sign in sign up
<<
Home , Cannabis, Cannabis (drug), Dronabinol, Medical cannabis

A Review of Medical Studies relating to Chemical Compositions and Dosages for Qualifying Medical Conditions JULY 2016

OFFICE OF

A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

A Review of Medical Cannabis Studies relating to Chemical Compositions and Dosages for Qualifying Medical Conditions

Minnesota Department of Health Office of Medical Cannabis PO Box 64882, St. Paul, MN (55164-0882) (phone) 651-210-5598 [email protected] www.health.state.mn.us

As requested by Minnesota Statute 3.197: This report cost approximately $4,316 to prepare, including staff time, printing and mailing expenses.

Upon request, this material will be made available in an alternative format such as large print, Braille or audio recording. Printed on recycled .

2 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS Contents

Executive Summary ...... 4

Introduction ...... 9

Cancer ...... 10

Severe or ...... 10

Nausea or Severe Wasting ...... 14

Cachexia or Severe Wasting ...... 18

Glaucoma ...... 21

Human Immunodeficiency Virus or Acquired Immune Deficiency Syndrome ...... 23

Tourette Syndrome ...... 28

Amyotrophic Lateral Sclerosis ...... 30

Seizures, including those characteristic of epilepsy ...... 31

Severe and persistent muscle spasms, including those characteristic of 35

Multiple Sclerosis ...... 35

Spinal Cord Injury ...... 37

Crohn’s ...... 50

Terminal illness ...... 51

Intractable Pain ...... 51

3 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS Executive Summary

On May 29, 2014 the Governor of Minnesota signed the medical cannabis therapeutic use : 2014 Minnesota chapter 311. This Act is designed to enable truly sick patients to engage in the therapeutic use of cannabis while preventing it from being misused or diverted from its medical purpose.

This report summarizes clinical trials and prospective observational studies in humans, published in peer reviewed journals, which focus on medical cannabis formulations consistent with Minnesota’s medical cannabis program. It is produced in fulfillment of Minnesota Statutes Section 152.25, subdivision 2. The report was first produced in December, 2014, and it is updated periodically. Relevant new study publications and newly discovered existing study publications will be included as they come to the attention of the Office of Medical Cannabis.

The medical conditions identified in the statute for inclusion in the medical cannabis program are:

1 Cancer, if the underlying condition or treatment produces one or more of the following: a. Severe or chronic pain; b. or severe ; or c. or severe wasting 2 3 Human immunodeficiency virus or acquired immune deficiency syndrome 4 Tourette’s syndrome 5 Amyotrophic lateral sclerosis 6 , including those characteristic of epilepsy 7 Severe and persistent muscle spasms, including those characteristic of multiple sclerosis 8 Crohn’s disease 9 Terminal illness, with a probable life expectancy of under one year, if the illness or its treatment produces one or more of the following: a. Severe or chronic pain; b. Nausea or severe vomiting; or c. Cachexia or severe wasting

On December 2, 2015 the Commissioner announced his decision to add to the list of the program’s qualifying medical conditions, effective August 1, 2016.

4 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

There are relatively few clinical trials, especially large clinical trials that can produce the most definitive results. In recent years the number of trials has increased to some degree, perhaps reflecting the commercialization of medical cannabis products around the world over the past few decades. Following are summary observations for each section.

Cancer: pain divided doses. Not everyone can tolerate these doses, and the FDA recommends a Trial results suggest a combination of THC lower for CINV, stating and CBD might be more effective than THC most patients respond to 5 mg three or alone and that doses of THC higher than four times daily. approximately 25 mg, even when divided over the course of a day, might be poorly tolerated by a substantial number of Cancer: cachexia/wasting patients. The recently completed Some small early trials showed international trials of approximately 1:1 effectiveness with doses of -derived THC:CBD oromucosal spray (, brand name Sativex) failed to meet their THC 10 to 15 mg three to four times daily primary endpoints. However, a pre- on days of infusion. Later specified pooled analysis of patients from trials with dronabinol, mostly in cancer U. S. Centers, from 2 of the 3 trials, patients not receiving chemotherapy, are showed better pain control with Sativex less encouraging. Using doses of 5.0 to than with placebo. The maximum daily 7.5 mg daily in divided doses there was dosage allowed was 10 sprays per day, either modest effectiveness compared to providing 27 mg THC and 25 mg CBD per placebo or inferior effectiveness day. compared to standard anti-emetic , Cancer: nausea and vomiting and a substantial number of patients could not tolerate these doses. A large Several studies of plant-derived THC for trial with cannabis treatment arms chemotherapy-induced nausea and of relatively small doses of THC only (2.5 vomiting (CINV) from the late used mg twice daily) or THC + CBD (2.5 mg 10 to 18 mg THC starting an hour or two THC/1.0 mg CBD twice daily) was stopped before chemotherapy initiation, then early for lack of effectiveness, yet dose repeating the dose every 2 to 4 hours for reductions were necessary in a third of an additional 2 to 4 doses over 12 to 24 both groups. hours. Clinical trials of dronabinol, synthetic delta-9-THC, have used daily doses similar to the trials of plant-derived THC from the 1970s: 30 to 80 mg/day in

5 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Glaucoma unacceptable side effects. Together, these studies provide modest evidence of CBD does not appear to be effective at effectiveness at reducing severity. lowering (IOP) and might even increase it. There is some Amyotrophic Lateral Sclerosis evidence that even relatively low (5 mg) single doses of THC significantly reduces The two small trials in ALS patients that IOP for 4 to 5 hours before it returns to were identified used dronabinol. One was baseline, but this isn’t a consistent finding reported in an abstract with few details, across studies. Larger single doses (20 but started patients on 2.5 mg daily and and 25 mg) appear to reduce IOP longer titrated up to a maximum daily dose of 10 (10 hours), but with a high occurrence of mg. The second used 10 mg daily in two intolerable side effects. divided doses. Both studies indicated patients tolerated the dronabinol doses well, but with little clear evidence of HIV/AIDS effectiveness. Each of the studies identified used dronabinol and assessed effect on Seizures and weight. Most used 5.0 to 7.5 mg daily in 2 or 3 divided doses, Reported trials that appear to have consistent with FDA label enrolled mostly adults each used 200 or recommendations. Though most patients 300 mg CBD daily with two of the three tolerated this dose well, a substantial suggesting evidence of effectiveness at minority could only tolerate 2.5 mg daily. reducing severity. A recent survey Results from three trials that enrolled of parents of children with epilepsy current users suggest current treated with CBD extract indicates a very marijuana users can tolerate higher doses, wide range of daily dose, but the results in the range of 20 to 40 mg daily in are hard to interpret because of lack of divided doses. standardization of the CBD preparations used. Recent studies mostly or entirely focusing on children have used 99% CBD extract, starting at a dose of 2 to 5 Two small studies of oral, plant-derived mg/kg/day, titrating up slowly to a goal of THC (source not specified) in adult TS 25 to 50 mg/kg/day. patients used single daily doses of 2.5 mg to 10 mg. About a third of the patients needed to decrease dose because of

6 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Muscle spasms approaches: THC: CBD ratio 1:10 (5 mg THC and 50 mg CBD, twice daily) and CBD Results of numerous trials focusing on only (5 mg CBD in twice daily). and muscle spasm have been The former is a completed trial, but published, mostly with multiple sclerosis results have not yet been reported. The patients, but also some with spinal cord latter is a trial now recruiting patients. injury patients. Whether in combination with CBD in various ratios or as a single Terminal illness agent (dronabinol), THC has been used in average dosages of 20 to 25 mg/day in Relevant studies can be found in other divided doses. Dosages are usually sections of this report, particularly the started fairly low and then titrated up to cancer sections. No published medical achieve a balance between symptom cannabis trials were found that specifically reduction and appearance of side effects. targeted patients with short life From the trial , it appears that expectancy, across medical doing this titration over weeks, rather conditions. than over days, helps to reduce incidence and severity of side effects. There is some Intractable pain indication that THC is more effective in reducing spasticity and spasm at higher For the Minnesota medical cannabis doses and that higher doses are better program intractable pain is defined as tolerated when given in conjunction with pain whose cause cannot be removed CBD in a THC:CBD ratio of 1:1 (versus 2:1 and, according to generally accepted or 3:1 or dronabinol). But some patients medical practice, the full range of pain cannot tolerate even quite low doses of management modalities appropriate for THC. Treatment appears to be effective in the patient has been used without only a subset of patients, perhaps around adequate result or with intolerable side half, and whether or not treatment will be effects. Trials of cannabis for pain in the effective can generally be determined literature generally follow this definition within a few weeks. in that their inclusion criteria specify patients with pain inadequately Crohn’s disease controlled with standard pain medications. The trials uniformly had the At this point there is no clear guidance on participants continue taking their routine composition or dosing. The two trials pain medications, so they assess the value included in this report both emphasize of cannabis treatment as an adjunct to CBD, with somewhat different other pain medications.

7 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

The quality of most of the studies summarized in this section is formally assessed in a report by the MN Evidence- based Practice Center called, “Medical Cannabis for Non-Cancer Pain: A Systematic Review” (http://www.health.state.mn.us/topics/canna bis/intractable/medicalcannabisreport.pdf).

Six of the studies assessed in that report are not summarized here because they used the synthetic , which is similar to – but distinct from – THC.

Eleven of the 15 trials studied an approximately 1:1 ratio of THC: CBD oro- mucosal spray (in most cases nabiximols, brand name Sativex) vs. placebo. Average dose in the clinical trials, after the titration period, of the 1:1 THC: CBD spray were around 6 to 10 sprays per day, representing a daily dose of approximately 15 to 27 mg THC and CBD per day. Two of the articles report studies of long-term use of nabiximols. Results showed no evidence of tolerance developing with dosages a bit lower than during the clinical trials lasting a month or two.

Two of the trials studied oral dronabinol, synthetic THC, vs. placebo. Only one of them reported an average dose after titration.

8 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS Introduction overview of the scientific articles that This report summarizes clinical trials and follow. Below the citation for each article is prospective observational studies in a condensed description of the study and its humans, published in peer-reviewed results. journals, hat focus on medical cannabis formulations consistent with Minnesota’s Trials involving non-smokeable medical medical cannabis program. It was produced cannabis usually use either extractions of in fulfillment of Minnesota Statutes Section cannabis, sometimes with processing that 152.25, Subdivision 2. The report will be enriches specific components of the plant’s updated periodically. Relevant new study constituent parts, or synthetic publications and newly discovered existing . Cannabinoids are a class of study publications will be included as they oxygen-containing aromatic come to the attention of the Office of found distinctively in from the Medical Cannabis. Cannabis.

To accomplish this review, the National The two cannabinoids typically found in Library of ’s MEDLINE database greatest quantity in cannabis plants are was searched using key words appropriate delta-9-tetrahydrocannibinol (typically for each qualifying medical condition in the referred to as THC) and (CBD). Minnesota medical cannabis program THC is the cannabinoid usually present in statute. Articles that appeared to be greatest quantity and it is psychoactive, results of clinical trials or reviews of clinical acting as a prominent cause of the trials were accessed through the MDH - and sometimes dysphoria, - perceptions of library for examination. References in such time distortion, and so forth that are well articles were studied to identify additional known from recreational use of marijuana. articles that were not found on the initial Both THC and CBD have been studied search. This continued in an iterative extensively in pre-, both in fashion until no additional relevant articles basic laboratory studies and in animal were found. Finally, the government models. Both have attributes and effects in maintained web site of registered clinical animal models that suggest beneficial trials, clinicaltrials.gov, was searched to effects with medical use in humans. CBD is learn about trials currently under way or not psychoactive and might attenuate the under development and to check whether psychoactive effects of THC in some additional articles on completed trials could patients. There are relatively few clinical be found. trials, especially large clinical trials that can produce the most definitive results. In The body of this report contains a section recent years the number of such trials has for each of the nine qualifying medical increased to some degree, perhaps conditions. At the beginning of each reflecting the commercialization of medical section (or subsection, in the case of cannabis products around the world over cancer) there are comments providing an the past few decades.

9 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Patients in Johnson 2010 self-titrated to an Cancer average of 8.75 sprays (23.6 mg THC, 21.9 mg CBD), delivered over the course of a If the underlying condition or treatment day. Patients taking nabiximols in the produces one or more of the following: Johnson 2010 study tolerated it fairly well. severe or chronic pain, nausea or severe vomiting, or cachexia or severe wasting The Johnson 2010 study also had a group (three separate sections presented below) taking a cannabis extract that had only THC. Patients in this group self-titrated to 8.34 sprays over the course of a day (22.5 mg Severe or Chronic Pain THC), tolerating it fairly well, with a side Two early trials studied delta-9-THC effect profile similar to the THC/CBD group. sourced from the U.S. government (Noyes J These studies, as a group, suggest the Clin Pharmacol 1975; Noyes Clin Pharmacol wisdom of dividing a day’s total dose over Ther 1975) and gave single oral multiple different administrations to administrations of 5, 10, 15, and 20 mg THC mitigate side effects. The Johnson 2012 to adult cancer patients. Oral extension study lacked large numbers of administration of 20 mg was not well- patients followed long-term on nabiximols, tolerated. Studies where similar daily but nevertheless it does provide some doses of THC, or larger, divided into smaller evidence of effectiveness over many dose administrations over the course of the months with no evidence of need for dose day, would be helpful. But such studies escalation over time. were not found in the published literature Three clinical trials of Sativex for adjunct and do not appear to be in the planning treatment of cancer pain have now been phases on clinicaltrials.gov. completed. Results have not been Later, larger trials have studied nabiximols, published but some information on results the US Adopted Name for Sativex. is included in press releases issued by the Nabiximols is an oromucosal spray sponsor company, GW Pharmaceuticals. produced through extraction and Each of the trials set an upper bound of processing of a strain of dosing at 10 sprays per day (27 mg THC and that results in high and stable 25 mg CBD). The primary endpoint in each concentrations of delta-9-THC and CBD and was reduction in patient reported pain on a minor amounts of other cannabinoids and 0-10 numerical rating scale. None of the terpenes. Each 100 micro-liter actualization three showed a statistically significant (spray) contains 2.7 mg THC and 2.5 mg difference in pain reduction between CBD. The high dose group in Portenoy Sativex and placebo. However, a pre- 2012, at least 11 sprays per day (3 in the specified pooled analysis of patients from AM, 8 in the PM), was not well tolerated. US centers from two of the trials, showed 11 sprays delivers 29.7 mg THC (8.7 mg in better pain control with Sativex that the AM, 21.6 mg in the PM) and 25 mg CBD. reached statistical significance.

10 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

SJohnson JR, Burnell-Nugent M, Lossignol placebo groups. A higher percentage of D, Ganac-Motan ED, et al. Multicenter, patients experienced somnolence (13%), double-blind, randomized, placebo- dizziness (12%), and confusion (7%) in the controlled, parallel-group study of the nabiximols group than in placebo. efficacy, safety, and tolerability of THC: Incidence of these side effects was similar in the THC/CBD and THC groups. However, CBD extract and THC extract in patients 3 episodes of hypotension were seen in the with intractable cancer-related pain. J Pain nabiximols group and none was observed in Symptom Manage 2010; 39:167-179. the THC or placebo groups. Side effects leading to study withdrawal occurred in The effect of two weeks of treatment with 17%, 12%, and 3%, respectively, for nabiximols, THC extract, or placebo was nabiximols, THC extract, and placebo. studied in this double-blind, randomized, placebo-controlled, parallel group study Johnson JR, Lossignol D, Burnell-Nugent M, involving 177 adult cancer patients from 28 and Fallon MT. An open-label extension European centers. The patients were study to investigate the long-term safety required to have advanced cancer with pain and tolerability of THC/CBD oromucosal not adequately controlled despite sprays and oromucosal THC spray in optimized management. Patients patients with terminal cancer-related pain with chemotherapy within the preceding refractory to strong opioid . J two weeks were excluded. Patients were Pain Symptom Manage 2013; 46:207218. randomized to nabiximols, to a cannabis extract containing only THC (2.7 mg per 100 This open-label extension to the parent micro-liter spray), or placebo spray. study reported in Johnson 2010 enrolled 43 Patients self-titrated with the instruction of patients: 13 had received nabiximols increasing the number of sprays each day (THC/CBD) in the parent study, 11 had by a maximum of 50% until they either had received THC spray and 19 had received satisfactory relief of their symptoms or placebo. 39 received nabiximols in the developed unwanted side effects. Sprays extension study and 4 received THC spray. were to be spread throughout the day, with Though it was conceived as a long-term at least 15 minutes between sprays. follow-up study, because of staggered Maximum number of sprays allowed within enrollment in the parent study (creating a 3 hour period was 8 and maximum within shorter follow-up for more recently- a 24 hour period was 48. The mean enrolled patients before end of the number of sprays in the nabiximols group extension study) and patients who dropped was 8.75 (23.6 mg THC, 21.9 mg CBD) and out of the study, median follow-up time for the average number of sprays in the THC patients receiving nabiximols was 25 days group was 8.34 (22.5 mg THC). The co- (range 2 to 579 days) and for the four primary end-point was reduction in pain patients receiving THC spray median follow- score between baseline and end of study. up was 152 days (range 4 to 657 days). 43% of patients in the THC/CBD group Patients were instructed to self-titrate dose achieved a 30% or greater reduction in their to reach a balance between effectiveness pain score, twice the number of patients and side effects and to not exceed 8 sprays who achieved this response in the THC and in a three hour period or 48 sprays per 24

11 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS hours. Actual dose experience of the medication upwards, four weeks at stable patients was not reported, except that the medication dose, up to two week period authors noted study medication was taken titrating dose down, then a two week wash- for more than six months by 10% of out period before a second round using the patients and for more than one year by 5% other agent. Dosing started with one spray without resulting in dose escalation. and participants were instructed to increase Effectiveness analyses were limited to 5 the study medication by one to two sprays weeks of observation time, over which a per day until they reached a dose that trend of improvement in pain control was helped their pain, up to a maximum of 12 noted. A total of 23 patients (59%) sprays per day, stopping increases if receiving nabiximols and one of the 4 unacceptable side effects developed. The receiving THC spray withdrew because of primary outcome was change in 11-point side effects. Of these, 12 patients taking rating scale of pain over the past seven nabiximols had been in the placebo group days. Secondary measures included SF-36 during the parent study. Improvements survey and QST sensory over time were observed for and testing. 18 patients started the study and fatigue and worsening of nausea and two dropped out for unspecified reasons. vomiting was observed over time. Mean dose used during active treatment was 8 sprays per day (range 3-12) and 11 Lynch ME, Cesar-Rittenberg P, Hohmann sprays during placebo treatment. Mean AG. A double-blind, placebo-controlled, baseline NRS score was 6.75. During active crossover pilot trial with extension using treatment, participants experienced 11.1% an oral mucosal cannabinoid extract for reduction in NRS score at week 4; during treatment of chemotherapy-induced placebo treatment the reduction was 5.2% . J Pain and Symptom (difference not statistically significant). Five Manage 2014; 47:166-173. participants were reported as having a two point or greater decrease in NRS score Randomized, placebo-controlled crossover during active treatment. Among these 5, pilot study of nabiximols vs placebo in 16 called “responders,” the mean baseline NRS patients with chemotherapy-induced scores were 6.0. During active treatment, neuropathic pain. Inclusion criteria these participants experienced 43.3% included neuropathic pain persisting for reduction in NRS score; during placebo three months after completing treatment the reduction was 10.0% chemotherapy with , vincristine, (difference statistically significant). Most or cisplatin, average seven day intensity of patients reported side effects during active pain ≥4 on an 11-point scale, and treatment and only two reported side concurrent analgesics stable for 14 days effects during placebo treatment. Most before entry into the trial. Participants had common side effects during active a wide of cancers. Average treatment were fatigue (n=7), dizziness (6), chemotherapy cycle number when pain nausea (6), and dry mouth (5). Authors started was 2.8; average duration of pain report there were no serious medication- was 17 months. The trial started with a related adverse events and that no patient one-week baseline pain assessment period, then up to two weeks of titration of

