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Integrative Healthcare Symposium 2019
The 2019 Integrative Healthcare Symposium took place in New York, New York on February 21 to 23, and hosted 1,500 health care practitioners. We review below key sessions on the prevalence of complementary and alternative therapies in cancer care, hemp-derived cannabidiol use for treatment of PTSD, and cannabis in cancer care.
National Cancer Institute: Complementary and Alternative Medicine Use by Patients and Practitioners at the National Institutes of Health Clinical Center
- Tara Berman, MD, Research Fellow, National Cancer Institute’s Women’s Malignancy Branch, Bethesda, Maryland
Patients do not readily divulge which “complementary and alternative modalities (CAM)” and substances they are using/taking to their doctors and pharmacists. However, it is the practitioners’ obligation to “open up the dialogue,” according to Dr. Tara Berman. “One of the red flags,” she said in an interview at her poster, “is that patients may be taking super-therapeutic doses of a ‘supplement’ like green tea that is metabolized through the liver, the cytochrome p450 enzyme system, and that can make their chemotherapy more toxic to the body or less effective at treating their disease.”
Dr. Berman’s concerns arose out of findings from her ongoing National Cancer Institute (NCI) survey. The interim analysis was based on approximately 100 patient responses and 25 practitioner responses. Many (~40%) of the practitioners were recently “minted” oncologists, ranging from 30 to 39 years old. About 40% of patients were aged between 60 and 69 years. The survey asked about patients’ use of CAM and about practitioners’ awareness of CAM use. The cancers being treated most frequently were genitourinary (33%), gynecologic (21%), and breast (21%).
Of 24 patients who responded to questions about diet, many were on vegetarian (22%), paleo (22%), vegan (28%), or ketogenic (17%) diets. Of 62 patients who responded to questions about supplements, 40% were taking vitamins/minerals, 24% were taking herbal therapies/teas, 12% were taking probiotics, and 24% selected “other.”
Of 44 patients who responded to questions about their mind-body/spirituality, the highest response rate (40%) was for prayer, with 24% selecting being prayed over or receiving spiritual healing from others, 14% selecting psychotherapy or support groups, and 10% selecting meditation.
Those responding to movement therapy questions (n = 52) overwhelmingly denoted use of physical exercise (82%), with 10% indicating yoga and 3% indicating tai chi or Qigong.
The percentage of time that patients reported discussing their use of CAM with NCI oncologists was about 50%; with non-NCI oncologists, about 30%; with primary care practitioners, about 20%; with nurse/nurse practitioners, about 25%; and with pharmacists, about 5%. More than 30% of patients did not discuss their CAM use with any health care provider.
Why not? “Other” was the most common reason cited, but 25% of patients said they were never asked and about 15% thought it was not important. Only several felt their health care providers would not understand or approve, or would discontinue working with them.
How did health care providers respond? Among 18 responders, almost 40% had no response and 25% were neutral. Approximately 30% encouraged the continued use of CAM, and only about 5% urged patients to stop using CAM. To the question “Have you ever advised your patients to stop this treatment?” about 80% of 16 responders answered affirmatively with respect to vitamins/minerals, 50% did so for herbal therapies/teas, and 50% did so for probiotics. Few responders said their patients had experienced adverse reactions to CAM (> 20% for vitamin/minerals and about 15% for herbal therapies/teas).
Which CAM-specific therapies did practitioners recommend? About 90% urged physical exercise, and more than 80% recommended acupuncture. Dr. Berman noted that acupuncture is often suggested for women on hormone-depletion therapy for genitourinary or gynecologic cancers who have hot flashes. Also, about 70% of practitioners recommended massage. Forty percent recommended energy healing/Reiki and the same percentage recommended chiropractic/osteopathic interventions. Dr. Berman observed that a palliative care center offering “energy” therapies is integrated with the National Institutes of Health (NIH) Clinical Center.
Dr. Berman concluded, “Patient CAM use is prevalent at the NIH Clinical Center. The future of oncology treatment will be affected by patients’ use of CAM and their practitioners’ experience with CAM.” She added, “Whether we advocate for the use of CAM therapies or not, patients are using them. It’s important that we become knowledgeable about them so we can see if cancer patients have a rational understanding of how a particular supplement or diet can affect their treatment.” She also stated, “Pharmacists should be asking patients directly about their use of vitamins, supplements, and other drugs.”
