Bio 22
Medical Marijuana
Evidence lacking to support cannabis for treating PTSD, chronic pain
S ide effects across all categories were more frequently reported with ket-
amine treatment compared with placebo for depression, a systematic review has found, but few of the studies that were included in the review examined long-term effects of ket- amine dosing. The researchers recommended the initiation of large-scale trials involving repeated doses of ketamine. Results of the re- view were published online July 27 in Lancet Psychiatry.
The need for more rapidly acting an- tidepressant treatments has contributed to the growing interest in the use of ketamine. However, few of the completed studies of
S ystematic reviews published online Aug. 15 in the Annals of Internal
Medicine concluded that there is insufficient evidence to support the use of cannabis in treating post-traumatic stress disorder (PTSD) and chronic pain. The review of research on cannabis in pain treatment did find limited evidence suggesting that the drug can relieve neuropathic pain in some patients, but that review also found evidence that cannabis use can generate or exacerbate psychotic or manic symptoms.
With more than half of the states in the United States now authorizing medical use of marijuana, such use has become increasingly common and accepted, with pain manage- ment and treatment of PTSD cited among the
adverse effects
VOLUME 28, NUMBER 12 DECEMBER 2017 ISSN 1068-5308 ONLINE ISSN 1556-7532
Editor: Lawrence H. Price, M.D.
Highlights… Our top story this month
illustrates the continuing difficulty of drawing firm conclusions about the possible therapeutic effects of cannabis. Systematic reviews of cannabis for post-traumatic stress disorder and chronic pain both concluded that there remains a lack of well-designed studies on the drug's effects.
Inside drug-drug interactions . . .2 • Warfarin and SSRIs
What’s neW in research • Risk of relapse to binge eating
disorder lower for lisdexamfetamine compared with placebo . . . . . . . .3
• Neonatal drug withdrawal risk increased by concurrent psychotropic plus opioid treatment versus opioid alone . .4
research roundup
• Omega-3 supplements improve symptoms in children with ADHD . .7
• Variable benefit of antidepressants for youths with depressive, anxiety disorders . . . . . . . . . . . . . . . . . . .7
• Use of SSRIs not associated with bone density change . . . . . .8
• FREE PATIENT HANDOUT: MEMANTINE (GENERIC) – NAMENDA (BRAND) •
KetaMine, continued on page 6
evidence, continued on page 5
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DOI: 10.1002/pu
Review of ketamine safety highlights need for analyses of long-term effects
précis • Two systematic reviews were conducted
to evaluate the benefits and harms of cannabis in the treatment of post- traumatic stress disorder (PTSD) and chronic pain.
• Researchers concluded in both cases that methodological limitations in most of the existing studies make it difficult to draw broad conclusions about the therapeutic effects of cannabis. There is some low- strength evidence that cannabis may alleviate neuropathic pain.
• The researchers raised concern about evidence showing an association between cannabis use and the development or worsening of psychotic symptoms.
précis • A systematic review encompassing 60
studies examined the safety of ketamine treatment for depression.
• In studies that included a placebo group, side effects across all categories were more common in ketamine patients than in placebo patients. Anxiety was the most commonly reported acute psychiatric side effect, and dissociation was the most commonly reported psychotomimetic side effect.
• More research on longer-term effects of ketamine is needed before ketamine can be formally recommended for use in depression treatment, the researchers suggested.
decemBer 2017 The Brown UniversiTy PsychoPharmacology UPdaTe 5
most common reasons for medical use. However, little comprehensive informa- tion about the potential benefits and harms of cannabis for either of these conditions has been available.
Maya E. O’Neil, Ph.D., and Shannon M. Nugent, Ph.D., both of the VA Port- land Health Care System in Oregon, led systematic reviews of the effects of canna- bis in the treatment of PTSD and chronic pain, respectively. The review of evidence in chronic pain treatment also included an overview of the physical and mental health effects of cannabis use.
Study methods PTSD
The review of studies of cannabis for PTSD involved a comprehensive search of data published through March 2017. Stud- ies eligible for inclusion were those that assessed the effects of plant-based can- nabis preparations or whole-plant extracts, such as the nonsynthetic pharmaceutical agent nabiximols (Sativex®). Synthetic pharmaceutical cannabinoids were not in- cluded in the analysis because they are generally not available in medical mari- juana dispensaries.
The primary outcome in the analy- sis was the effect of cannabis on PTSD symptoms and severity, with secondary outcomes including quality of life, mental health, and health care utilization. A meta- analysis was not conducted because of the small overall number of available studies and differences in their methodology.