12 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

discontinued medication or withdrew from with continuous moderate pain to a the study because of side effects. morning administration of either placebo, 10 mg THC (sourced from the U.S. Noyes R Jr, Brunk SF, Baram DA, and government), 60 mg , 20 mg THC, or Canter A. effect of delta-9- 120 mg codeine, in random order, on five tetracannabinol. J Clin Pharmacol 1975; successive days. Their usual analgesic 15:139-143. medications (“none were receiving large doses of ”) were continued until 4 Ten adults with advanced cancer and AM and study medication administered at continuous moderate pain were recruited 8:30 AM. Information on pain and other for a double-blind trial testing the effect of symptoms was collected just before single administrations of delta-9-THC at medication administration and hourly for different dosages. The THC was sourced seven hours thereafter. 10 mg THC showed from the U.S. government and oral dosages improved pain control compared with tested were 5 mg, 10 mg, 15 mg, and 20 placebo over 7 hours, but the difference mg. Over 5 days patients received each of was not statistically significant. The larger these dosages or placebo in random order. reduction in pain with 20 mg THC was a The patients remained on their usual pain statistically significant difference from medications (none on “large doses of placebo but caused substantial cognitive narcotics”) until 4 AM each day and the impairments and drowsiness. Side effects study medication was administered at 8:30 were much milder and shorter lasting with AM and pain assessments done before 10 mg THC. The authors noted that administration and hourly thereafter for six evaluating pain relief was especially difficult hours. Measures of pain reduction and pain in patients after receiving THC because in relief increased with larger doses. Analgesic many instances the patients appeared effect increased over time, peaking at 3 exceptionally peaceful while reporting little hours for the lower doses and at 5 hours for pain relief. And, in other instances, they the 20 mg dose. Interestingly, in all groups claimed that though the pain was a secondary peak can be seen at 5 hours – unchanged, it bothered them less. perhaps the result of THC’s mobilization from the gall bladder and reabsorption Portenoy RK, Ganae-Motan ED, Allende S, following food ingestion. The most Yanagihara R, et al. Nabiximols for opioid- prominent was dose-dependent treated cancer patients with poorly- drowsiness and slurred speech. controlled chronic pain: a randomized, placebo-controlled, gradeddose trial. J Pain Noyes R Jr, Brunk SF, Avery DA, and Canter 2012; 13:438-449. AC. The analgesic properties of delta- 9tetrahydrocannibinol and codeine. Clin This was a randomized, placebo-controlled Pharmacol Ther 1975; 18:84-89. graded dose study of patients with advanced cancer and pain despite This randomized, double-blinded trial optimized opioid therapy from 84 centers in followed the preliminary trial reported in , , South America and Noyes J Clin Pharmacol 1975. It . Patients who had received or randomized 36 advanced cancer patients planned to receive chemotherapy or other

13 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS treatments expected to change pain were ” scores were analyzed, where the excluded. Baseline pain had to be between largest improvement over placebo – and 4 and 8 on an 11-point scale at baseline and the only statistically significant differences – stable for three consecutive days during a were seen in the group that administered 1 qualifying period when opioid management to 4 sprays per day. Neither the use of was optimized. Study treatment was regularly scheduled nor the number nabiximols. Patients were randomized to of opioid doses taken as needed for one of three dose titration regimens and breakthrough pain varied significantly then half of each group was randomized to between treatment groups. Not only did nabiximols and half to placebo. Patients the high dose group not show effectiveness randomized to the Low Dose group were in pain relief, but the high doses were not instructed to titrate the study medication to well tolerated. Only 66% could continue at between 1 and 4 sprays per day. Those the lowest dose (11 sprays) to the end of assigned to Medium Dose group titrated the study. the number of sprays to between 6 and 10 sprays per day, and those assigned to the Nausea or Severe Wasting High Dose group titrated to between 11 and 16 sprays per day. Daily dosage was split Nausea and vomiting are common side between morning and evening effects of cancer and – especially - its administration. All three groups were given treatment. There are multiple a titration schedule that increased total therapies for nausea and vomiting, but not dose over 7 days (3 days for the low dose group). Patients were told to increase to all are effective for all patients and some the maximum dose for their group unless patients cannot tolerate the side effects. intolerable side effects prevented further There has been substantial study of dose escalation. After the week of dose cannabinoids for treatment of titration patients continued on stable chemotherapy-induced nausea and dosing for four weeks. Daily assessments vomiting (CINV). Most published trials have included average pain, worst pain, and studied three synthetic versions of THC or sleep disruption. There were also baseline THC analogs: dronabinol, nabilone, and and study-end pain questionnaires and . Dronabinol, a synthetically quality of life surveys. The primary end- produced delta-9-THC, and nabilone, a point was 30% or greater reduction of pain synthetic derivative of delta-9-THC, are from baseline. Results showed no statistically significant difference among both approved by the FDA for treatment of treatment groups, compared to placebo. nausea and vomiting associated with However, when the full distribution of cancer chemotherapy in patients who have percentage of pain relief is compared failed to respond to conventional among the groups, the two lower dose therapy. Levonantradol is a groups showed an improvement in pain synthetic analog of dronabinol that is much relief, compared to placebo, which was more potent than THC and remains an statistically significant. Similar results were investigational drug. Of these three drugs, seen when “worst pain” and “disrupted

14 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS dronabinol is the one directly relevant to placebo was observed in the trial with the Minnesota medical cannabis program. Adriamycin and Cytoxan chemotherapy (Chang 1981). Two additional trials of THC A systematic review and meta-analysis of for CINV from the same late-1970s era used trials of dronabinol, nabilone and similar dosing: 10 to 15 mg five times over levonantradol for CINV, some comparing 24 hours (Ekert 1979) and 10 to 15 mg 3 them to placebo and some comparing them times over 12 hours (Sallan 1980). to other antiemetic drugs, covered 30 studies (Machado Rocha 2008). Limitations A small randomized, double-blind trial of sample sizes and study designs studied nabiximols treatment as an adjunct prevented firm conclusions, but the to standard anti-emitic therapy for authors’ general conclusion was there was chemotherapy-induced nausea and evidence that dronabinol had better acute vomiting (Duran 2010). On the day of chemotherapy treatment three sprays of anti-emetic efficiency than the nabiximols were delivered and the patient conventional anti-emetic drug comparitors. was instructed to increase the number of Doses of dronabinol ranged generally from sprays throughout the day, up to a limit of 30mg/day to 80 mg/day in divided doses. 8 sprays within any 4 hour period. The The FDA label for dronabinol emphasizes mean number of daily sprays taken during the need for dosage individualization, but the four days after chemotherapy was 4.8 for use as an antiemetic, notes that most in the active treatment group (range 2.7- patients respond to 5 mg three or four 5.0), representing a daily THC dose of 13.0 times daily and that use of dronabinol with mg of THC per day (range 7.3 mg to 13.5 phenothiazines has resulted in improved mg). One patient withdrew from active efficacy as compared to either drug alone, treatment because of adverse effects. A higher proportion of patients in the active without additional . treatment group (5/7) had complete Two early trials of oral THC (with, in some response, compared to the placebo group (2/9). Complete response was defined by cases, the addition of smoked marijuana) no vomiting and a specified score on a self- for reduction of chemotherapy-induced assessed nausea rating scale. nausea and vomiting had mixed results. In both trials, the majority of patients were Chang AE, Shiling DJ, Stillman RC, Goldberg experienced marijuana smokers. The same NH, Seipp CA, Barofsky I, Simon RM, protocol was used in both trials, Rosenberg SA. Delta-9- administering five oral doses of as an antiemetic in approximately 18 mg delta-9-THC from one cancer patients receiving high-dose hour prior to 11 hours after time of methotrexate. A prospective, randomized evaluation. Ann Intern Med 1970; 91:819- chemotherapy infusion. Significant 824. reduction in nausea and vomiting occurred during the trial with methotrexate therapy Fifteen patients, age 15 to 49, with (Chang 1979), but no difference from osteogenic sarcoma and receiving high dose

15 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

methotrexate chemotherapy were studied. instead of a for the remaining Eleven of the 15 were experienced users of doses. Results showed no effect of THC on marijuana. In this randomized, double- nausea or vomiting in these chemotherapy blind, placebo-controlled trial patients patients. served as their own control. One hour prior to each instance of chemotherapy infusion Ekert H, Waters KD, Jurk IH, Mobilia J, et the patient received a capsule containing al. Amelioration of cancer chemotherapy- either 10 mg/m2 THC or placebo, with induced nausea and vomiting by delta- additional doses every three hours for a 9tetrahydrocannabinol. Med J Aust 1979; total of five doses. Based on a body surface 2:657659. area of 1.75 m2, the oral THC dose was 17.5 mg every 3 hours for five doses. If This short article reports on two studies – vomiting occurred during the treatment, or perhaps three. It is somewhat confusing. patients received a marijuana One study was a double-blind test of delta- instead of a capsule for the remaining 9-THC and meloclopramide on children with doses. Results showed THC was cancer requiring chemotherapy. Source of significantly more effective than placebo in the THC is not described. An oral dose of 10 2 reducing the number of vomiting and mg/m (with maximum of 15 mg) was retching episodes, degree of nausea, administered four hours before duration of nausea and volume of emesis. chemotherapy and at 4, 8, 16, and 24 hours after the first dose. Incidence of nausea, Chang AE, Shling DJ, Stillman RC, Goldberg vomiting, and was less than half in NH, Seipp CA, Barofsky I, Rosenberg S. A the patients taking THC, compared to those prospective evaluation of delta-9- taking meloclopramide, with the tetrahydrocannabinol as an antiemetic in differences achieving statistical significance. patients receiving Adriamycin and Cytoxan The side effect reported, drowsiness, was chemotherapy. Cancer 1981; 47:17461751. not common and was similar in both groups. Eight patients, age 17 to 58, with soft tissue sarcomas and receiving Adriamycin and Duran M, Preliminary efficacy and safety Cytoxan chemotherapy were studied. of an oromucosal standardized cannabis Seven of the eight were experienced users extract in chemotherapy-induced nausea of marijuana. In this randomized, double- and vomiting. Br J Clin Pharmacol blind, placebo-controlled trial patients 2010;70(4):656-663. served as their own control. One hour prior to each instance of chemotherapy infusion Small randomized, double-blind trial of the patient received a capsule containing nabiximols treatment as an adjunct to either 10 mg/m2 THC or placebo, with standard anti-emitic therapy for additional doses every three hours for a chemotherapy-induced nausea and total of five doses. Based on a body surface vomiting. 16 patients suffering from CINV area of 1.75 m2, the oral THC dose was 17.5 despite prophylaxis with standard anti- mg every 3 hours for five doses. If emetic treatment were randomized to vomiting occurred during the treatment, placebo (n=9) or nabiximols (n=7), to be patients received a marijuana cigarette taken in conjunction with standard anti-

16 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS emetic treatment. Nabiximols (Sativex) is Sallan SE, Cronin C, Zelen M, and Zinberg an oromucosal cannabis extract spray NE. in patients receiving developed by GW Pharmaceuticals. The chemotherapy for cancer: a randomized whole plant extract is highly standardized, comparison of delta-9tetrahydrocannibinol produced from cloned cannabis chemovars and . N Engl J Med grown under controlled conditions. Each 1980;302:135-138. 100 µliter actuation (spray) yields 2.7 mg delta-9-THC and 2.5 mg of CBD with these This was a study of delta-9-THC and two cannabinoids constituting at least 90% prochlorperazine as antiemetics in cancer of cannabinoid content. On the day of patients receiving chemotherapy resulting chemotherapy treatment three sprays of in nausea and vomiting inadequately nabiximols were delivered and the patient controlled by conventional antiemetics, was instructed to increase home-dose for including phenothiazines. It was carried out four days, up to 8 sprays within any 4 hour in the late 1970s using delta-9-THC sourced period. The mean number of daily sprays from the National Institute on Drug Abuse. taken during the four days after 84 patients were randomized to receive chemotherapy was 4.8 in the active three double-blind single-day courses of treatment group (range 2.7-5.0), drug on days of chemotherapy. The trial representing a daily THC dose of 13.0 mg of was structured so patients received THC per day (range 7.3 mg to 13.5 mg). different orderings of two kinds of one drug One patient withdrew from active and one kind of the other (to address treatment because of adverse effects. A potential order effect). When the course higher proportion of patients in the active was THC, the patient received 15 mg THC treatment group (5/7) had complete (or, in a few cases of small persons, 10 mg) response, compared to the placebo group an hour before start of chemotherapy and (2/9). Complete response was defined by the same dose 4 and 8 hours later. no vomiting and a specified score on a self- “Complete response” was defined as no assessed nausea rating scale. nausea or vomiting after chemotherapy. Regardless of the emetic activity of the Machado Rocha FC, Stefano SC, DeCassia chemotherapeutic agents, there were more HR, Rosa Oliveira LM, et al. Therapeutic complete responses to THC courses (36 of use of Cannabis sativa on chemotherapy- 79 courses) than to prochlorperazine (16 of induced nausea and vomiting among 78 courses). Increased food intake cancer patients: systematic review and occurred more frequently with THC. Side meta-analysis. Eur J Cancer Care (Engl) effects were not recorded, other than 2008;17:431-443. comments on proportions of patients who “got high.” Of 36 THC courses resulting in A systematic review and meta-analysis of complete response, 32 were associated trials of dronabinol and nabilone for with a high. chemotherapyinduced nausea and vomiting, some comparing them to placebo and some comparing them to other antiemetic drugs.

17 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Cachexia or Severe Wasting were necessary in approximately a third of both groups. Results of trials on effectiveness of cannabis formulations for increasing appetite in Brisbois TD, de Kock IH, Watanabe SM, cancer patients are mixed and not Mirhosseini M, et al. Delta- particularly encouraging. Two early trials 9tetrahydrocannabinol may palliate that used delta-9-THC derived from altered chemosensory perception in cannabis plants reported positive results in cancer patients: results of a randomized, patients receiving chemotherapy. double-blind, placebocontrolled pilot trial. Maximum daily dose in the trial with plant- Ann Oncol 2011;2086-2093. derived THC was up to 75 mg in five divided doses in children (Ekert 1979) and 30 to 45 This was a randomized, double-blind mg in 3 divided doses in adults (Sallan placebo controlled pilot study of 1980). effectiveness of dronabinol (synthetic delta- Three more recent trials used dronabinol, 9-THC) in improving and smell (chemosensory) perception as well as synthetic delta-9-THC. In one study with appetite, weight, and quality of life in positive results cancer patients (not cancer patients with chemosensory necessarily on chemotherapy) took 5 mg or alterations. 46 adult cancer patients with 7.5 mg daily in divided doses with minimal poor appetite and chemosensory side effects (Brisbois 2011). Another trial alterations were recruited from two with modestly positive results used 7.5 Canadian centers and randomized to mg/day in three divided doses, resulting in dronabinol or placebo for 18 days. A third intolerable side effects for 20% of patients of the patients were receiving (Nelson 1994). A large trial that compared chemotherapy at the time of data dronabinol and megestrol used 5 mg collection, but all patients had previously been on multiple rounds of chemotherapy. dronabinol daily in two divided doses. The Patients were started on one capsule (2.5 modest improvement in weight seen with mg dronabinol) daily for three days then dronabinol was inferior to that seen with increased to two capsules daily (5 mg megestrol; patients tolerated the dronabinol/day). Patients had the option of dronabinol well (Jatoi 2002). increasing dose to a maximum of 8 capsules (20 mg dronabinol/day). 21 patients A large comparing THC:CBD completed the study: 11 on dronabinol and extract, THC-only extract and placebo was 10 on placebo. Eight of the dronabinol stopped early because of lack of patients took two capsules per day (5 effectiveness (Strasser 2006). Patients in mg/day in 2 divided doses) and 3 patients the THC:CBD arm received 5.0 mg THC and increased dose to 3 capsules (7.5 mg/day in 2.0 mg CBD daily in two divided doses; 3 divided doses). Most patients receiving patients in the THC-only arm received 5.0 dronabinol had increased appetite at the mg THC daily in two divided doses. end of the study (7), 3 had no change and one had incomplete data. Among patients Temporary or permanent dose reductions receiving placebo half had decreased

18 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS appetite (5) and two showed no change Jatoi et al studied the effect of megestrol (status of the remaining 3 not reported, but acetate, dronabinol (synthetic delta-9-THC) could be either increased appetite or and combination therapy on 469 patients incomplete data). Compared with placebo, with uncurable cancer on no appetite dronabinol-treated patients increased their stimulating drugs. All patients reported loss protein intake as a proportion of total of 5 pounds or more over two months or energy and reported better sleep. Increase caloric intake of less than 20 calories/kg of in caloric intake and in quality of life scores body weight. Patients were randomized to was similar in the two groups. No (1) liquid suspension 800 differences in number of adverse events or mg orally daily plus capsule placebo; (2) serious adverse events between active dronabinol capsules 2.5 mg orally twice a treatment and placebo groups were day plus liquid placebo; or (3) both reported. medications. Patients were continued on treatment for as long as the health care Ekert H, Waters KD, Jurk IH, Mobilia J, et provider thought it beneficial or until toxic al. Amelioration of cancer chemotherapy- side effects prompted study withdrawal. induced nausea and vomiting by delta- The North Central Cancer Treatment Group 9tetrahydrocannabinol. Med J Aust questionnaires for appetite and weight 1979;2:657659. were used at baseline, weekly for a month, and monthly thereafter. Duration of This short article reports on two studies – observation was similar among the groups or perhaps three. It is somewhat confusing. (megestrol=80 days, dronabinol=57 days, One study was a double-blind test of delta- combination=74 days). A greater 9-THC and meloclopramide on children with proportion of patients taking megestrol cancer requiring chemotherapy. Source of (11%) gained more than 10% of baseline the THC is not described. An oral dose of 10 weight, by home weight measurements, 2 mg/m (with maximum of 15 mg) was than patients taking dronabinol (3%) or administered four hours before both drugs (8%). And a greater percentage chemotherapy and at 4, 8, 16, and 24 hours of patients taking megestrol reported after the first dose. Incidence of nausea, improved appetite (75%), than patients vomiting, and anorexia was less than half in taking dronabinol (49%) or both drugs the patients taking THC, compared to those (66%). Side effects were similar across the taking meloclopramide, with the treatment groups, except for impotence, differences achieving statistical significance. which was reported by 18 men taking The side effect reported, drowsiness, was megestrol, 4 men taking dronabinol, and 14 not common and was similar in both men taking both. groups. Nelson K, Walsh D, Deeter P, and Sheehan Jatoi A, Windschitl HE, Loprinzi CL, Sloan F. A phase II study of delta-9- JA, et al. Dronabinol versus megestrol tetrahydrocannibinol for appetite acetate versus combination therapy for stimulation in cancer-associated anorexia. cancer-associated anorexia: a North J Palliat Care 1994;10:14-18. Central Cancer Treatment Group study. J Clin Oncol 2002;20:567-573.

19 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Nineteen adult patients with advanced was THC, the patient received 15 mg THC cancer were recruited into an open-label (or, in a few cases of small persons, 10 mg) (unmasked) four week trial of dronabinol an hour before start of chemotherapy and (synthetic delta-9-THC) on appetite. Some the same dose 4 and 8 hours later. patients were receiving chemotherapy and “Complete response” was defined as no some were not. Patients were excluded if nausea or vomiting after chemotherapy. they were taking other drugs known to Regardless of the emetic activity of the affect appetite. Each was started on 2.5 mg chemotherapeutic agents, there were more dronabinol three times per day (patients complete responses to THC courses (36 of over the age of 65 were started on 2.5 mg 79 courses) than to prochlorperazine (16 of twice /day for three days and then 78 courses). Increased food intake increased to three times/day). Four occurred more frequently with THC. Side patients reported side effects and three effects were not recorded, other than dropped out because of them: one for comments on proportions of patients who slurred speech and two for nausea. A “got high.” Of 36 THC courses resulting in fourth patient experienced severe nausea complete response, 32 were associated but continued in the study. At four weeks with a high. 13 of 18 reported their appetite was at least slightly improved, compared with baseline Strasser F, Luftner D, Possinger K, Ernst G, (10 “slight improvement” and 3 “major et al. Comparison of orally administered improvement”). cannabis extract and delta-9- tetrahydrocannbinol in treating patients Sallan SE, Cronin C, Zelen M, and Zinberg with cancer-related anorexiacachexia NE. Antiemetics in patients receiving syndrome: a multicenter, phase III, chemotherapy for cancer: a randomized randomized, double-blind, placebo- comparison of delta-9tetrahydrocannibinol controlled clinical trial from the Cannabis- and prochlorperazine. N Engl J Med in-Cachexia-StudyGroup. J Clin Oncol 1980;302:135-138. 2006;24:3394-3400.