Dr. Berman noted that the views and attitudes she expressed are her own and are not the official views of the NIH. She is currently a medical officer for oncology products at the Food and Drug Administration.
Effects of Biological Hemp-Derived Cannabidiol on PTSD in U.S. Military Veterans
- Philip Blair, MD, Col. (ret.), U.S. Army
Hemp-derived cannabidiol, used with concurrent standard treatments or alone, may be highly effective for alleviating post-traumatic stress disorder (PTSD), according to an open-label pilot study among combat veterans. The greatest improvements, said Dr. Philip Blair, whose interest in PTSD arose from his experience as a combat physician during the Gulf War, were in reductions of repeated disturbing memories, thoughts, and feelings associated with a stressful military environment.
Common PTSD symptoms include avoidance, negative moods, re-experience, and anxiety. Prolonged activation of the stress responses can produce physical symptoms that compromise the body’s internal stability, resulting in physical dysregulations, decreased immune function, and chronic illness. Veterans with mental health issues also have an increased risk of suicide.
Current standard PTSD treatments include antidepressants, antianxiety agents, behavioral therapy, and sleep aid medications. Beyond recurring memories, many patients have chronic pain, opioid dependence, and musculoskeletal disorders that lead to additional drugs and therapies, Dr. Blair said.
He pointed out that although marijuana relieves the painful thoughts of PTSD, it does not seem to help recovery. Furthermore, for many people, the tetrahydrocannabinol (THC) component of marijuana has disabling effects including lethargy, drowsiness, and memory impairment. The very low THC levels in cannabidiol derived from industrial hemp (≤ 3%) make it non-psychoactive with respect to these adverse effects. On the other hand, cannabidiol has been shown to modulate fear memory, emotional reconsolidation, memory processing, and the hypothalamic–pituitary–adrenal axis of hormone production (see Figure 1). Also, cannabidiol appears to rebalance the endocannabinoid system by acting on endocannabinoid receptors CB1R and CB2R, and by inhibiting fatty acid amide hydrolase, the enzyme responsible for degrading endocannabinoids.1
In an interview at his poster, Dr. Blair emphasized that cannabidiol seems to inhibit the reconsolidation pathways behind repeating memories and open up the extinction pathway that allows one to forget these same memories.
The 30 study participants (aged 24–70 years), all veterans with PTSD diagnosed by the Veteran’s Administration, had continuing and chronically persisting symptoms. Lack of active medical management, however, was not an exclusion criterion. None of the participants had suicidal ideation nor a history of suicide attempts. Subjects completed the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) along with a brief clinical history. No changes in medications or therapies were recommended, and they were encouraged to continue their course of therapy.
Each participant received liposomal cannabidiol in liquid form and was instructed to take 5 mg sublingually twice daily, and then to adjust the dose as needed to control PTSD symptoms. Subjects repeated the PCL-5 checklist at weeks 2 and 4, and were asked to keep a daily log using the PCL-5 numerical values. The average self-dose of cannabidiol was 15 mg/day.
After two weeks, at mid-study, the average PCL-5 total score among 22 respondents was 57, down from the pre-cannabidiol treatment average score of 66. After four weeks of treatment, the average total score dropped to 41, with the most severe score down to 72 from an initial 100, and the lowest score down to 27 from 55. The average symptom score decreased by 67%.
At the pre-treatment evaluation, 50% of participants had rated themselves as being “extremely” affected by repeated memories/thoughts/feelings. After treatment, no subjects rated such symptoms as affecting them “extremely” and only 28% said they were affected “quite a bit.” Pre-treatment, none of the participants selected “not at all,” whereas post-cannabidiol treatment, 28% of them selected “not at all.”
With the permission of their primary medical providers, several participants discontinued using other prescription medications (including antidepressants and antianxiety drugs) during the course of the trial and have not restarted since its conclusion. Cannabidiol was well tolerated by all veterans, with no significant adverse events, hospitalizations, suicide attempts, or known emergency treatments.
Dr. Blair also commented that, in some veterans, the rapid symptom decreases on first dose may indicate a specific endocannabinoid deficiency that is highly responsive to cannabidiol and that could be identified immediately in a clinical setting.
