CannabisMD Reports : Willian Notcott, M.D.

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MEDICINAL CANNABIS EXTRACT IN CHRONIC PAIN: (1) DESIGN OF A COMPARATIVE "N OF 1" PRIMARY STUDY (CBME-1).
As published in the Journal of Cannabis Therapeutics, and presented at the International Association of Cannabis as Medicine meeting in Berlin, October 2001.
William Notcutt, Mario Price, Roy Miller, Sam Newport, Cathy Sansom, Sue Simmonds, James Paget Hospital, Lowestoft Road, Great Yarmouth, Norfolk, NR31 6la, UK.

Introduction: Herbal cannabis is widely used by patients suffering with chronic

pain. Previous attempts to study its use have been complicated the inability to standardize the cannabis extract and to measure the amount of cannabinoid used. We report the methodology of a study to investigate the use of Cannabis Based Medicinal Extracts (CMBE) in-patients with chronic pain. This study is the first to use a sublingual metered dose spray containing known quantities of pharmaceutically prepared Delta 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) extracted from plants grown under controlled conditions. The aims of the study were to determine the relative therapeutic windows, and to evaluate benefits and safety.

Methods: An "N of 1" format was used for the study because of the heterogeneous

nature of chronic pain conditions. The medicinal cannabis extract was administered as a sublingual spray. Initially the patients underwent a two week open run-in period (Part 1) using 1:1 mixture of cannabidiol and Delta 9-tetrhydrocannabinol (THC/CBD). If they gained benefit from this they then progressed to Part 2 of the study, which included two blocks of four weeks. During this time each patient received one week of each of high THC, high CBD, placebo and 1:1 THC/CBD. The order of the CBME was randomised and double blind. Patients who were regular cannabis users were given rescue medication of the THC/CBD to prevent them returning to their previous cannabis use. Patients attended weekly for a variety of assessments (Pain and Activity scores, General Health Questionnaire [GHQ28], Becks Depression Inventory [BD]). Following these assessments, the medication for the subsequent week was then titrated to an appropriate level. VAS pain scores were recorded and samples for serum concentrations of THC and CBD were taken during the titrations. Non-invasive BP, pulse and ECG were monitored. Throughout 12 weeks, the patients kept a daily diary (VAS pain, sleep, side effects, effectiveness, medication used). Those who gained benefit from the use of the cannabis extract were considered for entry into a long-term safety study.

Results: Patients with Multiple Sclerosis, chronic back pain and sciatica after

spinal surgery and other neuropathic pains have been recruited. The first 6 patients (5 regular "medicinal" cannabis users, 1 previous "medicinal" cannabis exposure) gave early information on safety and effectiveness of the new materials. Of 19 patients so far studied 15 have shown a variety of benefits and have started a long-term safety extension study.

Discussion: Benefits and problems with the trial design will be discussed. More

detailed results are reported in other posters and abstracts for this meeting.

MEDICINAL CANNABIS EXTRACTS IN CHRONIC PAIN: (2) COMPARISON OF TWO PATIENTS WITH BACK PAIN AND SCIATICA.
William Notcutt, Mario Price, Roy Miller, Sam Newport, Cathy Sansom, Sue Simmonds, James Paget Hospital, Lowestoft Road, Great Yarmouth, Norfolk, NR31 6LA, UK.

Introduction: In this abstract we describe the different experiences of two

patients, with back pain and sciatica, recruited for our "N of 1" study of Cannabis Based Medicinal Extract (CBME). We compare the benefits and side effects.

Methods: Two female patients, A (53 yrs) and B (33yrs) both suffering with chronic

back pain and sciatica were recruited as a part of a larger study of sublingual CBME in chronic pain (CBME-1 described in an earlier poster). Patient A suffers from ongoing neuropathic leg pain following spinal fusion and is confined to a wheelchair. She was an occasional cannabis user prior to the study. Patient B has pain as a result of a scarred nerve root following two lumbar diskectomies. She had not used cannabis before. Details of the study design are described in an accompanying abstract from this team.

Results: From the start of treatment with CBME, Patient A demonstrated a dramatic reduction

in VAS pain scores from 6-7 to less than one. During the weeks of placebo she demonstrated some increases in pain scores but her pain did not return to pre-study levels. Her sleep remained variable. In contrast, Patient B showed little change in VAS pain scores, but reported a substantial improvement in her sleep, which disappeared when using placebo. Patient A showed changes in her mood (BDI) and General Health Questionnaire (GHQ). Patient B did not score badly at the outset and little change was observed. Neither patient suffered significant side effects.