This was a study of delta-9-THC and A trial comparing effectiveness of cannabis prochlorperazine as antiemetics in cancer extract capsules containing 2.5 mg THC and patients receiving chemotherapy resulting 1.0 mg CBD twice daily, cannabis extract in nausea and vomiting inadequately capsules containing only 2.5 mg THC twice controlled by conventional antiemetics, daily and placebo on increasing appetite including phenothiazines. It was carried out and quality of life in terminal cancer in the late 1970s using delta-9-THC sourced patients was stopped early because of lack from the National Institute on Drug Abuse. of effectiveness. Before the study was 84 patients were randomized to receive stopped 243 patients with at least 5% three double-blind single-day courses of weight loss over the past 6 months, from 30 drug on days of chemotherapy. The trial European centers, were randomly assigned was structured so patients received to the three treatment arms for six weeks different orderings of two kinds of one drug of treatment. Many patients dropped out and one kind of the other (to address of the study – most because they withdrew potential order effect). When the course consent and 164 completed the study

20 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

(CBD/THC: 66/95, THC: 65/100, The few published clinical trials of medical placebo:33/48) Primary outcome was cannabis for glaucoma are quite small with improvement of appetite as measured by mixed evidence of temporary reduction in visual analog scale. Secondary outcome IOC. An early open-label (uncontrolled) measures included a cancer-specific quality trial of single-dose administrations of of life survey. After 6 weeks THC/CBD and dronabinol (synthetic delta-9-THC) found placebo patients showed similar 20 mg and 25 mg were equally effective in improvement in appetite; THC patients showed little improvement. Mean quality reducing IOP for at least 10 hours, but side of life measures showed no significant effects at these dosages were intolerable change in any of the three groups. Side (Merritt 1980). In a second, small, double- effects were common, with temporary or blinded study reported in the same article, permanent dose reductions necessary in 78 effects of single administrations of 5 mg patients (CBD/THC=34, THC=30, and 10 mg synthetic delta-9-THC were placebo=14). Side effects that appeared to compared with placebo. No difference in be more common in the active treatment IOP reduction was seen between active groups included nausea, fatigue, pain, drug and placebo patients. diarrhea, and obstipation. In a small prospective observational study patients were started on 2.5 mg THC four times per day and instructed to titrate dose Glaucoma up, balancing effectiveness of IOP reduction Glaucoma is a multi-factorial disease with appearance of side effects. During the characterized by the progressive course of the trial 2 patients received a degeneration of the optic nerve and the maximum dose of 7.5 mg 4x/day, 3 pts 5.0 death of retinal ganglion cells, ultimately mg 4x/day, and 3 did not increase from 2.5 leading to irreversible blindness. Increased mg 4x/day. Side effects were common and intraocular pressure (IOP) has been severe enough in four patients to cause implicated in the pathophysiology of withdrawal from the study. This occurred glaucoma; however, inadequate blood at a wide range of doses. IOP reduction supply to the optic nerve, oxidative was inconsistent across patient weekly damage, and apoptosis (programmed assessments, with only two of nine death) of the retinal ganglion cells are also participants having reduced IOP during the thought to play a role in the disease. Aside majority of assessments (Flach 2002). from lowering IOP, cannabinoids such as A well-controlled pilot study of six patients delta-9-THC and CBD may also have with ocular hypertension or early primary neuroprotective effects which could be open-angle glaucoma reported that single useful in the management of glaucoma. sub-lingual doses of 5 mg delta-9-THC Published trails to date have focused on (applied by means of an oromucosal spray) reduction of IOP. significantly but temporarily reduced IOP 2

21 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS hours after administration. After the four 4x/day (20 mg daily), and 3 did not increase hour measurement IOP had returned to from 2.5 mg 4x/day (10 mg daily). All normal (Tomida 2006). A single sub-lingual patients withdrew from the study, for a dose of 20 mg cannabidiol (CBD) variety of reasons, between months 1 and (containing around 1 mg delta-9-THC) had 9. Four withdrew because of side effects (3 weeks – taking 2.5 mg 4x/day, 8 weeks – no effect while a single sub-lingual dose 40 7.5 mg 4x/day, 20 weeks – 5 mg/day, 20 mg of CBD (containing around 2 mg of weeks – 15 mg/day, ) such as distortion of delta-9-THC) caused a significant transient perception, confusion, , depression, increase in IOP 4 hours after and severe dizziness. The dizziness and administration. There were no serious or lightheadedness reported by subjects in the severe adverse events and all but 2 (nausea study were never associated with systemic and hypertension after administration of 5 hypotension. All patients were observed to mg delta-9-THC, rated moderate) were have at least an initial improvement in IOP. rated mild. An improvement was noted during more than 50% of the office visits in two of the Flach AJ. Delta-9-tetrahydrocannabinol nine subjects. One subject was considered (THC) in the treatment of end-stage open- improved on all visits during a 36 month angle glaucoma. Trans Am Ophthalmol treatment period (withdrew from study Soc 2002;100:215-224. because of cataract surgery). Merritt, JC, McKinnon S, Armstrong JR, Nonrandomized, uncontrolled prospective Hatem G, Reid LA. Oral delta 9- observational study of nine adults Tetrahydrocannabinol in Heterogenous with primary open angle glaucoma on . Ann Opthalmol 1980;12:947- maximally tolerated medical therapy 950. available in the mid1980s. Oral capsules with 2.5 mg or 5 mg THC dissolved in The study report contains results from two sesame oil were used in the study. Initial small observational trials of different dosage for each patient was 2.5 mg or 5 mg designs at different US institutions. Group given each 4 hours (four times daily) while A was seven glaucoma patients treated with awake. The dose was increased or 20 mg or 25 mg synthetic delta-9-THC decreased by 2.5 mg increments as needed capsules obtained from the National to obtain a greater effect or less toxicity Institute on Drug Abuse. The dose was with a maximum permitted dose of 20 mg given in the morning. IOP was decreased four times daily. After initiation of THC, IOP 7.8 +/- 1.7 mm Hg at 5 hours. Doses of 20 was measured weekly until satisfactory mg and 25 mg were found equally effective control of IOP was achieved for 2 in lowering IOP for at least 10 hours. But consecutive weeks with examinations adverse effects (, acute monthly thereafter. Maximum allowed panic reactions, and ) occurred dose was 15 mg THC four times daily (60 mg with such frequency, in the opinion of the daily). During the course of the trial 2 authors (frequency not reported) as to patients received a maximum dose of 7.5 preclude further testing at these dosages. mg 4x/day (30 mg daily), 3 pts 5.0 mg Accordingly, Group B was administered 5

22 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS mg or 10 mg synthetic delta-9-THC or experienced a transient and mild panic-like placebo in a randomized, double-masked reaction after delta 9-THC administration. study with 10 subjects. Gradual decreases in IOP occurred with both cannabinoid and placebo therapies for up to 5 hours. But cannabinoid therapy produced no greater Human IOP reduction than placebo. One subject who took 5 mg delta 9-THC experienced Immunodeficiency , severe postural hypotension and severe anxiety and depersonalization reactions. Virus or Acquired

Tomida I, Azuara-Blanco A, House H, Flint Immune M, Pertwee R, Robson P. Effect of sublingual application of cannabinoids on Deficiency intraocular pressure: a pilot study. J Glaucoma 2006;15(5):349-353. Syndrome

A randomized, double-masked, placebo- Each of the relevant published trials controlled, 4 way crossover study at a single identified used dronabinol, synthetic delta- institution. Six subjects with either ocular 9-THC, and most studied its effectiveness hypertension or primary open-angle on improving appetite and increasing glaucoma discontinued their topical weight in HIV-positive patients. Dronabinol glaucoma medication (three had none) for 4 is approved by the FDA for anorexia to 6 weeks before receiving the test associated with weight loss in patients with medication. Subjects were administered AIDS (and for nausea and vomiting oromucosal spray preparations under the associated with cancer chemotherapy in tongue. The preparations delivered 5 mg delta-9-THC, 20 mg CBD, 40 mg CBD, or patients who have failed to respond placebo. The CBD preparations contained a adequately to conventional antiemetic small amount of delta-9-THC: 1 mg delta-9- treatments). The FDA label acknowledges THC for every 21 mg CBD. Intraocular the wide range of dosages of dronabinol pressure was measured at hours 0, 1, 2, 3, used in clinical trials and that the 4, 6, and 12. Two hours after sublingual pharmacologic effects of the drug have administration of 5 mg delta 9-THC, the IOP wide inter-individual variability. For was significantly lower than with placebo appetite stimulation, the label (23.5 mm Hg vs. 27.3 mm Hg, P=0.026). The recommends, for adults, to start with 2.5 IOP returned to baseline level after the 4- mg before lunch and 2.5 mg before supper. hour IOP measurement. CBD It goes on to recommend when adverse administration did not reduce the IOP at any time. However, the higher dose of CBD events are absent or minimal and further (40 mg) produced a transient elevation of therapeutic effect is desired, to increase IOP at 4 hours after administration, from the dose to 2.5 mg before lunch and 5 mg 23.2 to 25.9 mm Hg (P=0.028). One patient before supper or 5 and 5 mg. It notes that

23 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

10 mg twice daily has been tolerated in groups: marijuana, dronabinol, and about half of the patients in appetite placebo. The marijuana group (n = 22) stimulation studies. Those smoked up to three 3.95% THC marijuana recommendations are broadly consistent 1 hour before meals daily, as with the findings of the studies below tolerated. Dronabinol (n = 20) and placebo (n = 20) groups received either 2.5 mg (Abrams 2003, Beal 1995, Beal 1997), with dronabinol or placebo capsules 3 times the exception of trials that recruited regular daily before meals. HIV RNA level was marijuana users. In this patient group it monitored at baseline, days 2, 5, 8, 11, 14, appears that larger doses of dronabinol are 17, 19, and 21. CD4+ and CD8+ cell counts well tolerated (Bedi 2010, Haney 2005, were collected at baseline and every 7 days. Haney 2007). But even at these relatively Five patients left the study prior to day 14 high dosages of dronabinol, its and 14 completed the trial. Results showed effectiveness at improving appetite and no significant impact from cannabinoids on weight gain are mixed. A study of the HIV RNA level. Both cannabinoid groups effect of dronabinol and smoked marijuana had increased CD4+ and CD8+ cell counts, on viral load in HIV-infected patients taking compared with placebo group, indicating benefit rather than harm. antiretroviral protease inhibitor drugs gives Pharmacokinetics of both protease some assurance that THC treatment in this inhibitors were also unaffected by patient group is not unsafe (Abrams 2003) cannabinoid exposures. Significant increases in weight gain occurred in both Abrams DI, Hilton JF, Leiser RJ, Shade SB, the dronabinol (median = 3.2 kg; range -1.4 Elbeik TA, et al. Short-term effects of to 7.6 kg) and marijuana (median = 3.0 kg; cannabinoids in patients with HIV-1 range -0.75 to 8.6 kg) groups. infection. Ann Intern Med 2003;139:258- 266. Beal JE, Olson R, Laubenstein L, Morales JO, et al. Dronabinol as a treatment for A total of 67 HIV-positive patients anorexia associated with weight loss in participated in this randomized, placebo- patients with AIDS. J Pain Symptom controlled trial over 25 days (4 days lead-in Manage 1995;10:89-97. and 21 days inpatient treatment) whose primary objective was to determine the 139 patients at advanced stages of HIV with short-term effect of cannabis on the viral AIDS-related anorexia were included in this load in HIV-infected patients. Participants multi-center, randomized, double-blind, were at least 18 years old, experienced placebo-controlled, parallel-group trial over marijuana users, and were on stable 6 weeks. All participants were marijuana antiretroviral protease inhibitor regimens free for at least 30 days before the trial. with indinavir or nelinavir. None of them The trial had two treatment arms: smoked marijuana or ingested cannabinoids dronabinol and placebo. Patients were within 30 days of enrollment. Patients randomized to each group and received taking nefinavir and indinavir were capsules with either placebo or 2.5 mg stratified and allocated into 3 different dronabinol and received instruction to take one capsule twice a day. The dose was

24 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS reduced to one capsule per day if Beal JE, Olson R, Lefkowitz L, Laubenstein intolerable side effects developed (n = 17 in L, et al. Long-term efficacy and safety of dronabinol group). At baseline and three dronabinol for acquired immunodeficiency times weekly patients used a 100-mm visual syndrome-associated anorexia. J Pain analog scale (VAS) to rate their mood, Symptom Manage 1997;14:7-14. appetite, and nausea on a scale from 0 to 100 with 0 being no appetite, no nausea, This was a follow-up study on participants and terrible mood, and 100 representing from the Dronabinol as a Treatment of respective opposites. Subjects were also Anorexia Associated with Weight Loss in evaluated biweekly on weight, physical Patients with AIDS trial (Beal 1995) with a exam and Karnofsky score – a performance duration of 12 months. Ninety-four late- assessment with a score of 100 stage AIDS patients from the parent trial representing normal activity, 50 as need for enrolled in this multi-center, open-label frequent assistance and medical care, and 0 study. Of these, 46 received dronabinol representing death. Of the 139 patients, 51 and 48 received placebo during the parent were not evaluable due to protocol trial. Treatment initiated at 2.5 mg violation or noncompletion of study dronabinol twice daily for 90% and 2.5 g treatment. Evaluable patients’ outcomes daily for 10% (patients who could tolerate showed statistically significant only 2.5 mg daily in the parent trial). Dose improvements in appetite, mood, titration and adjustments were made decreased nausea, and stabilized weight according to each patient’s response and from dronabinol use compared with side effects. Dose increases were limited to placebo. No significant difference was 5 mg/day every 2 weeks. Dose was seen in the Karnofsky score between the decreased to 2.5 mg/day in 19% of patients two groups. Overall, dronabinol was well and increased to 7.5 mg/day or higher (2 tolerated, with central nervous system patients 10 mg/day, 1 patient 20 mg/day) in disturbances such as dizziness, euphoria, 19%. Only 22 patients (24%) completed the thinking abnormalities, and somnolence 12 month study. Side effects were the being the most commonly reported reason for discontinuation for 14 patients. treatment-related side effects. Only l6 The most common reason for drop-outs patients (8.3%) receiving dronabinol and 3 was intercurrent illness (n = 25). Patients (4.5%) receiving placebo discontinued treated with dronabinol in the parent trial treatment due to side effects. No continued to show improvements in significant interaction occurred between appetite. Patients treated with placebo in dronabinol and opioid analgesics or the parent trial showed substantial in terms of adverse improvement in appetite, especially during events. This trial was an important part of the first 4 months of dronabinol therapy. the evidence that led the FDA to approve Patient weight tended to remain stable for dronabinol as a treatment for anorexia the first 5 months and then showed modest associated with weight loss in patients with decline. Treatment-related adverse events AIDS. were reported in 44% of patients, with 2% having an adverse event considered severe (nature of events not specified). The most

25 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS common side effects were anxiety, HIV(+) marijuana smokers: acute effects on confusion, depersonalization, dizziness, caloric intake and mood. euphoria, somnolence, and abnormal (Berl) thinking. 2005;181:170178

Bedi G, Foltin RW, Gunderson EW, Rabkin Thirty HIV-positive marijuana-using patients J, Hart CL, Comer SD, Vosburg SK, Haney were recruited; 15 with and 15 without M. Efficacy and tolerability of high-dose clinically significant muscle wasting, for dronabinol maintenance in HIV-positive testing the effect of single administrations marijuana smokers: A controlled of dronabinol and marijuana. At eight 7- laboratory study. Psychopharmacol (Berl) hour testing sessions spread out over 4 2010;212:675-686. weeks, participants took capsules and then one hour afterward took three puffs of a Seven HIV-positive adults age 21-50 on at marijuana cigarette. The capsules least two antiretroviral medications and contained 0, 10, 20, or 30 mg of dronabinol who use marijuana at least twice per week and the cigarettes were 0.0, 1.8, 2.8, or 3.9 were recruited for this within-subjects, % THC. In any one session only one dose double-blind, placebo-controlled study. form was active. Mood, physical symtoms, During one of two 16-day inpatient stays food intake, cardiovascular data, and subjects received 10 mg dronabinol cognitive task performance were measured (synthetic delta-9-THC) 4 times per day; before and repeatedly during each session. during the other 16 day stay they received Caloric intake was significantly increased for placebo capsules. The two stays were the patients with muscle wasting with each separated by a 5 to 15 day outpatient of the dose forms, but not for patients period for study of medication clearance. without muscle wasting (who had a higher Despite sustained increases in self-reported baseline caloric intake). The 10 mg and 20 food cravings, dronabinol only increased mg of dronabinol were well tolerated in this caloric intake in the initial eight days of study’s cohort of marijuana users. The 30 dosing. During the initial eight days there mg dronabinol administration produced at was an average weight gain of 1 kg (not least one adverse event (headache, statistically significant) and no weight gain vomiting, and “uncomfortable level of in the second eight days of dronabinol intoxication”) in 20% of participants. Drug treatment. Similarly, sleep quality was effects on cognitive performance were improved only during the first 8 days of minor. dosing. Mood was enhanced for the duration of dronabinol use. These relatively Haney M, Gunderson E, Rabkin J, Hart C>, high dronabinol doses in habitual marijuana et al. Dronabinol and marijuana in HIV- users were well tolerated with few negative positive marijuana smokers. Caloric intake, subjective effects. There were minor effects mood, and sleep. J Acquir Immune Defic of dronabinol on aspects of cognitive Syndr 2007;45:545554. testing performance. Ten HIV-positive experienced marijuana Haney M, Rabkin J, Gunderson E, and smokers with an average age of 40 years Foltin RW. Dronabinol and marijuana in were included in this research. Subjects

26 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS took capsules and smoked marijuana center, randomized, open-label 12-week cigarettes four times per day over trial. The average age was 39 years. sequential four day periods, with each four Marijuana use in the past month was an day period separated by a four day wash- exclusion criterion. Patients were out period. Two dosages of capsules were randomized into 4 treatment arms: used, dronabinol 5 mg and 10 mg and dronabinol 2.5 mg twice daily (D; n = 12); marijuana cigarettes with two strengths of megestrol acetate 750 mg daily (M750; n = delta-9-THC were used, 2.0% and 3.6%. 12); megestrol acetate 750 mg daily + During any given four day treatment period, dronabinol 2.5 mg twice daily (M750 +D; n only one dose form was active. The courses = 13); and megestrol acetate 250 mg/day; of treatment were done in an inpatient dronabinol 2.5 mg twice daily (M250+D; n = setting with extensive patient assessments 13). The study was performed in an and testing, including a cognitive testing outpatient setting over 12 weeks. battery, hunger-satiety questionnaire, food Dronabinol doses were taken 1 hour before intake, and subjective experience surveys. meals at lunch and dinner. Megestrol was Results showed that dronabinol and taken 1 hour before lunch. Subjects smoked marijuana had similar dose- completed 4 different self-reported dependent improvements in total daily questionnaires for this study: visual analog caloric intake and frequency of eating as scale for hunger (VASH) was taken 3 times compared to placebo. The higher doses of daily before meals; visual analog scale for both also resulted in significant increase in nausea (VASN), and visual analog for mood weight within 4 days. Compared with (VASM) were both taken at noon; and placebo, neither dronabinol nor smoked functional assessment for HIV (FAHI) marijuana significantly altered performance questionnaire was completed in clinic. on any of the cognitive performance tests (e.g. measures of learning, memory, VASH scale ranged from 0 (extremely vigilance, psychomotor ability). This study hungry) to 330 (not hungry at all). No suggests that higher doses of dronabinol information was provided on VASN and (40 mg per day in 4 divided doses; 8 times VASM’s scoring methods. All VAS’s were the standard dosing) could be used safely taken at baseline and throughout the and effectively in HIV-positive marijuana outpatient phase on 2 weekdays and 1 smokers. weekend day. FAHI, a questionnaire with subscale and perception scores in 6 Timpone JG, Wright DJ, Li N, Egorin MJ, et categories (physical wellbeing, social/family al. The safety and pharmacokinetics of well-being, relationship with doctor, single-agent and combination therapy with emotional well-being, megestrol acetate and dronabinol for the fulfillment/contentment, and additional treatment of HIV wasting syndrome. The concerns), was also completed at baseline DATRI 004 Study Group. Division of AIDS and every 4 weeks along with chemistry Treatment Research Initiative. AIDS Res profile, physical examination, CD4+ cell Hum Retroviruses 1997;13:305-315. count. One patient from the M750 arm was erroneously switched into M250 + D during A total of 52 patients with HIV wasting the study. An average weight gain of 11% syndrome were enrolled into this multi-