He concluded that these preliminary results support a specific role for cannabidiol from industrial hemp for modulating PTSD physiology and indicate an “imperative need for more research.”
Cannabis and Cancer Care
- Donald I. Abrams, MD, Professor of Clinical Medicine, University of California, San Francisco
To begin, Dr. Abrams addressed concerns regarding cannabis smoking/use as a cause of cancer. He noted the following conclusions from the National Academies of Sciences, Engineering, and Medicine:
- There is moderate evidence of no statistical association between cannabis smoking and the incidence of lung cancer.
- There is moderate evidence of no statistical association between cannabis use and the incidence of head and neck cancers.
- There is limited evidence of a statistical association between current, frequent, or chronic cannabis smoking and non–seminoma-type testicular germ cell tumors.
He pointed out that while four trials do support an association between current/frequent/chronic cannabis smoking and some testicular tumors, the group (young men) that develops those tumors is the same group most likely to smoke cannabis, raising the likelihood that we are simply seeing an association rather than a causation.
The history of research into cannabis as an anti-cancer agent goes back to a 1975 NIH report indicating that delta-9-THC, delta-8-THC, and cannabidiol inhibited Lewis lung adenocarcinoma cell growth in vitro and in mice. Anti-cancer activity and antioxidant and anti-inflammatory effects were suggested, as were possible apoptotic and tumor vascularization impairment via cannabinoid receptors.
Most research was conducted in Spain and Italy. Velasco et al.2 showed in vitro inhibition of multiple tumor cell lines with cannabinoids. In nude mice, also, cannabinoids curbed the growth of various xenografts including lung, breast, colorectal, and pancreas carcinomas, skin carcinomas, melanoma, thyroid epithelioma, lymphoma, and glioma. Cannabinoids induced apoptosis in mouse gliomas and were associated with reduced expression of vascular endothelial growth factor (VEGF) and VEGF receptors, suggesting inhibition of angiogenesis. “That’s what the $100,000-per-year drug bevacizumab does,” Dr. Abrams commented. Cannabinoids also demonstrated decreases in the activity of matrix metalloproteinase-2 in gliomas, potentially inhibiting metastasis. Normal glial cells, however, were unaffected.
The charge for the National Academy of Sciences, Engineering, and Medicine was to look at human studies, of which there was only one—so they looked at cannabinoids in 34 in vitro and/or in vivo experimental studies and one human pilot trial. Thirty-three studies showed that cannabinoids selectively kill tumor cells through antiproliferative effects, decreasing viability, toxicity, apoptosis, necrosis, autophagy, and antiangiogenic and antimigratory effects. But the conclusion was that evidence was missing or was insufficient to make direct claims.
Investigating the effects of cannabidiol on colorectal cancer cell lines, Aviello et al.3 showed that cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation. In mice treated with azoxymethane, 1 mg/kg of cannabidiol decreased aberrant crypt foci, polyps, and tumor formation. Also, at non-cytotoxic concentrations, cannabidiol had anti-proliferative effects on colorectal cancer cell lines.
McAllister et al.4 showed cannabidiol to down-regulate Id-l expression in triple-negative human breast cancer cells in vitro. Inhibitors of DNA (ID) binding helix–loop–helix proteins, which control processes related to tumor progression, have increased expression in triple-negative breast cancer cells in vitro. A local newspaper headline (“Pot compound seen as tool against cancer”) led many women to approach Dr. Abrams asking if they could treat their triple-negative breast cancer with cannabidiol. “It saddens me that there are people out there promoting THC oil and cannabidiol oil as treatments for cancer,” he said. Some of them charge exorbitant rates ($6,000–$7,000 per month) for elaborate protocols, he added.
First Human Trials
In a 2006 pilot study, Guzman et al.5 showed treatment of recurrent glioblastoma in nine patients with catheter-delivered intra-tumoral 20–40 µg THC daily for 15 days to be well tolerated. Although in vitro THC had inhibited the proliferation of glioblastoma cells from biopsies and had decreased their viability, there was no effect on survival in these patients. In 2010, Marcu et al.6 demonstrated that cannabidiol enhanced the inhibitory effects of THC on glioblastoma cell proliferation and survival.