Discussion: These two patients with similar problems demonstrate the heterogeneity

of both chronic pain and of the response to treatment with CBME. While Patient A demonstrated substantial improvements in her pain scores, Patient B gained improved quality of sleep. Both patients considered these improvements to be of substantial importance to them and opted to continue into a long-term safety study (CBME SAFEX).

MEDICINAL CANNABIS EXTRACTS IN CHRONIC PAIN: (3) COMPARISON OF TWO PATIENTS WITH MULTIPLE SCLEROSIS.
William Notcutt, Mario Price, Roy Miller, Sam Newport, Cathy Sansom, Sue Simmonds, James Paget Hospital, Lowestoft Road, Great Yarmouth, Norfolk, NR31 6LA, UK.

Introduction: In this abstract we describe the different experiences of two patients

recruited for our study of Cannabis Based Extract (CBME). We compare their benefits and side effects

Methods: Two female patients, Patients C (55 yrs) and D (44yrs), both with Multiple

Sclerosis, were recruited as a part of a larger study of CBME for chronic pain. Patient C had no previous cannabis use, but D had used it once. She identified neuropathic knee to ankle pain and lumbar pain as her two most prominent symptoms. Patient D symptoms included severe urethral and pelvic floor pain, partly as a result of a previous cystectomy and colectomy. Details of the study design are described in an accompanying abstract from this team.

Results: Both patients showed a clear improvement in VAS pain scores at the start of

treatment during the 2-week open run-in period on 1:1 THC/CBD. Later in the crossover period pain scores for each symptom for Patient C were equally affected by the CBME. However, Patient D's pelvic floor pain was worse on weeks when on high CBD in contrast her urethral pain which did not change. Patient D had better overall symptom control when taking THC/CBD and worse symptom control with placebo, whereas Patient C showed no clear pattern of changes in this measure. Patient C had no change in quality of quantity of sleep throughout the study while Patient D had improved quality and quantity of sleep while taking THC:CBD. Patient C showed a sustained improvement in depression scores (BDI) throughout the study, Whereas Patient D has improved scores on THC:CBD and high CBD but worse scores on placebo.

Discussion: These two patients demonstrate the problem of studying patients with

multiple sclerosis. Although patient C initially gained benefit from treatment, D showed the more dramatic improvement and has continued into the long-term safety study. Towards the end of the 10-week study we realized that C was having a relapse of her MS. Although we gave her a subsequent challenge with THC:CBD we could not reproduce the initial 2 week period and concluded the study. Patient D had a flare up on her MS 3 months into the long-term study and it significant upset her pain control.

Multiple Sclerosis has been seen as the "most acceptable" disease in the UK for

trials of cannabinoids. Unfortunately, there are probably few diseases in which it is harder to conduct clinical trials.

MEDICINAL CANNABIS EXTRACTS IN CHRONIC PAIN: (4) CANNABIDIOL MODIFICATION OF PHYCHO-ACTIVE EFFECTS OF DELTA 9-THC.
William Notcutt, Mario Price, Roy Miller, Sam Newport, Cathy Sansom, Sue Simmons, James Paget Hospital, Lowestoft Road, Great Yarmouth, Norfolk, NR31 6LA, UK.

Introduction: It has long been suspected that cannabidiol (CBD) might modify the

psychoactive effects of Delta 9-tetahydrocannabidiol (delta 9-THC). Anecdotal evidence from patients using cannabis medicinally suggests a preference for the milder forms of cannabis containing significant levels of CBD. Zuardi demonstrated that CBD reduces the intoxicant effects of cannabis in human volunteers. This effect has been observed in a patient participating in a study of sublingual Cannabis Based Medicinal Extract (CBME).

Case Report: A 40-year-old women with Multiple Sclerosis was participating in an "N

of 1" study of CBME (GW Pharamceuticals). She had previously undergone a cystectomy and colectomy. Her main pain problems were severe urethral pain and a "bearing Down" type of pain deep within her pelvis. Both had been present for some 18 years. The CBME was administered sublingually. After an initial 2 week run in period with a mixture of 50% cannabidiol (CBD) and Delta 9-THC, she under went a double blind, placebo controlled "N of 1" study. This consisted of 8 X 1 week periods where she received one of four preparations on two occasions foe a week at a time. The four preparations were THC, CBD, 50-50 mixture of CBD and THC, placebo (see previous abstract for details).