27 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS from baseline was seen in both M750 and control of TS symptoms, but they are not M750 + D arms, and was most rapid during uniformly effective and many have the first 6 weeks. undesirable side effects. There are two clinical trials of medical cannabis in No weight gain was seen in D and M250 + D arms. Data from Karnofsky score, FAHI, and Tourette Syndrome patients – both small VAS questionnaire revealed no statistically and 8 of 12 participants from the first were significant change from the baseline or recruited into the second, raising some difference among treatment arms. No significant changes or differences were concerns about the validity of the results. seen in CD4+ cell counts from baseline Both used single daily dosages of delta-9- among all. Pharmacokinetics profiles of THC, ranging from 2.5 mg to 10 mg. The M750 and M750+D showed no statistically first tested the effect of single doses of significant differences, suggesting that delta-9-THC (Muller-Vahl 2002). The THC dronabinol has no impact on the dose differed based on gender, age, and metabolism or exposure to megestrol prior cannabis experience, ranging from 5.0 acetate. mg to 10.0 mg. Five of the 12 subjects experienced mild side effects after THC Regarding adverse events, no statistically significant differences were observed administration and the results suggested among the treatment arms for nausea, effectiveness of THC at reducing tic vomiting, diarrhea, headache, total severity. The second was a randomized neurological events, and total adverse double-blinded six week trial of delta-9-THC events. For central nervous system side on 24 subjects (Muller-Vahl J Clin Psychiatry effects, D arm reported confusion and 2003). The daily dose started at 2.5 mg/day emotional lability, and and was increased by 2.5 mg/day every somnolence; M750 arm had ; four days to a maximum of 10 mg/day or M250 had euphoria; and M750+D had less if intolerable side effects developed. seizure, and amblyopia. Megestrol was also One of the patients receiving THC dropped associated with hypertension, deep vein out because of side effects, six ended the (DVT), dyspnea, and edema. study taking the daily maximum of 10.0 mg/day, two were taking 7.5 mg/day and one could only tolerate 2.5 mg/day. Results Tourette suggested some reduction in tic severity. A companion paper reported on Syndrome measurement of cognitive function during the trial (Muller-Vahl Tourette syndrome is a complex Neuropsychopharmacology 2003). It found neurobehavioral disorder characterized by no differences in cognitive testing results motor and vocal that typically has its between the active treatment and placebo onset during childhood. and groups. other classes of drugs are used to attempt

28 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Muller-Vahl KR, Schneider U, Koblenz A, A small randomized, double-blind, placebo Jodges M. Treatment of Tourette’s controlled six-week trial of the syndrome with Delta 9- effectiveness of delta-9-THC at controlling tetrahdrocannabinol (THC): a randomized TS symptoms. The 24 subjects had an crossover trial. Pharmacopsychiatry average age of 33 (range=18-68 years). Fifteen patients were unmedicated for at 2002;35(2):57-61. least 6 months prior to the study and 9 A small randomized, double-blind, cross- were taking medications for the treatment over study of the effect of a single dose of of TS. Half the patients were randomly delta-9-THC on adult patients with Tourette assigned to the THC group and half to Syndrome. The THC dose differed based on placebo. THC was administered in gelatin gender, age, and prior cannabis experience. capsules with a starting dose of 2.5 mg/day. Females without prior use of marijuana and Source of THC was not specified. Dose was body weight <=60 kg or age >= 50 years titrated up by increasing dose 2.5 mg/day received 5.0 mg, otherwise 7.5 mg; men every four days. Target maximum dose was without prior use of marijuana and body 10 mg/day. Patients were instructed to weight <=70 kg or age >=50 years received take the pills once a day with breakfast. If a 5.0 mg; men who used marijuana regularly, subject could not tolerate the maximum body weight > 70 kg and age < 50 years dose, an adjustment could be made by received 10 mg.; all other men received 7.5 decreasing study medications up to 5.0 mg mg. Source of the delta-9-THC was not until a tolerated dose was achieved. The specified. Multiple measures of TS same dosing schedule was used to reduce symptoms were done just before and 3 to 4 medication at the end of the treatment hours after administration. After a four period. Patients were examined at baseline week washout period subjects who and days 9, 20-22, 30-31, one or two days received placebo at the outset received after medication stopped, and 6 weeks active treatment and vice-versa. after medication stopped. At each visit tic Statistically significant improvements in tic severity was measured using multiple severity were observed following THC clinician-rated measurement tools. The treatment, as well as small benefits in authors report seven patients dropped out some, but not all, additional measures of TS of the study or had to be excluded symptoms. After statistical adjustment for afterward. One patient receiving THC multiple comparisons, beneficial effects dropped out because of side effects were no longer significant. No serious (anxiety and restlessness). A companion adverse effects occurred. Five patients paper for this study (Muller-Vahl experienced mild transient adverse Neuropsychopharmacology 2003) notes reactions lasting between 1 and 6 hours. THC dose at end of study was 10.0 mg/day for 6 patients, 7.5 mg/day for 2 patients, Muller-Vahl KR, Schneider U, Prevedel H. and 2.5 mg/day for one. Most rating scales Delta 9tetrahydrocannabinol (THC) is demonstrated marked tic reduction at visits effective in the treatment of tics in 2, 3, and 4. However, statistical adjustment Tourette syndrome: a 6-week randomized for multiple measures eliminated the trial. J Clin Psychiatry 2003;64:459465. statistically significant observations, except

29 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS for those at visit 4. No serious adverse associated with ALS were found, both using reactions occurred. Five of the patients in dronabinol (synthetic delta-9THC). The the THC group reported mild side effects effectiveness results of the studies are (tiredness, dry mouth, dizziness), however mixed, but both agree dronabinol, in the none of these patients reduced study tested doses, is well tolerated with few side medication below 7.5 mg due to these side effects (dizziness). In one open-label effects because none felt seriously crossover pilot study of 20 ALS patients, impaired. escalating doses starting at 2.5 mg/day Muller-Vahl K. Treatment of Tourette (max 10 mg/day) of dronabinol for 3 syndrome with delata-9- months were associated with improvement tetrahudrocannabinol (delta 9THC): no in sleep, appetite, and spasticity, but few influence on neuropsychological details are provided (Gelinas 2002). In performance. Neuropsychopharmacology contrast, a small crossover study using a 2003;28:384-388. shorter two-week treatment period This article reports on study of cognitive reported no improvement in cramp function during the placebo-controlled trial intensity, number of cramps, fasciculation described above (Muller-Vahl J Clin intensity, sleep, appetite, depression, or Psychiatry 2003). Five tests of cognitive quality of life measure (Weber 2010). This function were done. No significant study used 5 mg dronabinal (in sesame oil differences in cognitive function between drops) twice daily. the two groups were seen. Though the target dose was 10.0 mg/day, only 6 of the Gelinas, D. F, Miller, R. G, and Abood, M. 9 in the placebo group titrated their dose (2002). Pilot study of safety and up to that level. The reason why is not tolerability of delta 9-THC (Marinol) stated, but presumably it was due to treatment for ALS. Amyotroph unpleasant side effects. THC dose at end of study was 10.0 mg/day for 6 patients, 7.5 Lateral Scler Other Motor Neuron Disord 3: mg/day for two patients and 2.5 mg/day for 23-24 (an abstract) one. One patient receiving THC dropped out of the study because of side effects In this open-label (uncontrolled) cross-over (restlessness and anxiety). No serious study 20 patients with ALS were recruited adverse events occurred. for a study of the effects of dronabinol (synthetic delta-9-THC) therapy. Subjects were split into two groups, with the first group receiving dronabinol for three Amyotrophic months, followed by a month of drug wash- out and then three months of no Lateral Sclerosis treatment. The other group was treated with dronabinol in months 5 to 7. The Only two published clinical trials of dronabinol dose was started at 2.5 mg/day cannabis for the treatment of symptoms and then increased to a maximum of 10 mg/day. Details were not provided on

30 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS achieved dose or pace of escalation. Dronabinol at these doses was reported as Seizures, including tolerated well with no treatment-related adverse events. Symptomatic benefits those were reported to have been seen in the areas of insomnia, appetite, and spasticity characteristic of (no further details provided). epilepsy Weber, M., Goldman, B., and Truniger. Tetrahydrocannabinol (THC) for cramps in Clinical trial data for effectiveness of amyotrophic lateral sclerosis: a cannabis on seizures is scant. Reported randomized, double-blind crossover trial. trials from the 1970s and 1980s, as outlined J.Neurol.Neurosurg.Psychiatry below are small and some have design 2010;81:11351140. problems and are incompletely described. This trial compared 10 mg dronabinol These trials generally used 200 mg to 300 (synthetic delta-9-THC) in two divided doses mg cannabidiol (CBD) daily. These doses to placebo as treatment for moderate to were very well tolerated with few side severe daily cramps in ALS patients. The 27 effects reported. Results show mixed patients were allowed to take any evidence of effectiveness. medications for ALS or its symptoms but were asked not to change this medication Additional studies have recently been during the study period. Cramp intensity completed. Geffrey 2015 describes a trial was rated daily by the patient using a visual designed to assess interaction between analog scale. In this randomized, double- CBD and the anti-epileptic drug clobazam, blinded, placebo-controlled crossover trial but it also describes CBD dosing and seizure patients received dronabinol in either the outcomes. Devinski 2015 reports on a set first two or last two weeks of the five week of open-label Program study period, with week 3 serving as the studies of an oral 99% CBD extract runin/wash-out period. Complete data were available from 22 patients. There produced by GW Pharmaceuticals (brand were no treatmentrelated serious adverse name Epidiolex) carried out in cohorts of effects and the only side effect was mild approximately 25 patients age one to 30 by dizziness experienced by one patient during multiple U.S. investigators. The dronabinol treatment. There was no studies started patients on 2-5 mg/kg/day evidence for a treatment effect on cramp divided in twice-daily dosing and then intensity, number of cramps, fasciculation titrated up by 2-5 mg/kg once a week until intensity or any of the other secondary intolerance or to a maximum dose of 25 outcome measures. mg/kg or 50 mg/kg (depending on study site).

Studies listed on the Clinical Trials website (www.clinicaltrials.gov) describe trials using

31 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS a synthetic CBD produced by INSYS statistically significant difference in seizure Therapeutics, Inc. Little information is frequency between the active treatment provided on dosing with the exception of 3 and placebo groups. The abstract reported of them noting the maximum dose will be the only side effect was mild drowsiness. 40 mg/kg/day. Finally, the U of is Cunha JM, Carlini EA, Pereira AE, Ramos organizing a study that will analyze genetic OL, Pimentoel C, Gagliardi R, Sanvito WL, differences between patients with Dravet Lander N, Mechoulam R. Chronic syndrome (ages one to 50 years) who do administration of cannabidiol to healthy and those who do not have a complete volunteers and epileptic patients. response (seizure free 3 months) to a Pharmacology 1980;21:175-185. proprietary CBD extract that is 98% CBD and has no THC. Anticipated completion 15 patients with temporal lobe epilepsy and secondarily generalized seizures, age 14-49 date for this study is February, 2016 per years, were enrolled in this double-blind clinicaltrials.gov trial. Each was instructed to add 2 to 3 (http://clinicaltrials.gov/ct2/show/NCT0222 capsules per day to their standard anti- 9032?term=%22epilepsy%22+AND+%22can epileptic regimen. Capsules of the 7 nabis%22&rank=1). patients randomized to cannabidiol received 100 mg capsules of CBD, so they Though not a clinical trial, the parent survey took 200 or 300 mg CBD daily. Treatment reported by Porter and Jacobson provides lasted at least 8 weeks and as long as 18 information on dosages of CBD used. Given weeks. Weekly patient evaluations the paucity of clinical trial data, this article included a four-point patient assessment of is included here. The parents of children degree of improvement in seizure activity: 3 age 2 to 16 with treatment-resistant = no improvement, 2 = small improvement, epilepsy reported a wide range of doses: 1 = partial improvement, 0 = complete from 0.5 mg/kg/day to 28.6 mg/kg/day. improvement. At baseline all patients were The treatments were well tolerated, with scored 3 and at the end of the trial 7 of 8 drowsiness and fatigue the most common placebo patients experienced no side effects. improvement while all but one of the CBD Ames FR, Cridland S. effect patients experienced at least some of cannabidiol. South African Medical improvement and four were “almost free of Journal 1986;69:14. convulsive crisis” for the entire study period. The patients tolerated CBD without Twelve patients (ages not given) living in an toxicity. institution due to mental retardation and with uncontrolled seizures were randomly Devinsky O, Marsh E, Friedman D, Thiele, assigned to receive 300 mg CBD orally or E, et al. Cannabidiol in patients with placebo for one week. During weeks two treatment-resistant epilepsy: an open- and three the number of capsules was label interventional trial. Lancet Neurology decreased so that CBD patients were 2015. Published online December 23, receiving 200 mg CBD. Seizure experience 2015:DOI:10.1016/51474-4422(15)00379- was recorded daily. Results showed no 8.

32 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Results of an open-label trial composed of drugs. Median number of concomitant physician-sponsored, expanded-access antiepileptic drugs was 3. The dose was programs at 11 institutions. Methodology increased by 2-5 mg/kg once a week to a at each center was similar, but with some maximum dose of 25 mg/kg/day at some variation since each was governed by site- centers and 50 mg/kg/day at others. The specific protocols. The primary endpoint mean CBD dose at 12 weeks in the safety was description of safety and tolerability. group was 22.9 mg/kg/day and in the The primary efficacy outcome was median efficacy group 22.7 mg/kg/day. Adverse percentage change in the mean monthly events were reported in 79% of the safety frequency of motor seizures at 12 weeks – group – mostly mild or moderate and comparing frequency during the initial four transient. Events reported in >5% were week observation period and during the 12 somnolence, decreased appetite, diarrhea, week treatment period. Patients at all sites fatigue, convulsions, appetite changes, were aged 1-30 years, had intractable status epilepticus, lethargy , changes in childhood-onset epilepsy, had four or more concentration of concomitant antiepileptic countable seizures with a motor component drugs, gait disturbance, and sedation. per 4 week period, and were receiving Serious adverse events were reported in 20 stable doses of antiepileptic drugs for at of the patients in the safety group (12%). least 4 weeks before enrollment. Between The one death –“a sudden unexpected January, 2014 and January, 2015, 214 death in epilepsy” was regarded as patients were enrolled for a 4 week unrelated to study drug. Among the serious baseline observation period and a 12 week adverse events, nine patients (6%) treatment period. 52 enrolled patients did experienced status epilepticus, 3 (2%) not have 12 weeks of follow-up after first experienced diarrhea, 2 (1%) experienced dose of cannabidiol and were excluded weight decrease and one patient each from both the safety analysis cohort experienced a variety of other events. (n=162) and the intention-to-treat efficacy Since there was no control group, it is analysis (n=137). The article does not difficult to determine the extent to which further characterize these 52 patients. An any of the serious adverse events were additional 25 patients were included in the caused by CBD. The authors suggest safety analysis cohort but excluded from diarrhea and weight loss are likely to be the efficacy analysis cohort, 23 because of related to CBD. CBD dose at 12 weeks was “no motor seizures” (this appears to mean not related to total number of adverse no motor seizures during the initial four events. There was no additional week observation period). In the safety information on dose at which adverse cohort 20% of patients had Dravet events appeared. The median change in syndrome and 19% had Lennox-Gastaut motor seizures, comparing the four week syndrome. The remaining patients had baseline and the 12 week treatment period, intractable epilepsies of a variety of causes was 36.5% reduction. This varied greatly, and types. Patients were started on however, among patients. A figure Epidiolex (GW Pharma, 99% CBD in sesame indicates approximately a third had an oil) at 2-5 mg/kg/day in two divided doses increase in seizures during the treatment in addition to their current anti-epilepsy period. And 39% of patients had a

33 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

reduction of 50% or more. 51% of the 70% of subjects (9 out of 13) experienced patients in the efficacy group were on the greater than 50% reduction in seizures aniti-epileptic drug clobazam and 51% of compared to their baseline levels. Two those patients had a reduction of 50% or participants showed an increase in seizure more, compared to 27% among patients frequency over their baseline levels. Study not receiving clobazam. It is recognized also concluded that CBD intake was that CBD increases concentration of an primarily affecting nCLB (norclobazam; an active metabolite of clobazam through active metabolite of CLB) metabolism – CBD’s inhibition of specific isozymes of the specifically that CBD inhibited nCLB cytochrome P-450 system. The authors metabolism (investigators found increased acknowledge that some of the observed concentrations of nCLB in blood levels decrease in motor seizures, as well as during CBD trial). higher rates of somnolence and fatigue, could be due to increased blood levels of Mechoulam R, Carini EA. Toward drugs the clobazam metabolite. derived from cannabis. Naturwissenschaften 1978;65:174179. Geffrey, A.L., Pollack, S.F., Bruno, P.L., & Thiele, E.A. Drug-drug interaction between In this double-blind trial nine patients were clobazam and cannabidiol in children with randomized to either 200 mg CBD daily or refractory epilepsy. Epilepsia 2015; 56: placebo for three months, while taking their 1246-1251. usual antiepileptic medication. Two of the four patients treated with CBD were Study’s main purpose was to look for a completely relieved of their epileptic drug-drug interaction between clobazam seizures for the duration of the study and (CLB) and CBD (Epidiolex), but the study only one of the four had no improvement. also included data on any changes in seizure None of the five treated with placebo frequency experienced by study experienced improvement. No toxic effects participants with refractory epilepsy (ages were observed. 4-19). This was an open-label, single design study where participants (n=13) taking CLB Porter BE, Jacobson C. Report of a parent took CBD as an adjuvant therapy for an 8- survey of cannabidiol-enriched cannabis week trial. Note that participants were also use in pediatric treatment-resistant taking other anti-epilepsy drugs (AEDs) epilepsy. Epilepsy Behav 2013;29:574-577. concurrently with CLB at the time of the study—study investigators note this and Stanford University carried out this survey mention a larger analysis presumably of parents of children (ages 2-16 yrs) with forthcoming in a future publication. The diagnosed, treatment-resistant epilepsy. All article includes info on what these other of the parents included in the survey had AEDs were; most participants were on 1-2 given their children CBD therapy, in extract other AEDs besides CLB. Participants form, and had recorded the results. They started on 5 mg/kg/day of CBD and were asked 24 questions about their child’s increased weekly by 5 mg/kg/day until they status, including seizure type, frequency, reached 25 mg/kg/day (reached 25 side effects, etc. Of the 19 parents in the mg/kg/day at Week 5). Conclusion: roughly survey, 13 were parents of children with

34 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Dravet syndrome. Because there is a drug known to be effective for treatment of characteristic of Dravet syndrome (stiripentol imported from Europe), an additional survey was multiple sclerosis performed with parents of children on this treatment to compare reported efficacy. Muscle spasm is a consequence of the The parents had tried an average of 12 drug underlying condition of spasticity seen therapies before starting CBD in doses that often in patients with multiple sclerosis, ranged from 0.5 mg/kg/day to 28.6 spinal cord injury, amyotrophic lateral mg/kg/day and the duration ranged from 2 sclerosis (ALS), and other neurological weeks to greater than a year. The results . Spasticity is an abnormal increase were that 16 of 19 parents reported a in muscle tone, resulting in stiffness, reduction in seizures, 11 of those stated the muscle spasm, and pain. Most studies of reduction was at least 50%, 8 children had greater than 80% reduction. Aside from medical cannabis that included evaluation seizure reduction, many parents also of muscle spasm have been in patients with reported their children had improved multiple sclerosis. Two small trials mood, alertness, and sleep, as well as involving spinal cord injury patients are at decreased negative self-stimulation. Some the end of this section. See the ALS section parents had discontinued their child’s prior for additional studies. therapy after having such success with CBD (12 of 19). Side effects reported were drowsiness (37%) and fatigue (16%). When compared to the survey on the European Multiple Sclerosis drug, stiripentol, 68% of parents reported a decrease in seizure activity, only 4 (of 22) Most clinical trials involving multiple said this reduction was “significant” and the sclerosis patients have used cannabis whole side effects were decreased appetite, plant extractions and a few have used weight loss, insomnia, and increased dronabinol, synthetic delta-9-THC. The negative self-stimulation. whole plant in the trials have varied in THC:CBD ratio. The paragraphs below comment briefly on dosages for each of the ratios – 1:1, 2:1, and 3:1. The final Severe and paragraph addresses trials that used persistent muscle dronabinol. Nabiximols (Sativex) is a highly standardized spasms, including oromucosal spray produced from cloned cannabis chemovars grown in controlled those conditions. Each 100 µliter actuation (spray) yields 2.7 mg delta-9THC and 2.5 mg CBD. An early trial (Wade 2003)

