Somewhat long, but I figured I'd post the entire study for anyone who actually felt like reading it all. They suggest rescheduling in the conclusion.
Medical Marijuana: Clearing Away the Smoke
Igor Grant, J. Hampton Atkinson, [...], and Barth WilseyAbstract
Recent advances in understanding of the mode of action of tetrahydrocannabinol and related cannabinoid in-gredients of marijuana, plus the accumulating anecdotal reports on potential medical benefits have spurred increasing re-search into possible medicinal uses of cannabis. Recent clinical trials with smoked and vaporized marijuana, as well as other botanical extracts indicate the likelihood that the cannabinoids can be useful in the management of neuropathic pain, spasticity due to multiple sclerosis, and possibly other indications. As with all medications, benefits and risks need to be weighed in recommending cannabis to patients. We present an algorithm that may be useful to physicians in determining whether cannabis might be recommended as a treatment in jurisdictions where such use is permitted.Keywords: Cannabis, chronic pain, pain.INTRODUCTION
In this article we review evidence that cannabis may be useful as medicine. We discuss potential indications for its use and provide an algorithm to guide medicinal cannabis recommendations.
The reasons for a revival of interest in medicinal cannabis are multiple, and beyond the scope of this review, but include increasing anecdotal and clinical study reports of potential benefit, advances in understanding of the endocannabinoid signaling system upon which cannabis acts, as well as growing public acceptance that cannabis should be available as a medicine if a physician recommends it.BRIEF REVIEW OF PAST CLINICAL STUDIES ON MEDICINAL CANNABINOIDSRECENT STUDIES ON MEDICINAL CANNABIS
As recently as a decade ago a review of the world literature on the status of the efficacy and safety of cannabinoids for pain and spasticity revealed that only nine randomized studies of acceptable quality had been conducted . All of these were single dose studies comparing oral synthetic THC (or cannabinoid analogs or congeners) to codeine or placebo. Two were “N of 1” randomized trials and two were of very small samples of acute post-operative pain. The remaining trials primarily addressed chronic cancer-related pain. Taken as a group it appeared that oral cannabinoids (e.g., THC 10mg) outperformed placebo and were analgesically equivalent to codeine 60mg; higher doses (THC 20mg) were comparable to codeine 120mg, but had a much higher incidence of adverse effects, particularly sedation . Authoritative reviews judged cannabinoids as being unlikely to have a role in acute pain management, but suggested there was enough evidence for efficacy in chronic neuropathic pain and muscle spasticity to warrant further research .
In the past decade, the scope and rigor of research has increased dramatically. This research has employed cannabis, cannabis-based extracts, and synthetic cannabinoids delivered by smoking, vaporization, oral, and sublingual or mucosal routes.Studies on Smoked Cannabis
Smoking cannabis provides rapid and efficient delivery of THC to brain. THC can be detected immediately in plasma after the first puff of a cigarette; peak concentrations occur within 10 minutes, then decrease to approximately 60% of peak by 15 minutes and 20% of peak by 30 minutes, but there can be wide inter-individual variation in concentrations achieved . Rapid onset and predictable decay means that self-titration of dosing is attainable.Chronic PainStudies of Oral Preparations.