Over 12 weeks, she kept daily diaries of her pain, her pain control, sleep and side

effects experienced. The total daily amount of drug was also measured. In her daily diary she recorded any episodes of a specified set of side effects (dry mouth, time distortion, panic, dizziness, drowsiness, hallucinations, high, etc.). Their presence only each day was recorded. No attempt to measure the intensity of the effects was made.

Results: She achieved almost total pain control from the CBME. Psychoactive side effects

were predominantly seen during the periods when she used THC alone. During the periods when she used a 1:1 mixture of THC and CBD, the incidence of side effects fell dramatically, although she was using the same overall amount of THC.

Discussion: Some have suggested that large doses of CBD are necessary to achieve

this effect. However, only small doses of cannabinoid were used (less than the equivalent of a "joint" per day). This observation will be assessed in other patients taking part in further patients in this CBME study. The preference for THC:CBD over THC is explored in a later paper from this team.

References: (1) Zuardi AW, et al. 1982. Action of cannabidiol on the anxiety and

other effects produced by delta 9 THC in normal subjects. Psychopharmacology 76:245-250. (2) Iversen LL. 2000. The science of marijuana. Oxford: Oxford University Press.

MEDICINAL CANNABIS EXTRACTS IN CHRONIC PAIN: (5) COGNITIVE FUNCTION AND BLOOD CANNABINOID LEVELS.
William Notcutt, Mario Price, Roy Miller, Sam Newport, Cathy Sansom, Sue Simmonds, James Paget Hospital, Lowestoft Road, Great Yarmouth, Norfolk, NR31 6LA, UK.

Introduction: One of the major concerns with the use of cannabis as a medicine is

the potential for side effects. Disturbances of psychomotor and cognitive function may put the patient at risk. Our "N of 1" study of Cannabis Based Medical Extracts (CBME) involves titrating patients with different extracts under direct supervision over a 4 hour period. (Details of the study design are described in an accompanying abstract from this team.)

Method: An initial cohort of 5 patients with chronic pain were given different

extracts of CBME (GW Pharmaceuticals) at weekly intervals. During the initial dose of each extract regular blood levels of cannabinoids were measured at pre-dose, 30 min, 1h and 4h. The patients completed a set of cognitive functioning test at pre-dose, 1h, 2h and 4h intervals. Two paper tests were used: (1) The Trail Making Test has two parts both require and measure visuospatial ability and motor sequencing skills, with part B incorporating a measure of flexibility. Patients are timed as they attempt to join numbered circles in part A and a combination of numbers and letters in part B in a dot-to-dot fashion (Golden et al. 1981). (2) The Information Processing Tasks A&B from the Adult Memory and Information Processing Battery (AMIPB). Both tasks required the patient to select and cancel out a target digit in a series of items. The patients were given a set amount of time to complete as many items as they could. A simple test of motor-speed accompanies each of the above tasks. The Information processing tasks were designed for clinicians to identify and evaluate impairments in mental ability (Coughlan & Hollows 1985).

Results: No apparent difference was seen in the ability of the patients to complete

the test up to serum levels of 4.9 Ng/ml THC but relief of symptoms was achieved in several patients. On two occasions patients experienced side effects to a degree that prevented them undertaking the tests at the 4 hour stage Subsequent serum THC levels were shown to have reached 6 Ng/ml and 14 Ng/ml.

Discussion: Generally, the CBME administered did not affect the patients' ability in

performing these tests, yet relief of symptoms were achieved. Therefore, these simple tests may serve as an indicator that patients are safe to carry out their normal activities at home when using their CBME to therapeutic levels.

References: (1) Golden CJ et al. Interpretation of the Halstead-Reitan

Neuropsychological Test Battery. Brune and Stratton 1981. (2) Coughlan A, Hollows SE. Adult Memory and Information-Processing Battery. Available from the first author, St. James Hospital, Leeds, UK: 1985.

MEDICINAL CANNABIS EXTRACT IN CHRONIC PAIN: (6) DESIGN OF LONG-TERM SAFETY EXTENSION STUDY (CBME-SAFEX).
William Notcutt, Mario Price, Roy Miller, Sam Newport, Cathy Sansom, Sue Simmonds, James Paget Hospital, Lowestoft Road, Great Yarmouth, Norfolk, NR31 6LA, UK.