35 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS demonstrates the need to limit the number doses. Dose escalation was more rapid in of sprays taken within a few hours of each the MUSEC trial (dose increased every 3 other to avoid undesirable side effects. The days vs. weekly), and patients experienced typical maximum set in clinical trials is 8 more numerous and more severe side sprays within any 3 hour period (Collin effects than in the CAMS trial. At the end 2010) and 12 (Novotna 2011, Freidel 2015, of the MUSEC trial’s titration period only Leocani 2015) or 24 (Collin 2010) within a 47% of patients were taking 25 mg THC 24 hour period. However, when the trials daily. The CAMS trial’s maximum was were carried out, patients typically came to weight dependent with the maximum for an average daily dose of approximately 7 to the lightest adults 10 mg THC/day; the 15 sprays per day (Wade 2004, Collin 2007, paper does not describe achieved dosages. Collin 2010, Novotna 2011, Tomassini 2015, Both studies found evidence of Leocani 2015). Most nabiximols trials in MS effectiveness for patient-reported patients have lasted 3 months or less, but improvements in muscle spasm and an extension to the trial reported in Wade spasticity. The CAMS trial found no 2004 studied participants for variable treatment effect for clinician-assessed amounts of time up to more than two years spasticity, but the validity of the tool used (Wade 2006). Results from this trial for that assessment (Ashworth scale) is now suggest patients who continue to derive suspect. benefit from nabiximols therapy (i.e. the ones who choose to continue using it) do so One trial used a cannabis extract with a at the same or somewhat lower dosing THC:CBD ratio of approximately 3:1 (Vaney than they were using at six weeks. A safety 2004). This trial started patients at a dose registry maintained by the manufacturer of containing 15 mg THC and increased the Sativex indicates dosing in actual clinical dose 5 mg THC/day each day to a maximum practice is considerably lower than of 30 mg THC/day. However, half of the 50 reported in clinical trials, with a reported patients could tolerate a dose no larger average dose of 4 sprays per day (Eltayb than the starting dose of 15 mg THC/day 2013). and only about a third achieved a dose of 25 mg THC/day or more. During this cross- Three large trials used a commercially over study side effects were reported as produced and distributed cannabis whole being only slightly more frequent and more plant extract with 0.8 to 1.8 mg CBD for severe during active treatment than during each 2.5 mg delta-9-THC (Cannador - a placebo treatment. Results showed no TBD:CBD ratio of approximately 2:1) effectiveness for Ashworth scale spasticity (Cannador). Both the CAMS study (Zajicek score and a trend toward effectiveness for 2003) and the MUSEC study (Zajicek 2012) improvement in patient-assessed spasm started patients on 5 mg THC/day in two frequency that became statistically divided doses, then increased dose to a significant when analysis was limited to the maximum of 25 mg THC/day in divided 37 patients who took at least 90% of their

36 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS prescribed doses during the 2-week No altered occurred with the treatment maintenance phase. The study 5 mg THC. suggested a correlation between tolerated dose and body weight and increased Three small trials involving spinal cord effectiveness at higher doses. injury patients were found. One used dronabinol, synthetic delta-9-THC Finally, two trials used dronabinol, (Hagenbach 2007). The second used synthetic delta9-THC. In one arm of the nabilone, a synthetic derivative of THC. CAMS trial (Zajicek 2003) dronabinol was Since the action of nabilone is different started at 2.5 mg twice daily (5 mg/day) from THC it is not directly relevant to and titrated up at weekly intervals by 5 Minnesota’s medical cannabis program and mg/day to a weight-dependent maximum is not described here. The third used of 10 mg to 25 mg per day in split doses. nabiximols (whole plant cannabis extract Dizziness or lightheadedness, dry mouth, with THC:CBD ratio of approximately 1:1) in and diarrhea were more common in the a group with a variety of neurological dronabinol group than in the placebo group conditions including SCI (Wade 2003). and similar in frequency to the patients Though results for SCI patients were not taking 2:1 THC:CBD capsules. The large broken out, the study is included here for 3year CUPID trial (Zajicek 2013) used the completeness. same starting dose and titration schedule but slightly different weight-based targets The dronabinol trial is a small double- of 14 mg to 28 mg daily in split doses. blinded, placebo-controlled six week trial Results showed no effect of dronabinol on preceded by a dose-setting six week study disease progression. Adverse events more in the same patients, conducted at a Swiss common in the dronabinol group than in center (Hagenbach 2007). In the dose- the placebo group were dizziness and setting study 25 adults with spinal cord lightheadedness (32%) and injury (11 paraplegic, 14 tetraplegic) had thinking or perception disorders (30%). their antispasticity drugs discontinued for three half-lives and were then started on dronabinol with a single 10 mg dose the first day. Titration was individualized Spinal Cord Injury without set protocol, with the goal of An early trial involving only one patient balancing maximal effectiveness with side gives some information on dosing and effects. Outcomes studied at days 1, 8, and effectiveness of delta-9THC (Maurer 1990). 43 included clinician-assessed Ashworth The investigators concluded 5 mg oral spasticity score, patient-reported numerical delta-9-THC and 50 mg oral codeine were rating scales of spasticity, pain, attention, equally effective, and more effective than mood, and side effects, and more. 15 placebo, for pain reduction. Only THC had patients completed the six weeks: four a significant beneficial effect on spasticity. dropped out because of increased pain and

37 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS the other 6 because of anxiety and other statistically significant reduction on side effects. Mean dose achieved was 31 nabiximols, CBD alone, and THC alone, mg/day in divided doses (range: 15 mg to compared with placebo. Spasm frequency 60 mg). Patients perceived a significant saw statistically significant reduction while reduction in pain at day 1 compared to on nabiximols and THC alone, but not while baseline. A second dose-setting study on CBD alone, compared with placebo. using rectally administered dronabinol had Occurrence of side effects was similar to be curtailed at 7 patients because of across the four treatment conditions during supply problems, but the daily dose the placebo-controlled phase and achieved after dosing adjustment for those substantially higher during the initial open- 7 patients was 43 mg (range 20-60 mg). label nabiximols treatment phase. Methodological issues make interpretation of effectiveness results problematic, but Collin C, Davies P, Mutiboko IK, et al. there is suggestion of early effectiveness in Randomized controlled trial of cannabis- reduction of pain and spasticity that based medicine in spasticity caused by diminishes over weeks of treatment. multiple sclerosis. Eur J Neurol 2007;14:290-6. Wade and colleagues (Wade 2003) carried out a small placebo-controlled crossover This was a randomized, double-blind, trial of nabiximols (Sativex) on patients with placebo-controlled trial involving patients with multiple sclerosis whose symptoms neurological disorders and troublesome were not adequately controlled on standard symptoms (Wade 2003) that indicates the drugs. 189 adult patients from 8 centers in need to set a maximum dose within UK and 4 in were randomized in a specified time periods. Twenty-four 2:1 ratio to nabiximols or placebo for a total patients with a variety of neurologic of 6 weeks. Nabiximols (Sativex) is a highly disorders, including 4 with SCI, enrolled and standardized oromucosal spray developed 20 completed the study. Patients first had by GW Pharmaceuticals. It is extracted a two week open-label trial with nabiximols from whole cloned cannabis chemovars with instructions to increase frequency of grown under controlled conditions. Each sprays, balancing symptom relief with side 100 µliter actuation yields 2.7 mg delta-9- effects up to a maximum of 8 sprays within THC and 2.5 mg of CBD. Patients were instructed to titrate their daily dose steadily 70 minutes. Because of side effects this as required over 2 weeks, to a maximum was changed to four sprays over 2 hours dose of 48 sprays per day (130 mg THC, 120 and changed again to two sprays over two mg CBD). Total treatment time was six hours. After the two week open-label trial weeks. the patient entered an eight week double- blind study phase with four two-week Primary outcome measure was the change stages using nabiximols, or CBD alone or from baseline in the severity of spasticity THC alone or placebo. Across all 20 based on daily diary assessments by the patients, spasticity severity had a subject on a 0-10 numerical rating scale

38 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

(NRS). Secondary outcome measures randomized to either nabiximols or placebo included the Ashworth scale, Motricity for 14 weeks. Subjects self-titrated to a Index, mean daily spasm scores (five point maximum dose of 24 sprays daily (with a spasm frequency score) and the patients’ max of 8 in a 3 hour period). The mean global impression of change in their disease number of daily sprays taken by the active (7 point scale from very much improved to treatment group was 8.5 (range 1-22). Nine very much worse). Mean and median active treatment subjects (5%) and 5 on number of sprays per day were placebo (3%) withdrew because of adverse events. The most commonly reported 14.7 (40 mg THC/37 mg CBD) and 13 (35 mg treatment-related adverse events which THC/33 mg CBD), respectively. Results showed a higher incidence in the active showed reduction in spasticity scores for treatment group compared with placebo both active treatment and placebo groups, were dizziness (32% versus 10%), fatigue but the larger decrease in the active (23% versus 16%), somnolence (14% versus treatment group was statistically significant. 4%), nausea (14% versus 5%), asthenia (13% The difference in the proportion of active versus 6%), and vertigo (11% versus 4%). treatment patients who achieved ≥30% The primary outcome measured was improvement (40.0%), compared with change in 11point patient-reported controls (21.9%), was also statistically spasticity scale. The estimated treatment significant. There was a trend of greater difference in decreased mean spasticity reduction in spasm frequency in the active scores, though favoring the active treatment group, but the difference lacked treatment group, did not reach statistical statistical significance. Serious adverse significance. When analysis was limited to effects were equally common in the two the 79% of participants who fully followed groups. Mild and moderate CNS effects the study protocol, the difference was (dizziness, impaired balance, disturbance in statistically significant. Among the active attention and blurred vision) were more treatment patients who achieved reduction common in the active treatment group, in spasticity score of at least 30% at any with 32% experiencing dizziness. Eight time, 98, 94, and 73% reported patients withdrew because of side effects, 6 improvements of 10, 20, and 30% from the active treatment group and 2 from respectively within the first 4 weeks. the placebo group. Eltayb A, Etges T, Wright S. An Collin C, Ehler E, Waberzinek G, et al. A observational postapproval registry study doubleblind, randomized, placebo- of patients prescribed Sativex. Results controlled, parallelgroup study of Sativex, from clinical practice (abstract no. P1041). in subjects with symptoms of spasticity Mult Scler. 2013;19(suppl 11):480. due to multiple sclerosis. Neurol Res 2010;32:451-459. All who prescribe Sativex (nabiximols) in the UK are contacted and In this multicenter, randomized, double- asked to participate in a safety registry blinded, parallel group trial 337 MS patients maintained by the manufacturer, GW with spasticity not fully relieved with Pharmaceuticals. This abstract presents current anti-spasticity medication were interim results. Physicians representing 687

39 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS of 2335 different patients prescribed other. At the final visit, the driving test Sativex (29%) participated. Median dose battery and spasticity measures were was 4 sprays per day; dosing considerably performed again along with recording for lower than used during clinical trials. 26% AEs that were experienced by patients from of patients had stopped taking Sativex. Sativex administration. Conclusions: on average, spasticity had been present for 6.7 The most common adverse events were: years with 39.4% of them concurrently fall (4.9%), depression (3.3%), and dizziness taking other spasticity treatment drugs. (1.9%). The mean dose of Sativex at the end of the study was 5.1 sprays (13.8 mg THC, 12.8 mg Freidel M, Tiel-Wilck K, Schreiber H, CBD). While a proportion of patients were Prechtl A, Essner U, Lang M. Drug-resistant considered unfit to drive at baseline, results MS spasticity treatment with Sativex add- showed that the proportion of those unfit on and driving ability. Acta Neurologica to drive did not change at the end of the Scandinavica 2015; 131: 9-16. study. All of the driving ability measures in the test battery did not show a significant This prospective, multicenter () change from baseline to final visit except non-interventional, open-label pilot study for the stress tolerance determination test investigated the effects of Sativex on 1) (DT). There was increased performance on driving ability, 2) spasticity, and 3) adverse DT at final visit than at baseline (it measures events (AEs). Thirty-three MS participants “attention and individual reaction time in with treatment-resistant (moderate to situations requiring continuous, swift and severe) spasticity started on Sativex as an varying responses to rapidly changing visual add-on therapy. Two dropped out due to and acoustic stimuli”; increase on this mild to moderate AEs), leading to n=31 (33- measure was not explained nor predicted a 68 years old) completing this 4-6 week priori). Overall, the authors interpreted the study. Patients started off with a two-week driving results as indicating that Sativex dose titration phase and were allowed to go does not contribute to any significant up to 12 sprays per day. At baseline, the declines in driving ability. Furthermore, following were administered: 1) driving average spasticity NRS self-rating scores ability test battery (Schuhfried-Wiener showed a significant decrease from baseline Testsystem) consisting of 5 driving-related to final visit by 2.4 points (6.0 pts at measures, and 2) MS spasticity measures baseline to 3.6 pts at final visit). In addition, (self-rated NRS of spasticity and physician there was a reported drop in patients rating of spasticity). While a strict ‘fit to categorized as suffering from ‘severe drive’ criterion is when a participant scores spasticity’ as reported by the patients’ above the 16th percentile on all 5 driving physicians (7 patients at baseline down to 1 measures, they also discussed Germany’s at the final visit). Lastly, 13% of patients (4 more flexible approach to driving fitness out of 31 patients) experienced non-serious that is occasionally applied to drivers. AEs (dizziness being the most commonly Specifically, if a participant scores below the reported). 16th percentile on a driving measure, they have to perform at 50% or higher to compensate for their low score on the

40 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Garcia-Merino A. Patients perceived a significant reduction in modulator use in everyday clinical practice pain at day 1 compared to baseline. A in the UK and . Expert Rev Neurother second dose-setting study using rectally 2013;13(3 suppl. 1):9-13. administered dronabinol had to be curtailed at 7 patients because of supply problems, This article is a short description and report but the daily dose achieved after dosing of interim analysis of the UK and Spanish adjustment for those 7 patients was 43 mg Sativex registries to monitor safety and (range 20-60 mg). The planned six-week effectiveness. Interim analyses suggest placebo controlled trial was carried out, but benefits are maintained over long term use because of a large difference in baseline and no new safety signals were seen with spasticity scores in the active treatment and long term use – beyond what has been seen placebo groups, planned analyses of in published clinical trials. differences in results between these groups were not conducted. Instead, results for Hagenbach U, Lux S, Ghafoor N, Berger JM placebo patients from this trial were et al. The treatment of spasticity with compared with results for patients from the delta-9tetrahydrocannabinol in persons dose-setting trial. Compared with placebo with spinal cord injury. Spinal Cord patients, there were large, statistically 2007;45:551-562. significant reductions in clinician assessed spasticity scores in the actively-treated A small double-blinded, placebo-controlled (dose setting) patients throughout the six six week trial of dronabinol (synthetic delta- week period. Patient assessments of 9-THC), preceded by a dose-setting six week spasticity and pain showed significantly study in the same patients, conducted at a lower pain at day one for the actively Swiss center. In the dose-setting study 25 treated patients, but the difference adults with spinal cord injury (11 paraplegic, narrowed and became non-significant as 14 tetraplegic) had their anti-spasticity the study period progressed. drugs discontinued for three half-lives and were then started on dronabinol with a Koehler J, Feneberg W, Meier M, et al. single 10 mg dose the first day. Titration Clinical experience with THC:CBD was individualized without set protocol, oromucosal spray in patients with multiple with the goal of balancing maximal sclerosis-related spasticity. Int J Neurosci effectiveness with side effects. Outcomes 2014;124(9):652-656. studied at days 1, 8, and 43 included clinician-assessed Ashworth spasticity Retrospective chart review of all multiple score, patient-reported numerical rating sclerosis patients at one German clinic who scales of spasticity, pain, attention, mood, were started on nabiximols between and side effects, and more. 15 patients September, 2011 and January, 2013. completed the six weeks: four dropped out Nabiximols is an oromucosal cannabis because of increased pain and the other 6 extract spray developed by GW because of anxiety and other side effects. Pharmaceuticals in Germany. The whole Mean dose achieved was 31 mg/day in plant extract is highly standardized, divided doses (range: 15 mg to 60 mg). produced from cloned cannabis chemovars

41 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS grown under controlled conditions. Each THC and codeine both had an analgesic 100 µliter actuation yields 2.7 mg delta- effect in comparison with placebo. Only 9THC and 2.5 mg of CBD with these two THC showed a significant beneficial effect cannabinoids constituting at least 90% of on spasticity. In the dosage of THC used no cannabinoid content. Of the 166 patients altered consciousness occurred. studied, 46 discontinued nabiximols therapy: 23 (13.9%) because of adverse Novotna A, Mares J, Ratcliffe S, et al. A effects (dizziness, fatigue, oral discomfort), randomized double blind placebo- 14 (8.4%) because of lack of efficacy, and 9 controlled, parallel group, enriched design (5.4%) for other reasons. The 120 who study of nabiximols (SATIVEX) as add-on continued therapy 95 received nabiximols therapy in subjects with refractory in addition to other anti-spasticity spasticity caused by multiple sclerosis. Eur medications and 25 received it as mono- J Neurol 2011;18:11221131. therapy (prior antispasticity medications had not been tolerated or were ineffective Multi-center, double-blind randomized, and had been discontinued). The 120 placebo-controlled parallel group study in patients achieved a 57% mean reduction in subjects with multiple sclerosis spasticity spasticity as measured on the 0-10 not fully relieved with current anti- numerical rating scale. Response to the spasticity therapy. Subjects were treated nabiximols usually occurred within 2 weeks, with nabiximols as add-on therapy in a suggesting that treatment can be single-blind manner for 4 weeks, after discontinued promptly in nonresponders. which those achieving an improvement in Mean dosage was 4 sprays per day with a spasticity of 20% or more as measured by range of 1 to 12 sprays per day, the self-reported 0-10 numerical rating emphasizing the need to individualize scale progressed to a 12-week randomized therapy. phase. Of the 572 subjects enrolled 272 (48%) achieved >=20% improvement and Maurer M, Henn V, Dittrich A, and were randomized for 12 weeks of Hoffmann A. Delta-9-tetrahydrocannabinol treatment. Most subjects were taking anti shows anti-spastic and analgesic effects in spasticity medications. The purpose of this a single case double-blind trial. Eur Arch design was to determine efficacy and safety Psychiatry 1990;240:1-4. of nabiximols in a way that more closely reflects likely clinical practice by limiting Following a dosing study, one patient with exposure to those patients who appear to spinal cord injury (paraplegia) and leg attain benefit during the first few weeks of spasticity and pain despite routine treatment. Subjects self-titrated during the medications, entered a trial to determine first ten treatment days according to a pre- effect of delta-9-THC versus codeine versus defined escalation scheme (not further placebo. At 18 times over 5 months he defined) to their optimum dose, balancing took by capsule, in randomized order, 5 mg effectiveness and side effects, to a THC (source not specified), 50 mg codeine, maximum of 12 sprays per 24 hour period. or placebo at the evening time when he During the first 4-week phase mean number regularly took codeine. Results showed of daily sprays was 6.9. In the 12-week

42 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS phase mean number of sprays was 8.3 for assessing ratings of effectiveness over time. active treatment subjects. Mean change in The initial trial studied effectiveness of NRS scale for all subjects during the first 4 nabiximols in multiple sclerosis patients week phase was decrease of 3.01 units whose spasticity was not adequately (change from 6.91 to 3.9). Half of those not controlled with standard drugs. Nabiximols randomized had an improvement of <5%. is an oromucosal cannabis extract spray Over the course of the 12 week second developed by GW Pharmaceuticals in phase, mean spasticity score improved in Germany. The whole plant extract is highly the active treatment group by another 0.04 standardized, produced from cloned points from a baseline of 3.87. The placebo cannabis chemovars grown under group worsened (increased) by 0.81 from a controlled conditions. Each 100 µliter baseline of 3.92. The estimated treatment actuation yields 2.7 mg delta-9THC and 2.5 difference between the two groups in mean mg of CBD with these two cannabinoids spasticity NRS was 0.84 points (CI: -1.29 to - constituting at least 90% of cannabinoid 0.40; P = 0.0002). A secondary outcome content. Among the 146 patients who measure during the second phase was participated in the extension study 68% spasm frequency, which saw a small were taking additional anti-spasticity decrease in the active treatment group and medications. Patients self-titrated an increase in the placebo group. The nabiximols dose upward using a pre-defined difference between the two groups was scheme that limited increases to 50% of the reported as being statistically significant. previous day’s dose with a maximum of 8 Across both phases, 3 subjects withdrew actualizations in any 3 hour period and 48 because of side effects. Two serious actualizations during a 24 hour period. The treatment-related adverse events occurred level of spasticity severity was rated each and both resolved rapidly after treatment week with a 0-10 numerical rating scale. discontinuation. Adverse events that Within the first 12 months of observation appeared to occur at higher rates in the 20 patients (14%) withdrew because of side active treatment group include vertigo, dry effects. Another 3 patients, among those mouth, nausea, dizziness, somnolence, and followed for more than a year, withdrew urinary tract infection. because of side effects. Serious adverse events that were considered treatment- Serpell MD, Notcutt W, Collin C. Sativex related included two cases of ‘pneumonia long-term use: an open-label trial in aspiration,’ and one case each of ‘ patients with spasticity due to multiple function tests abnormal,’ ‘convulsions,’ sclerosis. J Neurol 2013;260(1):285-295. ‘dizziness,’ ‘paresthesia, ‘tremor,’ ‘nausea,’ ‘delusion perception,’ and ‘paranoia.’ This study is an extension of the study Minor and moderate side effects occurred reported in Collin 2007. Its primary among nearly all patients with dizziness and objective was to assess the safety and fatigue most common. Among 90% of tolerance of long-term therapy with patients some additional improvement in nabiximols. Its secondary objective was to spasticity – beyond that observed in the determine whether there was evidence of original 6 week study – for approximately 8 tolerance with long-term nabiximols use by