Chronic pain The review of studies of cannabis for
chronic pain originally examined research published through February 2016, and then updated the search to include new randomized controlled trials and system- atic reviews in March 2017. As in the case of the PTSD review, only studies of plant- based cannabis preparations or whole- plant extracts were considered for inclu- sion. Studies of cannabis for neuropathic pain were included in a meta-analysis to examine how many patients experienced a clinically significant improvement of at least 30% in their pain. The review also examined the potential harms of cannabis use, including in this analysis case series and descriptive studies of emerging harms believed to be related to cannabis use.
Results PTSD
The review of studies of cannabis in PTSD treatment identified two system- atic reviews and three individual studies. One of the systematic reviews consisted of six studies, but two were prospective, open-label trials without a control group and one was a case series. The authors of that review concluded that evidence was insufficient to evaluate the effectiveness of cannabis. The other systematic review evaluated four observational studies, with three finding that cannabis was associated with less severe PTSD symptoms but the other finding that it was associated with worsening PTSD symptoms.
A large individual study of 47,000 vet- erans in VA programs for PTSD between 1992 and 2011 found that individuals who either started using cannabis after program admission or continued previous use had worse PTSD symptoms at 4 months than those who stopped cannabis use after program admission or had never used. Those who started or continued use also had higher levels of drug abuse, and can- nabis starters had a higher level of violent behavior than the other groups.
A study that examined cannabis’s effect on PTSD symptom severity after cognitive behavioral therapy for PTSD with substance use found that more fre- quent cannabis use was associated with more severe PTSD symptoms in the early stages of treatment, but less severe symp- toms later on. “Overall, we found insuffi- cient evidence regarding the benefits and harms of plant-based cannabis prepara-
tions for patients with PTSD,” authors of the systematic review wrote.
Chronic pain The review of studies of cannabis in
pain management identified 13 system- atic reviews and 62 individual studies. Research examining the effects of canna- bis on neuropathic pain related to various health conditions found low-strength evi- dence that cannabis may alleviate pain. More patients using cannabis in these studies showed clinically significant pain relief up to several months later. One study of 246 patients found a significant decrease in pain among study completers only, with reductions in pain no longer statistically significant when all of the enrolled participants were included.
There was insufficient evidence to sup- port the use of cannabis in the treatment of pain for patients with multiple sclerosis or cancer, the researchers reported, based primarily on a small number of studies and their methodological limitations.
The researchers did not find evidence of a higher risk of general adverse events from cannabis in the majority of the exam- ined pain trials. However, one systematic review and eight individual studies found an association between cannabis use and the development of psychotic symptoms, based largely on the tetrahydrocannabinol (THC) content of the drug. In addition, a systematic review of six studies found low-strength evidence of an association be- tween cannabis use and worsening of manic symptoms in patients with bipolar disorder.
Implications Researchers for both reviews stated
that the evidence is too limited to draw firm conclusions about the potential ben- efits and harms of cannabis for PTSD and pain. While there have been numerous an- ecdotal reports of individuals with PTSD benefiting from cannabis, O’Neil and col- leagues stated that it cannot be determined whether these perceived effects result from the drug, a placebo effect, or the natural progression of symptoms.
O’Neil told The Update that high-quality randomized controlled trials are needed in order to determine whether cannabis is ef- fective for PTSD. “Since there is some evi- dence that cannabis has been associated with adverse mental health and cognitive effects, future studies should carefully keep track of
evidence continued from page 1
continued on next page
“There is a growing body of evidence that pretty
consistently shows can- nabis use is associated
with an increased risk of psychotic symptoms, and
perhaps also an increased risk of psychotic spectrum
disorders.” Shannon M. Nugent, Ph.D.
6 The Brown UniversiTy PsychoPharmacology UPdaTe decemBer 2017
KetaMine continued from page 1
ketamine’s safety have been randomized controlled trials, and few have examined the effects of repeated treatments, which is emerging as a strategy in the use of ket- amine for depression.
In order to gain a broader under- standing of the acute and longer-term ef- fects of ketamine treatment, Brooke Short, M.D., of the New South Wales Institute of Psychiatry in Australia, and colleagues conducted the first systematic review of ketamine’s safety after single and repeated doses in the treatment of depression.
Study methods The researchers conducted a search for
studies between 1999 and 2016. Studies were eligible if they reported on the ef- fects of one or more doses of ketamine in
adults with unipolar or bipolar depression, with change in depression status included as a primary outcome. Numerous study designs were eligible for inclusion.