Introduction: Plant cannabis is commonly used, smoked or eaten over long periods of

time by patients suffering with chronic pain. Now that a standardized cannabis extract is available it is possible to accurately study the effects of the drug over months and years. We report the methodology of our study to investigate the long-term use of Cannabis Based Medicinal Extracts (CBME) in patients with chronic pain. This study follows on from our primary CBME-1 study to assess the effectiveness of sublingual Delta 9-tetrahydrocannabinol (Delta 9-THC) and cannabidiol (CBD) extracted from plants grown under controlled conditions (see Abstract 1 from this team). The aims of the study were to monitor the long-term effects and side effects. Because of legal restrictions, this study is the only option for continuation of supplies of CBME for the patients who had participated in the primary study. Methods: In the primary study we attempted to determine the optimum cannabinoid for the patient (THC, CBD or a 1:1 mixture). The objective was to provide the patients with the optimum cannabinoid for long-term use. However, for the first 8 months the Medicines Control Agency would only allow us to use THC. Subsequently they allowed patients to CBD if appropriate. Patients individualized their CBME usage under guidance from the team. The patients kept diaries to monitor drug usage, sleep, benefits and side effects. They were seen monthly and a variety of assessments were performed (Pain and Activity scores, General Health Questionnaire (GHQ28), Beck Depression Inventory (BDI). These were the same assessments as in the primary study. A formal assessment and examination including liver function test was carried out 3 monthly intervals. Patients were allowed to drive cars but were counseled and given specific instructions.

Results: Patients with Multiple Sclerosis, chronic back pain and sciatica after

spinal surgery and other neuropathic pains have been recruited. Of 19 patients who underwent the primary study 16 continued into the long-term study. One patient was quickly discontinued due to lack of effect. She had showed an equivocal result from the initial study complicated by a relapse in her MS. Approximately 14 patient's years of experience have been gathered (July 2001).

Discussion: Benefits and problems with the trial design will be discussed. Some

aspects of the results are reported in accompanying posters and abstracts for this meeting.

MEDICINAL CANNABIS EXTRACT IN CHRONIC PAIN: (7) RESULTS FROM LONG-TERM SAFETY EXTENSION STUDY (CBME-SAFEX).
William Notcutt, Kerry Jeavons, Mario Price, Sam Newport, Cathy Sansom, Sue Simmonds, James Paget Hospital, Lowestoft Road, Great Yarmouth, Norfolk, NR31 6LA, UK.

Currently the main target for the use of cannabinoids is in the management of

chronic disease. Therefore the study of these drugs over months and even years is essential. The control of symptoms, the changes in drug use, activity and quality of life and the incidence of side effects are the critical issues.

Methods: Fifteen patients with chronic pain from Multiple Sclerosis, spinal pain

(post spinal surgery) and a variety of other neurogenic pains are participating in the CBME-SAFEX study (see earlier abstract for details).

Results Symptom Control: All have maintained symptom control slthough several took

time settling onto the new regime. They had previously been having a variety of cannabinoids for peroids of 1 week. In addition visits to the clinic were reduced in frequency and duration. Benefits such as improved bladder function have also been maintained.

Cannabinoid and Other Drug Use: Most patients have maintained a static level of

cannabinoid use. Some have managed to slowly reduce other medication but this has not been dramatic. Several patients have stopped their cannabinoid medication for periods of time up to 1 month. None have reported any withdrawal symptoms. However, most have experienced an increase in pain on doing so.

Quality of Life: All patients say that their quality of life has improved and

statements from many spouses support this. Activity for many has not changed dramatically because of physical/motor iimitations.

Side Effects: The commonest side-effect has been dry mouth. For all patients the

side effects have been very tolerable. Two patients have had episodes of elevated hepatic transaminase levels but we have traced these back to the prescribing of antibiotics and steroids by the patients' general practitioners.
Other Problems: Over the peroid of the study so far the patients have encountered a range of physical and psychosocial problems. These include exacerbation of MS in 3 patients, marital difficulties, conception and birth of a baby, injuries, death of a spouse after a long illness, etc. All may substantially influence symptom control, mood and quality of life making evaluation of the benefits of CBME more complex.

Discussion: Perhaps the most important conclusion is that the CBME has remained

effective and that we have not seen any significant problems when used in the way described. However, larger numbers of patients studied over longer periods of time will be needed to increase confidence in safety of cannabinoid extracts.

MEDICINAL CANNABIS EXTRACT IN CHRONIC PAIN: (8) EVALUATION OF THC:CBD AGAINST THC IN THE MANAGEMENT OF CHRONIC PAIN.
William Notcutt, Kerry Jeavons, Mario Price, Sam Newport, Cathy Sansom, Sue Simmonds, James Paget Hospital, Lowestoft Road, Great Yarmouth, Norfolk, NR31 6LA, UK.