43 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS weeks, with maintenance of the improved Following all these measures, there was a 2- status for the duration of observation. week washout period after which time participants crossed over into the other Tomassini V, Onesti E, Tinelli E, Frasca V, condition for a 3-week period (same Antonilli L, Aragona M, et al. Assessing the measures were collected again after this Neurophysiological Effects of Cannabinoids crossover treatment period, and it was on Spasticity in Multiple Sclerosis. Journal followed by another 2-week washout of Neuroscience and Rehabilitation period). Conclusions: the median number 2014;1(2):1-13. of daily sprays were 7.4 with Sativex (20 mg THC, 18.5 CBD) and 16.1 with placebo. Authors cited some research evidence Mean plasma concentrations for THC was suggesting that cannabinoids have actions 1.84 ng/ml and for CBD was 2.13 ng/ml at on the brain that are not specifically tied to the end of the Sativex treatment condition actual stimulation of cannabinoid receptors, (THC/CBD was not detected at the end of specifically relating to changes in cortical placebo treatment). Compared to placebo, excitability in motor areas. Therefore, if Sativex treatment was not any better at Sativex leads to decreases in MS-related improving spasticity symptoms. In addition, spasticity, they decided to investigate for an there was no difference in cortical motor associated change in cortical motor regions activation (based on fMRI and TMS results) via fMRI and TMS. Twenty cannabis-naïve between Sativex and placebo. And there MS participants initially started out in this was no correlation between THC/CBD randomized, double-blind, placebo- plasma levels and the neurophysiological controlled crossover study, with eighteen measures. They suggest that the failure to (n=18) eventually completing the study (10- find a neurophysiological correlate be week study). Baseline measures were: 1) indicative of cannabinoids not heavily EDSS, 2) Ashworth Scale, and 3) NRS of influencing the motor system. Rather, they spasticity. Participants were randomly suggest that cannabinoids’ actions might assigned to either a 3-week Sativex or somehow modulate “the painful placebo condition, during which time components of spasticity”. Overall, while subjects were instructed to complete a study results suggest Sativex’s lack of effect symptom diary along with their daily usage on spasticity and modulation of motor (# of sprays) of treatment. After the 3-week regions, limitations in the study itself make treatment, the following were measured in their conclusions harder to interpret. participants 1) neurophysiological measures (fMRI and TMS), 2) clinical assessments, and Vaney C. Heinzel-Gutenbrunner M, Jobin P, 3) THC and CBD plasma measures. FMRI et al. Efficacy, safety and tolerability of an and TMS data were collected during drug orally administered cannabis extract in the steady state concentrations (generally treatment of spasticity in patients with within 3 hours of the last treatment intake). multiple sclerosis: a randomized, double- During the fMRI scan, participants engaged blind, placebo-controlled, crossover study. in a motor task. TMS was delivered in a Mult Scler 2004;10:417-24. region within left M1 (primary motor cortex) to optimally induce first dorsal interosseous muscle contractions.

44 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Randomized, double-blind, placebo- significant. Spasm frequency reduction was controlled cross-over parallel group study greater for early active treatment group of 50 Swiss multiple sclerosis patients. patients who tolerated a significantly higher Patients were randomized to early group or THC dose (mean 15 mg/day versus 10 late group active treatment. Active mg/day). No serious adverse events were treatment was a cannabis whole plant observed, but three patients dropped out of extract containing 2.5 mg THC and 0.9 mg the early treatment group because of side CBD in a capsule. A five day dose titration effects. Adverse events were only slightly phase increased starting dose of six active more common and more severe during capsules daily (equivalent to 15 mg active treatment. THC/day) by two capsules per day with the maximum daily dose of 12 active capsules Wade DT, Robson P, House H, et al. A daily (equivalent to 30 mg THC/day). After preliminary controlled study to determine 14 days of active treatment patients were whether wholeplant cannabis extracts can switched to placebo capsules without improve intractable neurogenic symptoms. tapering the active dose. Patients received Clin Rehabil 2003;17:2129. the same number of total capsules each day, but the ratio of active drug capsules to A small placebo-controlled crossover trial of placebo capsules varied. Patients in the nabiximols (Sativex) on patients with early active treatment group stayed on neurological disorders and troublesome placebo 7 days before initiating active symptoms. Twenty four patients with a treatment. Outcome measures included variety of neurologic disorders enrolled and daily self-report of spasm frequency and 20 completed the study (14 with multiple symptoms, clinician-assessed Ashworth sclerosis, 4 with spinal cord injury, and one Scale of muscle tone, Rivermead Mobility each with brachial plexus lesion with Index, and others. The daily self-report of neuropathy and an amputated leg with spasm frequency had the patient record phantom limb pain). The symptoms varied; spasm frequency five times per day, asking 16 had muscle spasm as a symptom. about the most recent four hours. Patients first had a two week open-label Response categories were: 0=no spasms, 1= trial with nabiximols with instructions to 1 to 3 spasms, 2 =4 to 6 spasms, 3 = >6 increase frequency of sprays, balancing spasms. The maximal tolerated dose was 15 symptom relief with side effects up to a mg THC or less for half the patients and maximum of 8 sprays within 70 minutes. there was a weak but significant correlation Because of side effects this was changed to between mean dose during the 2 week four sprays over 2 hours and changed again dose maintenance phase and body weight. to two sprays over two hours. After the Results showed no effect on Ashworth Scale two week open-label trial the patient measurement and a non-significant trend entered an eight week double-blind study for spasm frequency. When analysis was phase with four two-week stages using limited to the 37 patients who received at nabiximols, or CBD alone or THC alone or least 90% of their prescribed doses (“as placebo. Results were not reported broken treated” set), the observed treatment in out by neurologic condition. Across all 20 spasm frequency was statistically patients, spasticity severity had a

45 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS statistically significant reduction on objective (Ashworth scale) measures of nabiximols, CBD alone, and THC alone, spasticity, compared to the placebo group. compared with placebo. Spasm frequency No significant difference in symptom scores saw statistically significant reduction while between groups was found for spasms, on nabiximols and THC alone, but not while pain, tremor, bladder control, or a on CBD alone, compared with placebo. composite symptom score. Side effects Occurrence of side effects was similar that occurred more often in the active across the four treatment conditions during treatment group included dizziness, the placebo-controlled phase and disturbance in attention, fatigue, substantially higher during the initial open- somnolence, disorientation, vertigo, label nabiximols treatment phase. diarrhea, and mouth ulceration.

Wade T. et al. Do cannabis-based Wade DT, Makela PM, House H, et al. medicinal extracts have general or specific Long-term use of a cannabis-based effects on symptoms in multiple sclerosis? medicine in the treatment of spasticity and A double-blind, randomized placebo- other symptoms in multiple sclerosis. Mult controlled study on 160 patients. Mult Scler 2006;12(5):639-645. Scler 2004; 10:434-441. Patients who completed the study reported A randomized, double-blind, placebo- in Wade 2004 and reported receiving controlled, parallel group trial of nabiximols benefits from the 10 weeks of active (Sativex) for patients with multiple treatment were offered the opportunity to sclerosis. 160 patients from 3 UK centers participate in a long-term follow-up study. were enrolled and indicated whether their The purpose of the study was to assess primary symptom was spasticity, spasms, whether symptom reduction achieved at 10 bladder problems, tremor, or pain not weeks of treatment was maintained over obviously musculoskeletal. Intensity of the long term and to further assess adverse each symptom was self-rated on a 100 mm events. 137 choose to participate. The visual analog scale throughout the study. mean duration of study participation in Patients were randomized to nabiximols or subjects who entered the follow-up study placebo for the initial six week double-blind was 434 days (range: 21-814 days). The trial and told to titrate slowly during home average number of daily doses taken by the dosing, aiming for optimal balance between subjects remained constant or was slightly symptom relief and side effects, but not to reduced over time. The average number of exceed 120 mg THC (44 sprays) per day or daily doses of nabiximols was 11 (30 mg 20 mg THC (7 sprays) within a 3 hour THC/28 mg CBD) per day. Results indicated period. Average number of sprays per day patients with MS who derived symptom in the active treatment group increased relief within 10 weeks of nabiximols steadily over three weeks and then treatment generally sustained that plateaued at 14 to 16 sprays per day (38 to symptom relief over an extended period 43 mg/day THC; 35-40 mg/day CBD). without increase in dose. Side effects were Subjects receiving nabiximols showed generally minor, but 17 patients withdrew improvement in subjective (VAS), but not because of side effects.

46 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Zajicek J, Fox P, Sanders H, et al. category-rating scales – each given at the Cannabinoids for treatment of spasticity end of the study to patients with those and other symptoms related to multiple symptoms at the beginning of the study. sclerosis (CAMS study): multicentre The patients were asked to compare their randomized placebo-controlled trial. symptoms over the past week with how Lancet 2003;362:1517-26. they were just before the study started. Symptoms surveyed included: irritability, Randomized, placebo-controlled clinical depression, tiredness, muscle stiffness, trial involving 630 adult patients with all tremor, pain, sleep, muscle spasm, and forms of multiple sclerosis from 33 UK amount of energy. Results showed no medical centers. Subjects were randomized treatment effect on the primary outcome. to cannabis extract (n=211), dronabinol Compared to the placebo group, the active (synthetic delta-9-THC; n=206) or placebo treatment groups showed significant (n=213). The cannabis abstract was improvement in pain, sleep quality, spasm, Cannador – registered trademark – and spasticity, though no effect was noted manufactured to contain 2.5 mg of delta-9- with respect to irritability, depression, THC and approximately 1.25 mg CBD and tiredness, tremor, or energy. Improvement less than 5% other cannabinoids in each in these categories was similar among capsule. The dronabinol capsules patients taking cannabis extract and those contained 2.5 mg delta-9-THC. The trial taking dronabinol, with approximately half included a five week titration phase, 8 reporting improvement in each of these weeks of maintenance treatment and categories. Numbers of serious adverse weaning off treatment over several days. events were similar across the three Subjects started with one capsule twice treatment groups, with slightly more events daily and were instructed to increase the in the placebo group. Dizziness or dose by one capsule twice daily at weekly lightheadedness, dry mouth and diarrhea intervals. If side effects developed subjects were more common among both active were advised to not increase the dose and if treatment groups. Constipation was more the side effects were considered intolerable common in the cannabis extract group. the dose was reduced. Target daily dose varied with patient weight: 4 capsules (10 Zajicek JP, Sander HP, Wright P, et al. mg THC) for 30-49 kg, 6 capsules (15 mg Cannabinoids in multiple sclerosis (CAMS) THC) for 50-69 kg, 8 capsules (20 mg THC) study: safety and efficacy data for 12 for 70-89 kg, and 10 capsules (25 mg THC) months follow up. J Neurol Neurosurg for >89 kg. Achieved dosages were not Psychiatry 2005;76:16641669. described. Primary outcome measure was change in spasticity as measured by the At the end of the 13 week CAMS study, clinician-assessed Ashworth scale. subjects were given the option of Secondary measures included the continuing treatment, at their previously Rivermead mobility index (a timed walk) the determined dose, for a total of 52 weeks. UK neurological disability score (UKNDS), Participation was as follows: cannabis the Barthel index (an index score related to extract group – 138, dronabinol – 125, activities of daily living) and a series of nine placebo – 120. Results showed a small treatment effect on the change in Ashworth

47 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS score (spasticity). Responses to category titration phase and a 10 week maintenance response scales, comparing symptoms at 52 phase. Total treatment duration was 12 weeks to those symptoms before treatment weeks. Participants were assessed at 2, 4, began showed significant improvement in 8, and 12 weeks after start of treatment. active treatment groups, compared to Starting dose was 2.5 mg THC (one capsule) placebo, in pain, shaking, spasms, spasticity, twice daily. Subsequent doses were sleep, energy, and tiredness, but not in individually titrated upwards by 5 mg depression or irritability. All hospital THC/day every 3 days for up to 12 days to admissions were classified as serious optimize the balance between therapeutic adverse events and similar numbers effect and side effects. Maximum total occurred across the three treatment allowable daily dose was 25 mg THC. In the groups. event of intolerable side effects, the daily dose was reduced by one capsule until the Zajicek JP, Hobart JC, Slade A, Barnes D, side effect(s) resolved. After resolution, Pattison PG, on behalf of the MUSEC one re-challenge with a further dose Research Group. Multiple Sclerosis and escalation was required. If the side effect(s) Extract of Cannabis: results of the MUSEC returned, the dose was reduced again, with trial. J Neurol Neurosurg Psychiatry no further re-challenge allowed. The 2012;83:1125-1132. primary outcome measure was perceived change in muscle stiffness after 12 weeks of Double-blind placebo controlled study of treatment compared with the 279 patients age 18-64 with MS by premedication phase. At the final visit, McDonald criteria, stable disease for the participants answered the following last 6 months and troublesome and ongoing question on a symptom questionnaire: muscle stiffness for at least 3 months “Compared with before the study started, before enrollment (as shown by a current my muscle stiffness over the last week has disability score of at least 4 on an 11 point been …” providing a rating on an 11 point category rating scale (CRS) at 22 UK numerical scale where 0=very much better, centers). Treatment = 144, placebo = 135. 5= no difference and 10=very much worse. Physiotherapy regimens or medications Categories 0-3 of the rating scale were likely to affect spasticity were adjusted classified as ‘relief of muscle stiffness’ – where necessary and then not altered in that is, as a clinically relevant response. the 30 days before study start. Patients Secondary measures included relief from with active sources of infection or taking body pain, muscle spasms and sleep immunomodulatory drugs that might affect disturbance using 11 point scales. Also, the spasticity (e.g. Beta-interferon, but not validated disease specific multi-item rating azathioprine) were excluded. Active scales measuring aspects of spasticity in MS treatment was an extract of Cannabis sativa (MS Spasticity Scale (MSSS-88), and other L (extraction 96%) in soft gelatin scales including Expanded Disability Status capsules, standardized on cannabidiol Scale (EDSS). Main result: proportion with (range 0.8-1.8 mg) and containing 2.5 mg self-reported relief from stiffness was delta-9 THC as the main cannabinoid higher by a statistically significant amount (CANNADOR). The study consisted of a compared to the placebo group (29.4% vs. screening period of 1-2 weeks, 2 week dose

48 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

15.7%; OR=2.6 95%, CI = 1.24-4.13). are similar to two other studies that Proportion of patients with relief of body showed significant reduction in spasticity pain (0-3 on 11 point scale) was higher by a using an 11 point rating scale (Novotna statistically significant amount at each time 2011; Colin 2007). of measurement (44% vs. 18% at week 12). At the end of the titration period Zajicek J, Ball S, Wright D, Vickery J, et al. approximately 87% of participants in the Effect of dronabinol on progression in placebo group were taking the maximum progressive multiple sclerosis (CUPID): a daily dose of 25.0 mg. In contrast, only 47% randomized, placebocontrolled trial. of participants in the active treatment Lancet Neurol 2013;12(9):857865. group had titrated up to a maximum daily dose of 25.0 mg. Of the active treatment Multi-center (UK), randomized, double- patients who did not achieve the maximum blind, placebo-controlled three year study daily dose, most were taking daily doses of of the effect of dronabinol (synthetic delta- 10.0 to 15.0 mg. Sixteen participants in the 9-THC) on MS disease progression. 493 active treatment group discontinued study subjects age 18-65 with primary or medication during titration, compared with secondary progressive multiple sclerosis. four in the placebo group. At the end of the Dronabinol was initiated at a starting dose study, only 24.5% of the active treatment of one capsule (3.5 mg THC) twice daily. group was taking the 25.0 mg dose. By the Participants were instructed to increase end of the study, 84% of all patients their twice-daily dose by one capsule twice experienced at last one treatment daily (i.e. first increase = 7.0 mg twice daily) emergent adverse events: 98% in active at weekly intervals. If adverse effects treatment group and 74.6% in the placebo appeared, participants were advised to not group. 23.8% in the active treatment group increase the dose; if unwanted side-effects and 14.9% % in placebo group were were intolerable, dose was reduced. withdrawn from the study or discontinued Maximum daily dose varied by weight: < 60 study medication due to adverse events. In kg = 14 mg/day, 60-80 kg = 21 mg/day, >90 the active treatment group adverse events kg = 28 mg/day. Primary outcomes were were highest during titration and decreased time to disease progression as measured by continuously over the course of the study. the expanded disability status scale (EDSS) Adverse events that occurred at clearly and change from baseline to end of study in higher rates in the active treatment group the physical impact subscale of the patient- than in the placebo group were dizziness, reported 29-item MS impact scale (MSIS). disturbance in attention, balance disorder, Secondary measures outcomes included somnolence, dry mouth, nausea, diarrhea, adverse events, MS functional composite fatigue, asthenia, feeling abnormal, urinary (MSFC) Z score change from baseline to tract infection, disorientation, confusional final visit, MS walking scale (MSWS-12) and state, and fall. The relatively rapid titration Rivermead Motility Index. Subjects were was done for technical study reasons – in reviewed after 2 weeks and 4 weeks from clinical practice it is not likely to be done so when they began taking the study drug for rapidly. Results in this study confirm results adverse event screening and drug in the CAMS study, which was larger, and monitoring and dose adjustment.

49 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Assessment visits were held at 3 months, 6 Fred Konikoff; Responsible party: Timna months, and then every 6 months to 36 Naftali. Both from Meir Hospital, . months. Results showed no overall (clinicaltrials.gov NCT01037322) treatment effect on clinical disease course. And results showed little evidence of an This small double-blind, placebo-controlled effect of treatment on MSFC, MSWS-12 or trial was completed in September, 2012, RMI. Serious adverse events (life but it has not yet been published. It threatening event, hospitalization, death) anticipated recruiting 20 patients 20 years were common, with no significant and older with a Crohn’s Disease Activity difference between treatment (35%) and Index (CDAI) of 200 or greater or Mayo placebo (28%) groups. Moderate adverse Score > 3 in ulcerative colitis. Prior use of effects were common in both groups. marijuana was not an exclusion criterion. Those that occurred in the treatment group The methodology calls for patients to be at a significantly higher frequency than in randomized to CBD (5 mg CBD in olive oil the control group were dizziness and drops, sub-lingual, twice per day,) or to lightheadedness (32%) and dissociative and placebo drops, for eight weeks of thinking or perception disorders (30%). treatment. Primary outcome: reduction of 70 points on CDAI. Secondary outcomes: change in quality of life score, adverse events.