Information collected for each study included but was not limited to ketamine administration details and pre-adminis- tration health screening for issues such as pre-existing medical conditions and concurrently used medications. Adverse effects from treatment were categorized into subgroups that included psychiatric, psychotomimetic or dissociative, cardio- vascular, neurological, and other.
The researchers also examined factors affecting the quality of study data, such as selective outcome reporting, withdrawal from treatment, and use of a control group. Plans to conduct a meta-analysis were discarded because of a lack of consistency among selected studies in their dosing and reporting methods, as well as variation
in the level of reporting bias among the studies.
Results Sixty studies were included in the anal-
ysis, encompassing a total of 899 patients receiving at least one dose of ketamine. Most of the studies did not include a pla- cebo group, and only 20% of the studies examined long-term side effects. Among
these effects and should be conducted for a long enough period of time to get a sense of the duration of benefits and whether po- tential harms might emerge with long-term use,” she said. She added that future research will need to test a number of different can- nabis preparations with varying amounts of THC and cannabidiol.
Nugent told The Update that while a great deal still needs to be researched in the area of the mental health effects of cannabis use, “There is a growing body of evidence that pretty consistently shows cannabis use is associated with an in- creased risk of psychotic symptoms, and perhaps also an increased risk of psychotic spectrum disorders. The other area of con- cern is the risk of substance use disorder. About one in three people reporting any cannabis use in the last year have cannabis use disorder.”
For both conditions examined in the systematic reviews, there are well-designed studies underway that should expand the knowledge base on cannabis’s effects. Nu- gent said that seven ongoing clinical tri- als in pain management “are examining a more broad range of cannabis preparations and various routes of administration, and include chronic pain populations that have previously been understudied.”
In an editorial accompanying the jour- nal articles, Sachin Patel, M.D., Ph.D., of
Vanderbilt Psychiatric Hospital in Nash- ville, Tennessee, theorized that the results of the ongoing studies might not do much to sway the direction of public policy or public opinion that increasingly favors the use of cannabis for a variety of medical conditions.
“Even if future studies reveal a clear lack of substantial benefit of cannabis for pain or PTSD, legislation is unlikely to remove these conditions from the list of indications for medical cannabis,” Patel wrote. “It will be up to front-line practic- ing physicians to learn about the harms and benefits of cannabis, educate their pa- tients on these topics, and make evidence- based recommendations about using can- nabis and related products for various health conditions.”
[Editor’s note: We addressed the co- nundrum of medical marijuana in a Com- mentary in our September 2011 issue. At that time, we observed: “… pretending that the problem of ‘criminalized’ mari- juana is solved by the current process of ‘medicalizing’ it demeans and trivializes the entire drug evaluation system we have developed to ensure the integrity of our pharmacopoeia. It’s inconceivable that any other pharmaceutical agent would be simi- larly ‘approved’ for prescription by physi- cians without regard to provenance, purity, dosage, indication, safety, or efficacy. Ul- timately, this is bad for medicine and bad
for the public. If we want to use marijuana for medical purposes, we should subject it to the kind of rigorous research we have come to require for those purposes.” Six years later, these two important reviews underscore those comments.] ▪
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PTSD study co-author Benjamin J. Morasco, Ph.D., reported receiving grants from the U.S. De- partment of Veterans Affairs during the study.
RefeRences
O’Neil ME, Nugent SM, Morasco BJ, et al. Ben- efits and harms of plant-based cannabis for post- traumatic stress disorder: A systematic review. Ann Intern Med 2017; published online Aug 15; doi: 10.7326/M17-0477. Correspondence to: Maya E. O’Neil, Ph.D., VA Portland Health Care System, RD 66, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239; Email: maya.oneil@ va.gov.
Nugent SM, Morasco BJ, O’Neil ME, et al. The effects of cannabis among adults with chronic pain and an overview of general harms: A systematic review. Ann Intern Med 2017; published online Aug 15; doi: 10.7326/M17-0155. Correspondence to: Shannon M. Nugent, Ph.D., VA Portland Health Care System, RD 66, 3710 Southwest U.S. Veter- ans Hospital Road, Portland, OR 97239; Email: shannon.nugent@va.gov.
Patel S. Cannabis for pain and posttraumatic stress disorder: More consensus than controversy or vice versa? Ann Intern Med 2017; published online Aug 15; doi: 10.7326/M17-1713. Correspondence to: Sachin Patel, M.D., Ph.D., Vanderbilt Psychiatric Hospital, 1601 23rd Avenue South, Nashville, TN 37232; Email: sachin.patel@vanderbilt.edu.
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