Introduction: Twelve out of fifteen patients coming out of our primary CBME-1 trial

preferred the 1:1 mixture of THC:CBD. However, we were initially unable to provide this mixture for about 8 months on the long-term safety study (see Abstracts 1 and 6 from this team). When we were able to use this, 5 patients were charged from THC to the 1:1 mixture of THC:CBD.

Methods: This paper examines a variety of parameters recorded in the 2 months before

and 2 months after the change in medication. Comments written by the patients in their monthly diaries were also studied. The group consisted of 4 patients with chronic back and sciatic pain following spinal surgery, and 1 patient with multiple sclerosis. There were 4 females and 1 male. All of the patients had expressed a preference for THC:CBD in the initial CBME-1 study.

Results: (1) Medication use (number of sprays) rose slightly in one patient, fell in

two, and remained constant in another two (1spray = 2.5 mg of THC or 2.5 mg THC + 2.5 mg CBD). (2) Depression scores were stable over the whole of the month study period in all of the patients. (3) The symptom control of the medication was constant in 4 patients. One patient demonstrated a substantial improvement in symptom control, which paralleled that observed during the CBME-1 trial. (4) The ability to perform specific activities increased dramatically in only 1 patient, paralleling the effect seen in the primary study (sexual activity). (5)The dry mouth that 2 patient experienced on THC disappeared with THC:CBD. One patient had very few side-effects were similar before and after the change. (6) Sleep quality and duration improved markedly in on patient, and was unvarying in the other subjects. However, on3 or 5h3w3 patients did comment on an improvement in sleep. (7) Two patients showed a decrease in pain, one of which experienced little or no pain while on the THC:CBD. The other three patients had no dramatic improvement in pain scores. (8) 4 out of 5 patients recorded comments on the benefit of the mixture, but the test used in the study were probably too insensitive to identify these subtle effects. (9) All 5 patients remain on the THC:CBD mixture preferring it to the THC alone.

Discussion: CBD seems to be important for many patients in improving the quality of their pain relief. However, the direct analgesic effect is not dramatic. It may be that CBD merely prevents some of the adverse effects of THC. Other combinations of the 2 cannabinoids will be interesting to study.

MEDICINAL CANNABIS EXTRATS IN CHRONIC PAIN.
William Notcutt, James Paget Hospital, Lowestoft Road, Great Yarmouth, Norfolk, NR31 6LA, UK.

We have had a long interest in cannabinoids for chronic pain having explored the use

of nabilone. Most patients informed us that they preferred plant cannabis. The availability of standardized plant extracts has allowed us to start formal clinical trials.

Patients Studied: All the patients we have studied have chronic pain and associated symptom (e.g., lack of sleep). Most have been drawn from the local Pain Relief Clinics and most are well known to the senior clinician. The first group was comprised of current materials and new route.

Materials Used: Whole plant extracts derived from cloned plants. These are either

high THC strains (>95% THC-no CBD) of high CBD strains (>95% CBD + some THC). The remainder (>5%) consists of other cannabinoids, terpenes, etc. The material is formulated as a sublingual spray.

Designing the Studies: The main objectives of the studies are to identify therapeutic windows of the CBME being used (including safety and tolerability) and to determine the approaches to more extensive and detailed studies. Chronic pain is a complex biophysical, pshychological and social problem and patients vary greatly even with the same underlying pathology. MS is a perfect example with the additional problem of being a variably progressive disease. Cannabis has variavle sites of action, variable psychoactive effects and variable dose response/adverse effect profile. Additionally there is the problem of requiring Home Office Licenses and being under substantial professional, bureaucratic and public observation. It was decided to first study patients individually using "N of 1" format. Subsequent aggregation of elements of dats will inform the design of future studies whilst developing a depth of clinical experience. When a patient has shown clear benefit then they are entered onto a long-term study whereby the chronic use of cannabinoids can be observed.

Conducting the Study: Acute side effects were encountered during acute dosing periods but these reflected our inexperience with the agents. Overall the materials have been well tolerated and have produced therapeutic benfits without disabling psychoactive effects.

Benefits and Problems: For the individual patient it has proved relatively easy to establish benefits. Side effects have been common but usually well tolerated. These themes will be developed in this presentation and overall results will be discussed, linking in with the poster presentations from this team.