Crohn’s Disease “Combined THC and CBD Drops for Treatment of Crohn’s Disease” Principal One small clinical trial using smoked Investigator: Timna Naftali, Meir Medical cannabis has been published, showing Center, Israel. (clinicaltrials.gov symptom reduction during the time of NCT01826188) cannabis use. No clinical trials or prospective clinical studies of cannabis This double-blind, placebo controlled trial is extract products or now in recruitment, with an estimated have been published Two trials in progress completion date of March, 2015. It or recently completed (and not yet anticipates enrolling 50 patients age 20 years or older with Crohn’s Disease Activity published) have emphasized CBD, but with Index (CDAI) of 200 or more. Prior use of somewhat different approaches. The trial marijuana is not an exclusion criterion. now recruiting patients (clinicaltrials.gov Patients will be randomized to THC plus NCT01826188) is using capsules with 5 mg CBD (5 mg THC and 50 mg CBD in olive oil, THC and 50 mg CBD in olive oil, twice daily. twice daily) or placebo for eight weeks of The study that is completed but has not yet treatment. Primary outcome: reduction of been published (clinicaltrials.gov CDAI of at least 100 points. Secondary NCT01037322) used 5 mg CBD in olive oil outcomes: remission of disease, as defined drops, sub-lingual, twice per day. by CDAI <150, improvement of at least 1 point in endoscopic activity index, “Use of Cannabidiol for the Treatment of improvement of CRP and calprotectin Inflammatory Bowel Disease” Study Chair: levels, improvement of blood cytokine

50 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

levels (IL-10, TNF, IL-23), improvement of at cannabis treatment as an adjunct to other least 30 points in SF-36 quality of life pain medications. survey, monitor safety and side effects. Most of the 15 trials summarized here are relatively small (six have >100 participants) and short (only 2 of the controlled trials are Terminal illness longer than 5 weeks) and they are spread across multiple types of pain. These are With a probable life expectancy of under important limitations to their value in giving one year, if the illness or its treatment understanding of the potential for cannabis produces one or more of the following: products in pain management. The quality severe or chronic pain; nausea or severe of most of the studies summarized in this vomiting; or cachexia or severe wasting section is formally assessed in a report by Relevant studies can be found in other the MN Evidence-based Practice Center sections of this report, particularly the called, “Medical Cannabis for Non-Cancer cancer sections. No published medical Pain: A Systematic Review” cannabis trials were found that specifically http://www.health.state.mn.us/topics/can targeted patients with short life nabis/intractable/medicalcannabisreport.p expectancy, cutting across medical df. Six of the studies assessed in that report conditions. are not summarized here because they used the synthetic cannabinoid nabilone, which is similar to – but distinct from – THC. Intractable Pain Eleven of the 15 trials studied an approximately 1:1 ratio of THC:CBD oro- For the Minnesota medical cannabis mucosal spray (in most cases nabiximols, program intractable pain is defined as pain brand name Sativex) vs. placebo (Blake whose cause cannot be removed and, 2006, Langford 2013, Nurmikko 2007, Rog according to generally accepted medical 2005, Selvarajah 2010, Serpell 2014, Wade practice, the full range of pain management 2004) or 1:1 THC:CBD plus additional active modalities appropriate for the patient has treatment arms of mostly THC extraction been used without adequate result or with product (Berman 2004, Notcutt 2004, intolerable side effects. Trials of cannabis Wade 2003) and mostly CBD extraction for pain in the literature generally follow product (Notcutt 2004, Wade 2003) vs. this definition in that their inclusion criteria placebo. There are also two open-label specify patients with pain inadequately long-term studies of Sativex (Hoggart 2015, controlled with standard pain medications. Rog 2007). Average dose in the clinical The trials uniformly had the participants trials, after the titration period, of the 1:1 continue taking their routine pain THC:CBD spray, the mostly THC spray, and medications, so they assess the value of the mostly CBD spray were all around 6 to

51 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

10 sprays per day, representing a daily dose due to brachial plexus avulsion occurring at of approximately 15 to 27 mg THC and/or least 18 months prior to the start of trial. CBD per day. In the trial studying Symptoms were assessed at baseline and approximately 2:1 THC:CBD capsules were documented in a daily diary. Each (Zajicek 2012) the average daily dose of patient was given a treatment or placebo for 14-20 days before switching arms. THC was similar. In the two long-term open-label studies of Sativex, average daily Patients were provided either placebo or dose was somewhat less, at around 6 to 8 whole-plant extracts oral spray with either sprays per day (Hoggart 2015) and 6.5 to 1:1 THC:CBD (Sativex) or THC alone during 7.5 sprays per day (Rog 2007) representing three 2-week treatment phases. Initially, 16-22 mg THC and 15-20 mg CBD per day. the dosing was monitored in clinic while These long-term studies showed no subsequent doses were self-administered evidence of tolerance developing. Side on a titration schedule with the maximum effects were very common but mostly mild daily doses being 129.6 mg THC or 129.6mg THC/120 mg CBD in 24 hours. Starting dose or moderate in severity. Though a few was 8 to 10 sprays per day (22-27 mg THC). studies using nabiximols reported few or no Forty of the 48 patients were currently participants withdrawing due to side taking pain medication and were instructed effects, several reported withdrawal rates to remain on their current regimen. in the nabiiximols treatment group in the range of 5 to 25%. The primary outcome measure was based on the eleven point Box Scale (BS-11) where Two of the trials studied oral dronabinol, “0” represented the ‘Best Imaginable’ and synthetic THC, vs. placebo (Narang 2008, 10 the worst. The average score during the Svendson 2004). Only one of them last 7 days of treatment was compared to reported an average dose after titration the average during the 7 day baseline, prior (Svendson 2004): 21 patients @ the study to treatment initiation. Secondary maximum of 10 mg/day, 3 patients @ 7.5 outcomes included a patient-reported mg/day, and one patient @ 5 mg per day. rating of pain over a week-long period as well as sleep quality using the BS-11 and Berman JS, Symonds C, Birch R. Efficacy of sleep disturbance based on number of two cannabis based medicinal extracts for nighttime awakenings. Other measures relief of central neuropathic pain from included questionnaires such as the short brachial plexus avulsion: results of a form McGill questionnaire (SF-MPQ), Pain randomized controlled trial. Pain 2004; 112 Disability Index (PDI) and General Health (3): 299-306. Questionnaire-12 (GHQ-12), administered at baseline and again at subsequent visits. This was a randomized, double-blind, Also at each visit, a visual analogue scale placebo-controlled, crossover study (VAS) of intoxication was recorded and at involving 48 patients (46 male) with two visits, a complete physical was intractable pain scoring >4 on an eleven- performed. point scale. Patients were a minimum of 18 years of age (average 39 years) with pain

52 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Forty-five of the 48 enrolled patients The primary endpoint tested was based on completed the study with the main reasons a 0-10 pain scale assessing pain upon for dropout being GI upset, movement each morning and comparing lightheadedness, and anxiety. Pain the baseline rating to the average of the last reduction was greater for each of the two 14 days of the trial. Secondary outcomes treatment arms than for placebo. The were pain at rest, sleep quality, morning number needed to treat was 9.0 (1:1 stiffness and used the Short Form McGill THC:CBD) and 7.7 (THC only) based on a Pain Questionnaire (SF-MPQ) as well as the 30% decrease in pain. Average dose of 28- Disease Activity score (DAS28). All active treatment was approximately 8 outcomes except morning stiffness and SF- sprays per day (22 mg THC).The most MPQ intensity showed a statistically commonly reported side effects were significant improvement when compared to dizziness, somnolence, mild intoxication, GI placebo, including the SF-MPQ pain at upset, and unpleasant taste. present rating. Side effects were approximately twice as common in the Blake DR, Robson P, Ho M, Jubb RW, active treatment group than in the placebo McCabe CS. Preliminary assessment of the group. All but two of the side effects in the efficacy, tolerability and safety of active treatment group were mild or cannabis-based medicine (Sativex) in the moderate; two patients rated side effects as treatment of pain caused by rheumatoid severe (constipation, malaise). The side . Rheumatology 2006;45(1):50-52. effects more common in the active treatment group than in the placebo group This was a double-blind, randomized, were mild dizziness, dry mouth, light- placebo-controlled study carried out for five headedness and fall. Three patients weeks in patients diagnosed with withdrew from the study because of side (RA) that were effects – all 3 from the placebo group. stabilized on traditional therapy but who There were no serious s adverse events in did not gain adequate pain relief from the active treatment group and two in the standard treatments. A total of 58 placebo group. participants (12 male/46 female; average age 62.8 years) met the inclusion criteria Hoggart B, Ratcliffe Sj, Ehler E, Simpson KH, and 31 were randomized to treatment, Hovorka J, Lejcko J, Taylor L, Lauder, while 27 received placebo. The patients Serpell M. A multicenter, open-label, were instructed to limit use to evening follow-on study to assess the long-term dosing to prevent daytime intoxication from maintenance of effect, tolerance and the Sativex oral spray (2.7 mg THC/2.5 mg safety of THC/CBD oromucosal spray in the CBD per 100 μl actuation) that was used management of neuropathic pain. J Neurol throughout the trial. The titration schedule 2015;262:27-40. was one actuation before bed and increase by one actuation every two days, based on This nine month open-label study was a patient response, up to a maximum of six continuation of two parent studies: the actuations per night. clinical trial reported in Serpell 2014 (neuropathic pain associated with allodynia) and an unpublished clinical trial involving

53 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

patients with carried that no increase in dose over the parent out by GW Pharma. 439 participants studies was seen, suggesting no evidence of completed these two studies and were tolerance developing. eligible for the continuation study; 57 (13%) chose not to continue for unspecified Langford RM, Mares J, Novotna A, Vachova reasons. Of the 380 who entered the M, Novakova I, Notcuff W, Ratcliffe S. A extension study, 234 (62%) completed it. double-blind, randomized, placebo- Average nabiximols dose during the two controlled, parallel-group study of parent studies was 8.9 sprays per day THC/CBD oromucosal spray in combination (Serpell 2014) and 9.5 sprays per day (GW with the existing treatment regimen, in the Pharma study). Details on the starting dose relief of central neuropathic pain in of nabiximols spray (2.7 mg THC and 2.5 mg patients with multiple sclerosis. J Neurol CBD per spray) are not provided, but 2013; 260(4):984-997. patients self-titrated during a baseline period, increasing dose by 50% from This was a two-part study involving patients previous day to a maximum of 8 sprays per with a diagnosis of multiple sclerosis (MS) 3 hour period and 24 sprays per 24 hours. made at least three months prior (mean of Mean dose during months 1-9 was reported 11 years with pain an average of 5 years) as 6 to 8 sprays per day. 84% of and stable on prior drug therapies for at participants were on concomitant pain least two weeks. The study drug was an medications and 63% were on two or more. oromucosal spray containing 2.7 mg Primary outcome was pain numeric rating THC/2.5 mg CBD per actuation (spray). scale assessing pain over the past week, Patients were allowed up to 12 sprays/24 completed at parent study baseline and hours. completion and at baseline and weeks 2, Phase A: double-blind, randomized, 14, 26, and 38 of the extension study. At placebo-controlled, parallel-group study the beginning of the extension study just over 14 weeks with a week of baseline over half of participants had reduction in titration and observation. A total of 339 pain score of 30% or greater (i.e. during patients (109 male/ 230 female; average parent study) and during the nine month age 49 years; treatment arm = 167/placebo extension trial this proportion gradually = 172) were enrolled and response to increased to approximately 60%. 78% of THC/CBD, in addition to standard participants had at least one adverse event treatments was evaluated using pain levels and 59% were judged to have had a on a 0-10 scale. The average number of treatment-related adverse event. Four sprays was 11.1 for placebo compared to serious adverse events were reported, two 8.8 for THC/CBD. The primary endpoint was patients experiencing amnesia, one event of reduction of pain by 30% using a 0-10 scale, paranoia, and one attempt. and secondary endpoints were sleep Dosages of nabiximols being used when quality, Brief Pain Inventory-Short Form, these occurred were not reported. 23% of and Subject Global Impression of Change. participants permanently ceased nabiximols because of adverse events. The authors At the end of Phase A the small benefits in comment in the Discussion section note pain reduction favoring the treatment

54 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

group did not meet statistical significance, withdrawal phase of the trial and only one nor did any of the secondary endpoints. withdrew from the placebo withdrawal Seventy-five percent of treatment patients group due to adverse events. Time to and 62% of placebo patients reported at treatment failure was significantly increased least one adverse event during phase A. in the THC/CBD group versus placebo and Adverse events at least twice as common in the probability of treatment failure was the treatment patients than in control statistically increased in the placebo group. patients were: vertigo, vision blurred, The decrease in average pain using 0-10 nausea, fatigue, feeling abnormal, dizziness, scale was statistically significant in favor of somnolence, disturbance in attention, the treatment when compared to placebo dysgeusia, and memory impairment. Thirty- at the end of the phase B treatment period; five patients (10%) in phase an experienced the same was true for sleep quality. All a severe treatment-emergent adverse other secondary endpoints favored event, 21 (13%) in the THC/CBD spray group THC/CBD, but not significantly. The most and 14 (8%) in the placebo group. Five common AEs noted were dizziness/vertigo, patients (3%) in the THC/CBD spray group fatigue/somnolence, and GI complaints. and three (1%) in the placebo group permanently stopped study medication due Narang S, Gibson D, Wasan AD, Ross EL, to severe adverse events. Dosages at which Michna E, Nedeljikovic SS, Jamison RN. severe adverse events were experienced Efficacy of dronabinol as an adjuvant were not described. treatment for chronic pain patients on opioid therapy. The Journal of Pain Phase B: 14-week, open study with two 2008;3:254-264. weeks re-titration to maximum of 12 sprays/24 hours. Participants then This study was done in two phases: a proceeded to 12 weeks of stable dosing, double-blinded, randomized, 3-treatment, followed by a 4-week, randomized 3-period, single-dose crossover trial (phase withdrawal period. To enter this phase, 1) followed by a 4 week open-label, multi- patients were required to use at least three dose extension study (phase 2). Subjects in sprays per day for the previous seven days the study had been taking stable doses of and had proven tolerability and stability opioids for pain for at least 6 months and with other medications. The average had pain of at least 4 on a 10-point scale. number of sprays used during phase B was Subjects were excluded for unstable 6.7. Primary endpoint was treatment failure psychiatric disorders or significant during withdrawal and secondary endpoints depression and/or anxiety. In phase 1 were sleep quality, Brief Pain Inventory- subjects each received identically appearing Short Form, and Subject Global Impression placebo, 10 mg or 20 mg dronabinol of Change. capsules in 1 of 6 randomly allocated sequences. The 3 treatment options were Fifty-eight patients (21 male/37 female; separated by a minimum of 3 days between average age 48 years) entered phase B and visits. Thirty patients with a variety of types five withdrew (3 due to adverse events). of pain were enrolled in phase 1; one Forty-two patients (17 male/25 female; dropped out because of inability to average age 48 years) entered the concentrate (10 mg dronabinol). Total pain

55 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

relief at 8 hours in Phase 1 was found to be particularly as an adjunct medication for significantly greater in subjects receiving patients with non-cancer pain on opioid both the 20 mg and the 10 mg dronabinol therapy. “Although this study was not treatments compared with placebo. Side described to address problems that may effects were more frequent with 20 mg arise from the long-term use of THC, than with 10 mg dronabinol. For both, and psychosis are known risk most common side effects were factors that must be considered before a drowsiness, sleepiness, dizziness, dry cannabinoid can be offered as part of a mouth. All were clearly more common with treatment regimen.” dronabinol than placebo except for sleepiness. All resolved within 2 hours Notcutt W, Price M, Miller R, Newport S, except for sleepiness and drowsiness, which Phillips C, Simmons S, Sansom C. Initial each lasted 2 to 3 hours. The authors with medicinal extracts of considered side effects for two subjects cannabis for chronic pain: Results from 34 “adverse events:” one subject reported ‘N of 1’ studies. Anaesthesia 2004;59(5): anxiety, tremors, dizziness, and inability to 440-452. concentrate that resolved within 3 hours. The second occurred in a subject who The extracts used in this study were from reported high anxiety and dizziness that cloned plants with standardized levels of lasted for the duration of the treatment active ingredients prepared as either an day. Both events occurred in subjects who aerosol or pump-action spray where each received 20 mg of dronabinol. No one actuation delivered either 2.5 mg THC or reported any psychosis or hallucinations CBD or 2.5 mg 1:1 of both THC:CBD. All 34 during phase 1 or phase 2. The 28 subjects patients were 18 years or older and who enrolled in phase 2 started with 5 mg presented with varying conditions, none of dronabinol twice per day and could titrate which was responsive to traditional up after being on a stable dose for two treatments. Before beginning the trial, days, up to a maximum of 20 mg three baseline assessments were performed for times per day. They could reduce their two weeks and each patient was then dose at any time if they experienced subjected to an observed dosing of adverse effects. In phase 2 there was a THC:CBD (2-8 sprays per patient) before significant decrease in average pain scores allowing the patient to self-dose at home from baseline to week 4, with average pain for two weeks. Although this study scores dropping each week. A significant consisted of patients with several decrease was found in pain interfering with diagnoses, each experienced pain and sleep. Side effects were of similar therefore the level of pain using the Visual type/frequency as in phase one, and they Analogue Scale (VAS) 0-10 and sleep appeared to decrease in frequency from patterns were the focus of the trial and week to week (despite increases in dose for each patient was responsible for some patients). Achieved dronabinol doses documenting these values, as well as side not reported. “These positive results do not effects in a journal daily during the two- address the controversy about the long- week initial phase. To continue to the eight- term use of cannabinoids for pain, week period, a patient must have shown some benefit in these areas during this

56 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

time. Further evaluations used the Beck the cannabis compounds to be equally or Depression Inventory (BDI) and General more effective. Health Questionnaire 28 (GHQ28). Each patient then identified their worst Improvement in sleep quality was greater symptoms and were instructed to while taking the cannabis preparations, in document the severity of the two worst comparison with placebo. The average symptoms three times each day, as well as duration of sleep was higher and self- the hours and quality (good, fair, poor) of reported depression levels were lower in sleep, appetite, bowel, and bladder habits the drug arms when compared to placebo, and side effects. All current medications although not statistically. Side effects more were continued. common during active treatment, compared with placebo, were dry mouth, During the two week run-in period, all 34 drowsiness, and euphoria/dysphoria. All lab participants were given 1:1 spray and all values remained within normal limits. had a decrease in their two main symptoms – 16 of those were a greater than 50% Nurmikko T, Serpell MG, Hoggart B, reduction in either symptom and 10 Toomey PJ, Morton BJ, Haines D. Sativex reported a 50% reduction in both. After the successfully treats neuropathic pain crossover, patients were entered in a characterized by allodynia: A randomized, randomized, double-blind, placebo- double-blind, placebo-controlled clinical controlled testing of THC, CBD, and 1:1 for trial. Pain 2007; 133(1-3): 210-220. one week intervals. Each week, the test compound changed and therefore each This study took place over five weeks and patient was given each compound and was randomized, double-blind, and placebo for two one-week intervals. All placebo-controlled involving patients with a were allowed access to 1:1 (THC:CBD) for history of nerve pain for at least six months. rescue analgesia and 24 patients completed A total of 125 patients (74 women/51 men; the trial without use – these patients are average age 53 years) were randomized to included in the comparison. Patients receive either drug (n=63) or placebo (n=62) reported using 1-8 sprays as a single dose. and baseline pain and sleep disturbance Average daily dose of each of the three were recorded daily for 7-10 days prior to active medications was approximately 8 start of trial. All current medications, sprays per day. including those for pain, were continued throughout – although any current use of For symptom control, THC and THC:CBD cannabis products were cause for exclusion. showed a statistically significant improvement when compared to placebo. Sativex oral spray (2.7 mg THC/2.5 mg CBD Of the 24 patients, nine reported a per 100 μl actuation) and all initial dosing decrease of at least 50% in either symptom was performed in the clinic and patients with the use of all three cannabis-based were monitored for intoxication using a 0- compounds – three with CBD. When asked 100 Visual Analog Scale (VAS). After to compare effectiveness of current therapy administration of eight sprays over two with initial run-in tests, all patients reported hours, any patient scoring over 25 on the VAS, or presenting with any clinical

57 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

concerns, was allowed no further doses. fatigue, vomiting, dry mouth, feeling drunk, Once patients had completed the initial diarrhea, somnolence, disturbance in dosing test, they were allowed self- attention, and memory deficit. Eleven titration, up to 48 sprays/24 hours (129.6 patients from the treatment group and two THC/120 CBD). Throughout the trial, from placebo withdrew from the trial as a patients recorded daily pain and sleep result of adverse events. Adverse events patterns in a journal. The primary endpoint causing withdrawal in the Sativex group: was pain relief based on a 0-10 scale; dizziness, nausea, vomiting, feeling drunk, secondary endpoints included the anorexia, and diarrhea. Neuropathic Pain Scale (NPS), mechanical allodynia testing, verbal sleep disturbance Rog D, Nurmikko T, Friede T, Young C. scale, Pain Disability Index (PDI), Patient Randomized, controlled trial of cannabis- Global Impression of Change (PGIC) for pain based medicine in central pain in multiple and allodynia, the General Health sclerosis. Neurology 2005; 65(6): 812-819. Questionnaire (GHQ-12) and possible cognitive decline was assessed using the This randomized, double-blind, placebo- Brief Repeatable Battery of controlled, parallel-group trial lasted four Neuropsychological tests (BRB-N). Lab weeks and included 66 patients (14 values and and ECG was taken prior to the males/52 females; average age 49.2 years) study, and again at completion. diagnosed with multiple sclerosis (MS) at least six months prior and experiencing pain Thirteen patients from the drug arm and for at least three months. Thirty-four seven from placebo withdrew from the patients were treated with Sativex (2.7mg study prior to completion – the reasons TCH/2.5 mg CBD) oromucosal spray and were side effects, lack of effectiveness, and were compared to 32 patients given failure to comply with study requirements. placebo. Patients maintained current drug The results of the primary outcome were therapies but were allowed a maximum of statistically significant in favor of the drug 75 mg/day of any tricyclic . arm and the NNT was 8.5 (50% reduction) Before the trial began, each patient and 8.6 (30% reduction). All areas besides identified their most concerning symptom the GHQ-12 showed a significant difference and noted most bothersome time of day as in favor of the Sativex arm. No difference well as baseline pain levels for 7-10 days. was seen in the BRB-N test for cognitive decline. After the titration period, average In addition to pain levels, sleep disturbance dose for patients in the Sativex group was on an 11-point scale was completed for approximately 13 sprays per day. Fifty- three days prior to start. Cognitive function seven (91%) of patients in the Sativex group (Brief Repeatable Battery of experienced at least one adverse event Neuropsychological Tests), mood Hospital compared with 48 (77%) in the placebo Anxiety and Depression Scale – HADS) and group. Most were observed at onset of disability attributed to MS (Guy’s treatment and in the majority described as Neurological Disability Scale) and Patient’s mild. Adverse events more common in the Global Impression of Change (PGIC) were Sativex group were dizziness, nausea, also evaluated prior to start and at completion.