Some other completed human trials in solid tumors with cannabidiol have fared no better. A small safety study of nabiximols compared with placebo with dose-dense temozolomide in recurrent glioblastoma, however, showed a significant (P = 0.042) one-year survival advantage (83% vs. 53%, respectively) and a longer median survival (550 days vs. 369 days, respectively)7,8.
The rationale for cannabidiol use in gliomas and other tumors (colon, hepatocellular, pancreatic, breast, prostate, non–small-cell lung), Dr. Abrams noted, is the overexpression of either or both CB1 and CB2 receptors.9
The clearest positive findings for cannabis use in cancer patients is not for demonstrated effects on the disease itself but on related symptoms. An Israeli study10 among ~2,000 cancer patients showed positive effects on nausea and vomiting (91.0%), sleep disorder (87.5%), restlessness (87.5%), anxiety and depression (84.2%), pruritis (82.1%), and headaches (81.4%). Changes in medications were reported in 1,018 of these patients, with decreased use in 35.1%. Among 344 patients taking opioids at the trial onset, 367% stopped opioid use and 10% reduced their dosage.
Dr. Abrams noted research suggesting that cannabidiol helps only with pain caused by inflammation, while cannabis helps with neuropathic pain.
Touching on the adverse effects of cannabis in cancer patients, Dr. Abrams said that an association between cannabis and aspergillosis comes mostly from case reports, and that concerns about stimulation of schizophrenia may well be simply an association reflecting a higher use of cannabis among individuals at the age when schizophrenia onset often occurs. They might use cannabis, he suggested, because they find it helps with disordered thoughts.
“There is a lot we don’t know about cannabis and cancer,” Dr. Abrams summarized.
Finally, he questioned referring to “cannabis-induced euphoria” as an “adverse experience,” particularly in palliative care settings. He asked, “Is a single treatment that increases appetite, decreases nausea and vomiting, relieves pain, and improves mood and sleep a potential useful tool in symptom management?”
- Lee JLC, Bertoglio LJ, Guimarães FS, Stevenson CW. Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders [published online March 9, 2017]. Br J Pharmacol 2017; 174(19):3242–3256. doi: 10.1111/bph.13724
- Velasco G, Galve-Roperh I, Sánchez C, et al. Hypothesis: cannabinoid therapy for the treatment of gliomas? Neuropharmacology 2004; 47(3):315–323. doi:
- Aviello G, Borrelli F, Guida F, et al. Ultrapotent effects of salvinorin A, a hallucinogenic compound from Salvia divinorum, on LPS-stimulated murine macrophages and its anti-inflammatory action in vivo [published online April 16, 2011]. J Mol Med (Berl) 2011; 89(9):891–902. doi: 10.1007/s00109-011-0752-4
- McAllister SD, Murase R, Christian RT, et al. Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis [published online September 22, 2010]. Breast Cancer Res Treat 2011;129(1):37–47. doi: 10.1007/s10549-010-1177-4
- Guzmán M, Duarte MJ, Blázquez C, et al. A pilot clinical study of ∆9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme [published online July 11, 2006]. Br J Cancer 2006;95(2):197–203. doi:
- Marcu JP, Christian RT, Lau D, et al. Cannabidiol enhances the inhibitory effects of ∆9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival [published online January 6, 2010]. Mol Cancer Ther 2010;9(1):180–189. doi: 10.1158/1535-7163.MCT-09-0407
- GW Pharmaceuticals plc. GW Pharmaceuticals achieves positive results in phase 2 proof of concept study in glioma. February 7, 2017. Available at: http://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-achieves-positive-results-phase-2-proof. Accessed February 27, 2019.
- Twelves C, Short S, Wright S, et al. A two-part safety and exploratory efficacy randomized double-blind, placebo-controlled study of a 1:1 ratio of the cannabinoids cannabidiol and delta-9-tetrahydrocannabinol (CBD:THC) plus dose-intense temozolomide in patients with recurrent glioblastoma multiforme (GBM). Presentation at 2017 ASCO Annual Meeting, Chicago, Illinois, June 2–6, 2017.
- Ladin DA, Soliman E, Griffin L, Van Dross R. Preclinical and clinical assessment of cannabinoids as anti-cancer agents. Front Pharmacol 2016;7:361. doi:
- Bar-Lev Schleider L, Mechoulam R, Lederman V, et al. Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med 2018;49:37–43. doi: 10.1016/j.ejim.2018.01.023