A series of randomized clinical trials at the University of California Center for Medicinal Cannabis Research (CMCR) investigated the short-term efficacy of smoked cannabis for neuropathic pain. Sponsored by the State of California Medical Marijuana Research Act of 1999, and conducted under the auspices of the Department of Health and Human Services, the National Institute on Drug Abuse, and the Food and Drug Administration, this research allocated participants to smoke cannabis cigarettes containing from 1% to 8% THC by weight (4 to 32 mg THC) or to placebo cannabis cigarettes from which THC had been extracted. The total daily dose of THC ranged from 4 mg to 128 mg. Two trials enrolled patients with painful HIV peripheral neuropathy [4, 5]; one consisted of mixed neuropathic pain due to peripheral or central dysfunction of the nervous system (i.e., complex regional pain syndrome, peripheral neuropathy, and traumatic focal nerve or spinal cord injury) . Patients were allowed to continue their usual regimen of analgesics. Results consistently indicated that cannabis significantly reduced pain intensity, with patients reporting 34%-40% decrease on cannabis compared to 17-20% on placebo. Moreover a significantly greater proportion of individuals reported at least 30% reduction in pain on cannabis (46%-52%) compared to placebo (18%-24%) [4-6], which is relevant since 30% decrease in pain intensity is generally associated with reports of improved life quality . The number needed-to-treat to achieve a 30% reduction in pain intensity was 3.5-4.5, a range achieved by standard non-opioid analgesics (i.e., noradrenergic antidepressants and anticonvulsants). Interestingly “medium” dose cannabis cigarettes (3.5% THC) were as effective as higher dose (7% THC) . In this same vein, a fourth trial employing an experimental model of neuropathic pain (intradermal injection of capsaicin) in healthy volunteers suggested that there may be a “therapeutic window” or optimal dose for smoked cannabis: low dose cigarettes (2% THC) had no analgesic effect, high dose (8%) was associated with reports of significant pain increase, and medium dose cannabis cigarettes (4% THC) provided significant analgesia . Separately, another recent placebo-controlled, cross-over study of neuropathic pain due to surgery or injury examined the effect of 25 mg doses of smoked cannabis at various potencies (2.5%, 6%, and 9.4% THC by weight), administered three times daily for 14 days . Results suggested that although lower potency dosing was ineffective, 9.4% THC produced modest but significant analgesic effects compared to placebo, in a sample selected for failure to respond to conventional therapy.
Oral preparations are available as synthetic THC (dronabinol, MarinolR) and a synthetic analog of THC (nabilone, CesametR). Absorption from the gut is slower and exhibits a delayed peak plasma concentration compared to smoking with bioavailability ranging from about 5-20% of dose; peak concentrations occur 1-6 hours after ingestion, with a magnitude approximately 10% of that achieved with smoking .Chronic Pain
Most research using oral preparations has targeted neuropathic pain and spasticity associated with multiple sclerosis (MS). These randomized trials suggest that dronabinol (up to 25 mg daily) significantly reduces pain compared to placebo (50% “improved” on dronabinol compared to 30% on placebo, p < .05) , with a number-needed-to-treat for 50% pain reduction of 3.5, which is in the range of efficacy observed for standard non-opioids . Effects on spasticity are mixed: there may be no observable change in examiner-rated muscle tone, but patients report significant relief .
There is less research with nabilone, although one three-week randomized crossover trial reported that nabilone 2mg provided modest analgesia, comparable to dihydrocodeine 240mg daily in neuropathic pain .Nausea-Emesis and Appetite Stimulation
Although serotonin receptor (5 HT3) antagonists (e.g., ondansetron, ZofranR) and Substance P/neurokinin-1 (NK-1) receptor antagonists (e.g., aprepitant, EmendR) are the mainstays for treatment, dronabinol and nabilone are also FDA-approved for control of acute and delayed nausea and emesis due to cancer chemotherapy. Meta-analyses indicate these cannabinoids are equivalent to or more effective than metoclopraminde and neuroleptics, but their side effect profile is less favorable in terms of sedation, dizziness, dysphoria, hypotension, and anxiety [13, 14]. There are no head-to-head comparisons of cannabinoids with serotonin 5 HT3 receptor or Substance P/NK-1 receptor antagonists.
Anorexia, early satiety, weight loss and cachexia are prevalent in late stage cancer and advanced HIV disease, but there are few effective treatments. Trials in AIDS patients with clinically significant weight loss indicated that dronabinol 5mg daily significantly outperformed placebo in terms of short term appetite enhancement (38% vs. 8% at 6 weeks), and that these effects persisted for up to 12 months [15, 16], but were not accompanied by significant differences in weight gain, perhaps because of disease-associated energy wasting. The major practical limitations are the accompanying psychoactive side effects, and the problems of oral administration (eg, delayed onset of action, variable absorption, extended duration of effects).Studies on Cannabis-based ExtractsStudies with Alternative Delivery Systems
Outside the US, extracts of whole plant are licensed and available in capsules (CannadorR), with the main constituents being THC and the non-psychoactive plant cannabinoid, cannabidiol, in a ratio of 2:1. Rectal suppositories are also used to deliver THC hemisuccinate. Several small to medium-sized, randomized, controlled trials in MS suggest improvements in pain and perceived spasticity at daily doses of THC ranging from 7.5mg to 27.5mg [10, 17, 18]. In some trials  but not others [10, 20] observer-assessed spasticity also improved.