58 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Before releasing any drug for home use, This trial was an extension of the trial each patient completed an in-clinic trial of reported in Rog 2005 involving 63 patients up-to four sprays of Sativex within two (49 female/14 male; average age 49 years) hours. They were observed for intoxication with multiple sclerosis (MS) and related levels using a 100-point visual analogue central neuropathic pain (CNP). Before scale where any patient scoring greater beginning the extension, all patients than 25 would have a reduced dosing received a complete physical, including an schedule. The home titration allowed for a EKG, blood and urine labs, and etcetera. maximum of 48 sprays (129.6 mg THC/120 mg CBD) in 24 hours with no more than Prior to beginning the parent trial, each eight doses in a three-hour period. patient reported their most severe symptom and recorded time of day and Improvement of pain in the Sativex group rating of pain (0-10) and were again was larger than in the placebo group, instructed to document their pain rating the reaching statistical significance (-2.7 [95% CI week prior to beginning the open-label = -3.4 to -2.0] vs. 1.4 [-2.0 to -0.8]). follow-up and throughout the testing Improvement in sleep disturbance related period. Patients receiving placebo in the to pain was also statistically significantly randomized trial were now given Sativex greater in the Sativex group. There was no and instructed to titrate as directed in the significant difference between groups for parent trial. Nursing staff made phone PGIC, neuropsychological outcomes or contact with patients 14-20 days after HADS neurological disability. initiation to ensure tolerability. The patients were then reviewed at 4 weeks and again At week 4 the mean daily number of Sativex every 8 weeks to assess changes in pain, sprays was 9.6 (range 2 to 25). Thirty perceived benefit, intoxication (0-100 VAS patients (88%) developed at least one score) as well as number of sprays taken at adverse event (AE), compared with 22 the time at which it was used. Participants patients (69%) on placebo. Dizziness, dry also completed physical re-checks mouth, somnolence, and GI upset were throughout the trial. some of the most common side effects noted. No serious AEs were observed. The primary endpoint was evaluation of However, two Sativex patients withdrew adverse events (AEs) and secondary from the study due to adverse effects: one endpoints included any changes in pain with hypertension/tachycardia and the score as well as hematology and lab results, second with paranoid ideation. vital signs, trial drug usage, and intoxication. Ninety-five percent of patients Rog DJ, Nurmikko TJ, Young CA. experienced at least one AE; 58 patients Oromucosal Δ9 – report treatment-related AEs (75% of tetrahydrocannabinol/cannabidiol for patients experienced mild AEs, 78% neuropathic pain associated with multiple moderate, and 51% severe). Ten patients sclerosis: An uncontrolled, open-label, 2- experienced a relapse of MS; 10 reported year extension trial Clin Ther. aggravation of MS symptoms. Of the AEs, 2007;29(9):2068-2079. dizziness and feeling intoxicated, GI upset, and oral/application site irritation were

59 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS among the most common. Seventeen controlled study testing the effectiveness of patients withdrew from the study as a Sativex sublingual spray (27 mg/ml THC: 25 result of AEs; nausea, weakness, dizziness, mg/ml CBD). A two week dose titration fatigue, and intoxication were among the period was followed by a 10-week reasons. Two patients experienced maintenance phase. The only information significant increases in white cell count, on dosing was a statement that doses were mean cell volume, and liver function tests administered sublingually in divided doses and one participant experienced an up to four times a day. All current increase in lymphocytes, neutrophils, medications were continued. Pain levels for alkaline aminotransferase, , and superficial, deep, and muscular pain were potassium. No other changes were seen. documented using 100-mm Visual Analogue Scale (VAS), the Neuropathic Pain Scale Thirty-four patients completed a full year of (NPS), and the total pain score (TPS) at treatment and the average number of baseline and study end, as were the sprays per day was 7.5 throughout the year, possible level of depression using the however, during the last six days, the Hospital Anxiety and Depression Scale average was 6.1 sprays. For the 28 (HADS-D), as well as the patients’ quality of participants that completed two years of life (QOL) using the McGill Pain and QOL, study, the average number of sprays was SE-36 Health Survey, and Euro QOL. Results 6.5 and 10 of these patients were able to showed no significant difference between reduce or discontinue concomitant pain the Sativex and placebo groups for change medication. No development of tolerance in any of the measured parameters. Of the was seen from the randomized trial to the 30 patients randomized, 6 withdrew end of the first year of the extension trial. because of adverse events; no further Pain levels decreased by 3.4 points (0-10 information was provided on whether these scale) when compared to the completion of participants were receiving Sativex or the randomized trial. Intoxication levels placebo and what adverse events occurred. were generally low and in patients that did experience this effect, the average level on Serpell M, Ratcliffe S, Hovorka J, Schofield a 0-100 VAS scale was 3-6 and stable. M, Taylor L, Lauder H, Ehler, E. A double- blind, randomized, placebo-controlled, Selvarajah D, Gandhi R, Emery C, Tesfaye S. parallel group study of THC/CBD spray in Randomized Placebo-Controlled Double- peripheral neuropathic pain treatment. Eur Blind Clinical Trial of Cannabis-Based J Pain 2014;18:999-1012. Medicinal Product (Sativex) in Painful Diabetic Neuropathy. Diabetes Care 2010; 303 patients with peripheral neuropathic 33(1): 128-130. pain (PNP) associated with allodynia were screened and met inclusion and exclusion Thirty patients (11 female/19 male; average criteria at 39 centers in the UK, Czech age 56 years) with painful diabetic Republic, Romania, and . (DPN), despite 57 withdrew before randomization, 128 standard treatment with a tricyclic were randomized to THC/CBD spray antidepressant, were enlisted in this (nabiximols: 2.7 mg THC and 2.5 mg CBD randomized, double-blind, placebo- per 100 µl spray), and 118 to placebo.

60 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Eligible patients were ≥18, had PNP ≥ 6 patients (28%) receiving nabiximols were months, had allodynia confirmed, were classified as responders at the 30% level receiving the appropriate treatment for compared with 19 patients (16%) on their PNP, had specified causes of their PNP placebo, achieving a statistically significant (PNP due to cancer or diabetes excluded), odds ratio in favor of nabiximols treatment and took no analgesics on a PRN basis. At (OR = 1.97, 95% CI = 1.05-3.70; p=0.034) in baseline they were required to have pain the full intention to treat (ITT) cohort and in not entirely relieved by their analgesic the subset of participants who completed regimen with a pain rating intensity ≥ 4 on a the study with no protocol violations likely 0-10 scale. After screening, participants to affect outcome measures (per protocol had a one week baseline period and a 14 (PP) group: OR = 2.7 CI = 1.12-4.57 week treatment period with visits at the p=0.021). The adjusted mean reduction in end of weeks 2, 6, 10; at the end of the NRS score showed a treatment difference in study (treatment week 14 or earlier if they favor of nabiximols, but the difference withdrew); and 28 days after study didn’t meet statistical significance in either completion or withdrawal. Participants the ITT or the PP groups. A variety of remained on their concomitant analgesic secondary outcome measures were used, medications with the exception of but only two showed statistically significant acetaminophen, provided that a stable dose change, both in favor of nabiximols: sleep was maintained throughout the study. The quality and Global Impression of Change rescue analgesia provided contained (general assessment of health). Distribution acetaminophen, with maximum single dose of number of sprays per day at end of study of 1000 mg and maximum total daily dose not provided. Side effects were common in of 4 grams. Participants began nabiximols both nabiximols (85%) and placebo (70%) at a maximum of one spray per four hour groups (side effect occurrence reported for period and self-titrated to a maximum of 24 both ITT and PP groups; percentages from sprays per day (limit of 8 sprays per 3 ITT included here). Most common side hours), increasing dosage by no more than effects in nabiximols group were dizziness, 50% from preceding day. Patients were nausea, and fatigue. Ten nabiximols instructed to rate their pain on a 0 – 10 patients (8%) and six placebo patients (5%) numeric rating scale at the end of each day. experienced serious adverse events; none Co-primary outcome measures were, 1) were deemed related to treatment. A total proportion of patients showing ≥ 30% of 33 patients stopped receiving study reduction in pain from baseline to end of medication due to adverse effects, 25 in the study period as measured by NRS and 2) nabiximols group and 8 in the placebo mean change in NRS score from baseline to group (additional detail on dosage and end of study. The study took place from nature of AEs in this group not provided). September, 2005 to October, 2006. A total of 173 of the 246 completed the study, 21 Svendsen KB, Jensen TS, Bach FW. Does ceased treatment but remained in the the cannabinoid dronabinol reduce central study, and 52 withdrew. Six patients were pain in multiple sclerosis? Randomised not included in the analysis as they had no double blind placebo controlled crossover on-treatment efficacy data. A total of 34 trial.

61 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

BMJ,doi:10.1136/bmj.38149.566979.AE treatment included dizziness, tiredness, (published 16 July 2004). balance problems, headache, euphoria, feeling drunk, muscle pain, and muscle 25 patients age 23-55 with MS who met weakness. criteria for central pain ≥3 on a 0-10 numeric rating scale were recruited and one Wade DT, Robson P, House H, Makela P, was excluded due to EKG findings. After a Aram J. A preliminary controlled study to one-week baseline period patients were determine whether whole-plant cannabis randomized and then treated with either extracts can improve intractable dronabinol or placebo for approximately 3 neurogenic symptoms. Clin. Rehabil 2003; weeks with a three week washout period 17(1): 21-29. before three weeks treatment with the other medication. Primary outcome was Twenty-four patients (average age 48 years) pain intensity over the past week on a 0-10 with unresponsive neurologic symptoms, numeric rating scale. Secondary outcomes including pain, were included in this study included SF-36 quality of life survey, several using whole-plant extracts of cannabis. The sensory neurologic tests, and the expanded cannabis was prepared as CBD or THC-rich disability status scale score. Dronabinol 2.5 extract or a 1:1 ratio of THC and CBD and mg capsules were used, starting at one delivered as a -flavored capsule per day. Participants self-titrated, sublingual spray with 2.5 mg active increasing by one capsule every other day ingredient per actuation. Patients were to a maximum of 2 capsules twice daily (10 instructed to use no more than 120 mg in mg dronabinol in two 5 mg doses). All 24 hours. Initially, patients were subjected participants completed the study protocol. to a two-week, open-label THC:CBD testing Decrease in pain intensity rating was under professional supervision to ensure significantly greater during dronabinol they would tolerate the possible side treatment (3.0; 25th-75th %tile = 0 to 6.7) vs. effects and intoxication. Plasma levels were placebo (0; 0 to 2.3). The bodily pain and collected to ensure proper . mental health components of the SF-36 Those patients that were particularly showed modest benefits during dronabinol susceptible to the effects were assigned a treatment vs. placebo. No differences reduced dosing regimen. between dronabinol and placebo treatment were seen for the sensory tests or Following the open-label period, patients functional ability. 96% of participants began a randomized controlled study experienced side effects during dronabinol lasting eight weeks, receiving each of the treatment vs. 46% during placebo three treatment or placebo during one of treatment. Four patients reduced dosage the four 2-week stages. Patients were of dronabinol because of intolerable side assigned to either a THC (mostly, CBD effects (3 reduced from 10.0 to 7.5 mg and (mostly), 1:1 THC:CBD, or placebo arm, one to 5.0 mg); the remainder continued on though all were allowed access to the 1:1 10.0 mg dronabinol. Side effect severity spray as a rescue medication and were was not described. The side effects instructed to use is only when needed. occurring more often during dronabinol Those patients that reported using the rescue spray were analyzed separately from

62 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS those that reported little or no use. Wade T. et al. Do cannabis-based Throughout the trial, patients were medicinal extracts have general or specific instructed to make daily journal entries effects on symptoms in multiple sclerosis? regarding their symptoms using a visual A double-blind, randomized placebo- analog scale (VAS) with a 0-100 scale were 0 controlled study on 160 patients. Mult would be the worst possible level of Scler 2004; 10:434-441. severity. Patients also participated in a series of assessments every two weeks A randomized, double-blind, placebo- including the Short Orientation-Memory- controlled, parallel group trial of nabiximols Concentration (SOMC), Barthel Activities of (Sativex) for patients with multiple Daily Living Index, the Revermead Mobility sclerosis. 160 patients from 3 UK centers Index and the General Health were enrolled and indicated whether their Questionnaire, as well as the Nine Hole Peg primary symptom was spasticity, spasms, Test of manual dexterity and the Ashworth bladder problems, tremor, or pain not scale for spasticity when applicable. obviously musculoskeletal. Intensity of each symptom was self-rated on a 100 mm Of the 24 initially enrolled, 20 patients (10 visual analog scale throughout the study. male, 10 female) completed the study. The Patients were randomized to nabiximols or reasons for withdrawal from the study were placebo for the initial six week double-blind intoxication, GI upset, or local irritation. trial and told to titrate slowly during home Average dose for the three active dosing, aiming for optimal balance between treatments was between 8 and 10 symptom relief and side effects, but not to sprays/day. Using data from all patients, 12 exceed 120 mg THC (44 sprays) per day or reported pain as a main concern, although 20 mg THC (7 sprays) within a 3 hour 16 reported spasm and 8 spasticity – both period. Average number of sprays per day of which can be linked to pain symptoms. in the active treatment group increased All three of these symptoms showed a steadily over three weeks and then statistically significant reduction in the plateaued at 14 to 16 sprays per day (38 to treatment arms and none in the placebo 43 mg/day THC; 35-40 mg/day CBD). arm. Pain was most relieved by CBD or THC, Subjects receiving nabiximols showed while spasm (frequency) strongly improvement in subjective (VAS), but not responded to THC and 1:1 THC:CBD and objective (Ashworth scale) measures of spasticity (severity) most responded to THC spasticity, compared to the placebo group. only. Of the additional quality-of-life tests, No significant difference in symptom scores only the SOMC showed statistical between groups was found for spasms, significance in the THC group. During the pain, tremor, bladder control, or a open-label phase when 1:1 THC:CBD was composite symptom score. Side effects administered 67% of patients experienced that occurred more often in the active adverse events. During the 2-week treatment group included dizziness, treatment stages the proportion of patients disturbance in attention, fatigue, with at least one adverse event were as somnolence, disorientation, vertigo, follows: placebo – 48%, THC (mostly) – 55%, diarrhea, and mouth ulceration. CBD (mostly) – 33%, 1:1 THC:CBD – 30%

63 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS

Zajicek JP, Hobart JC, Slade A, Barnes D, dose was reduced by one capsule until the Pattison PG, on behalf of the MUSEC side effect(s) resolved. After resolution, Research Group. Multiple Sclerosis and one re-challenge with a further dose Extract of Cannabis: results of the MUSEC escalation was required. If the side effect(s) trial. J Neurol Neurosurg Psychiatry returned, the dose was reduced again, with 2012;83:1125-1132. no further re-challenge allowed. The primary outcome measure was perceived Double-blind placebo controlled study of change in muscle stiffness after 12 weeks of 279 patients age 18-64 with MS by treatment compared with the McDonald criteria, stable disease for the premedication phase. At the final visit, last 6 months and troublesome and ongoing participants answered the following muscle stiffness for at least 3 months question on a symptom questionnaire: before enrollment (as shown by a current “Compared with before the study started, disability score of at least 4 on an 11 point my muscle stiffness over the last week has category rating scale (CRS) at 22 UK been …” providing a rating on an 11 point centers). Treatment = 144, placebo = 135. numerical scale where 0=very much better, Physiotherapy regimens or medications 5= no difference and 10=very much worse. likely to affect spasticity were adjusted Categories 0-3 of the rating scale were where necessary and then not altered in classified as ‘relief of muscle stiffness’ – the 30 days before study start. Patients that is, as a clinically relevant response. with active sources of infection or taking Secondary measures included relief from immunomodulatory drugs that might affect body pain, muscle spasms and sleep spasticity (e.g. Beta-interferon, but not disturbance using 11 point scales. Also, the azathioprine) were excluded. Active validated disease specific multi-item rating treatment was an extract of Cannabis sativa scales measuring aspects of spasticity in MS L (extraction ethanol 96%) in soft gelatin (MS Spasticity Scale (MSSS-88), and other capsules, standardized on cannabidiol scales including Expanded Disability Status (range 0.8-1.8 mg) and containing 2.5 mg Scale (EDSS). Main result: proportion with delta-9 THC as the main cannabinoid self-reported relief from stiffness was (CANNADOR). The study consisted of a higher by a statistically significant amount screening period of 1-2 weeks, 2 week dose compared to the placebo group (29.4% vs. titration phase and a 10 week maintenance 15.7%; OR=2.6 95%, CI = 1.24-4.13). phase. Total treatment duration was 12 Proportion of patients with relief of body weeks. Participants were assessed at 2, 4, pain (0-3 on 11 point scale) was higher by a 8, and 12 weeks after start of treatment. statistically significant amount at each time Starting dose was 2.5 mg THC (one capsule) of measurement (44% vs. 18% at week 12). twice daily. Subsequent doses were At the end of the titration period individually titrated upwards by 5 mg approximately 87% of participants in the THC/day every 3 days for up to 12 days to placebo group were taking the maximum optimize the balance between therapeutic daily dose of 25.0 mg. In contrast, only 47% effect and side effects. Maximum total of participants in the active treatment allowable daily dose was 25 mg THC. In the group had titrated up to a maximum daily event of intolerable side effects, the daily dose of 25.0 mg. Of the active treatment

64 A REVIEW OF MEDICAL CANNABIS STUDIES RELATING TO CHEMICAL COMPOSITIONS AND DOSAGES FOR QUALIFYING MEDICAL CONDITIONS patients who did not achieve the maximum continuously over the course of the study. daily dose, most were taking daily doses of Adverse events that occurred at clearly 10.0 to 15.0 mg. Sixteen participants in the higher rates in the active treatment group active treatment group discontinued study than in the placebo group were dizziness, medication during titration, compared with disturbance in attention, balance disorder, four in the placebo group. At the end of the somnolence, dry mouth, nausea, diarrhea, study, only 24.5% of the active treatment fatigue, asthenia, feeling abnormal, urinary group was taking the 25.0 mg dose. By the tract infection, disorientation, confusional end of the study, 84% of all patients state, and fall. The relatively rapid titration experienced at last one treatment was done for technical study reasons – in emergent adverse events: 98% in active clinical practice it is not likely to be done so treatment group and 74.6% in the placebo rapidly. Results in this study confirm results group. 23.8% in the active treatment group in the CAMS study, which was larger, and and 14.9% % in placebo group were are similar to two other studies that withdrawn from the study or discontinued showed significant reduction in spasticity study medication due to adverse events. In using an 11 point rating scale (Novotna the active treatment group adverse events 2011; Colin 2007). were highest during titration and decreased

65