excessive triglycerides and “bad” cholesterol and other problems increasing the risk of diabetes, heart attack and stroke. There is growing acceptance of the notion that the body can adjust to even a heavy blockade of the CB1 system. Perhaps when the CB1 receptor is blocked, the endocannabinoids are redirected to other targets. At times the layman is struck by how rudimentary the biochemists’ understanding of the body’s mechanism of action really is.
“ We’re on plateau one or two and the answer is on plateau 12,” said Guy. “ We could spend the next 30 years on receptors and still not fully understand them. When we talk about receptors and agonists and antagonists we should be talking in the same breath about functionality —real functionality, not models in non-pathological situations. We need an understanding of the clinical outcome.”
Osteopathic Manipulation Boosts Endocannabinoid System
John McPartland of GW Pharmaceuticals reported that osteopathic manipulative treatment (OMT) works via the endocannabinoid system. McPartland and co-workers conducted a randomized, placebo-controlled study involving 31 patients of a New Zealand osteopath.
“ Cannabimimetic effects” were measured by patients filling out a questionnaire before and after treatment defining levels of light-headedness, hunger, alterness, etc. Anandamide levels in the blood were also measured before and after treatments.
The “sham” manipulation mimicked a new technique called “biodynamic osteopathy in the cranial field.” The sham practitioner sabotaged her own concentration and mental healing intention by silently reciting “backwards serial sevens” while she applied light manual contact to the patient’s head.
Subjects receiving OMT indeed reported feeling cannabi-mimetic effects (more creativity, less coherence, for example) and their serum anandamide levels increased 168% over pre-treatment levels. Subjects receiving sham manipulation reported no changes in the questionnaire and there was no change in their serum anandamide levels.
McPartland et al noted that patients receiving OMT often experience an improved sense of well-being, sedation and euphoria —effects similar to those brought on by cannabis consumption. Previous studies indicated these psychotropic effects are not elicited by endorphins (as once had been assumed).
A recent study by Andrea Giuffrida, who contributed to the OMT study, showed that “runner’s high” correlated with elevated anandamide and not endorphins. Patients receiving chiropractic, massage, acupuncture, and energy healing also experience parallel psychotropic effects. The authors conclude that the endocannabinoid system may be mediating a widespread but heretofore unrecognized therapeutic phenomenon.