The hazards of smoking and the pharmacokinetic limitations of ingestion of cannabinoids has led to a search for alternative systems of administration. One alternative is devices which vaporize cannabis leaves by heating the plant product to below the temperature of combustion (175-225 degrees C), permitting inhalation of volatilized gases minus hazardous pyrroles produced by burning. Preliminary work using plant material with a range of THC content (e.g., 1-7% THC) suggests that there is rapid onset, with peak concentrations and six-hour area under the plasma concentration curves comparable to those achieved by smoking . Vaporization is not a perfect solution since carbon monoxide is formed, but levels are significantly lower than with smoking . Clinical trials are currently in progress at the CMCR assessing the efficacy of vaporized cannabis as an analgesic in chronic neuropathic pain.
Sublingual delivery systems of whole cannabis plant extract, which employ metered spray devices to deliver measured doses of THC (2.7mg) and cannabidiol (2.5mg), are undergoing Phase IIb/III trials in the US, and are licensed elsewhere for cancer pain and multiple sclerosis-associated neuropathic pain and spasticity (nabiximols, SativexR). The apparent advantages of such systems are known cannabinoid concentrations, predetermined dosing aliquots, and time-out systems which may help prevent overuse. Some placebo-controlled trials suggest significant analgesia in neuropathic pain due to multiple sclerosis  and mixed neuropathy (e.g., post-herpetic, traumatic, vascular neuropathies,  but others do not . Other controlled trials suggest efficacy for cancer-related pain inadequately responsive to opioid analgesia . Responders participating in the open label extension phases of controlled trials appear to maintain analgesia on one-year follow-up .
In regard to spasticity in multiple sclerosis, a recent meta-analysis combining three trials with nabiximols in over 600 patients noted that mean intensity of patient rated spasticity was significantly reduced compared to placebo [20, 25, 26], and that the proportion of “responders” (30% reduction) was also significantly greater, with about 37% on the cannabinoid compared to 26% on placebo experiencing relief. Those reporting relief of spasticity seemed to maintain their gains over one year follow-up . As with other studies noted above, observer-rated spasticity is often not reduced [20, 25, 28]; however, a recent CMCR study did find a significant reduction in observed spasticity among those administered active smoked marijuana vs. placebo marijuana .PRESERVATION OF MASKING IN CLINICAL TRIALS
Because of the acute psychoactive effects of the experimental agent there is understandable concern that blinding cannot be preserved in placebo-controlled clinical trials of cannabinoids, particularly with cross-over designs. Few studies assess masking, but two cross-over trials tested maintenance of the blind by asking participants to “guess” assignment at different points of the study. Results suggest that participants, whether they are naïve or experienced cannabis users, are in the first week of a trial no more likely than by chance to guess assignment [5, 9]. With continued exposures rates of correct guesses exceed 75%, but exceed chance only in a high potency arm (9%) . In another study correct guessing was related to two factors: whether the subject received placebo or cannabis first; and when during the study the participant guessed assignment . Among individuals randomized to receive placebo first, guessing was no better than chance through the end of the first treatment week, whereas the majority of those randomized to receive cannabis first correctly guessed their treatment assignment at all time points. Furthermore, by the conclusion of the study, when all subjects had been given the opportunity to compare the cannabis placebo and treatments, even those randomized to receive placebo first correctly guessed their treatment assignment . This raised the possibility that some of the pain reduction was placebo driven. Secondary analyses to assess whether correct treatment guessing influenced treatment responses showed that in the placebo group during the first treatment week, when guessing was no better than chance, cannabis still provided pain relief superior to that of placebo. This finding suggests that although placebo effects were present, treatment effects were independent .
Edited by ISnuff, 21 July 2013 - 08:11 PM.