title: Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. Short sleep duration in prevalent and persistent psychological distress in young adults: the DRIVE study. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. The Spread of Sleep Loss Influences Drug Use in Adolescent Social Networks Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Effect of Δ-9-Tetrahydrocannabinol and Cannabidiol on Nocturnal Sleep and Early-Morning Behavior in Young Adults Smoked cannabis for chronic neuropathic pain: a randomized controlled trial MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial The Effects of Nabilone on Sleep in Fibromyalgia: Results of a Randomized Controlled Trial Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial Efficacy and tolerability of high-dose dronabinol maintenance in HIV-positive marijuana smokers: a controlled laboratory study Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Initial experiences with medicinal extracts of cannabis for chronic pain: Results from 34 ‘N of 1’ studies Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial Acute and residual effects of alcohol and marijuana, alone and in combination, on mood and performance Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebo-controlled clinical trial Dronabinol and Marijuana in HIV-Positive Marijuana Smokers: Caloric Intake, Mood, and Sleep An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain Open-Label, Add-on Study of Tetrahydrocannabinol for Chronic Nonmalignant Pain Reinforcing and subjective effects of oral delta 9-THC and smoked marijuana in humans. Effects of nabilone, a synthetic cannabinoid, on postoperative pain A double-blind trial of delta 9-tetrahydrocannabinol in primary anorexia nervosa. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis Childhood sleep problems, early onset of substance use and behavioral problems in adolescence.
abstract: UNLABELLED We assessed the efficacy of dronabinol ( Marinol capsules ; Solvay Pharmaceuticals , Brussels , Belgium ) , a synthetic Delta(9)-THC ( tetrahydrocannabinol ) , in 30 patients taking opioids for chronic pain to determine its potential analgesic effects as an adjuvant treatment . Phase I of this 2-phase study was a r and omized , single-dose , double-blinded , placebo-controlled , crossover trial in which subjects were r and omly administered either 10 mg or 20 mg of dronabinol or identical placebo capsules over the course of three , 8-hour visits . Baseline self-report measures , hourly ratings of pain intensity , pain relief , pain bothersomeness , treatment satisfaction , mood , side effects , and blood serum levels were obtained . Phase II was an extended open-label titrated trial of dronabinol as add-on medication to patients on stable doses of opioids . Results of the Phase I study showed that patients who received dronabinol experienced decreased pain intensity and increased satisfaction compared with placebo . No differences in benefit were found between the 20 mg and 10 mg doses . In the Phase II trial , titrated dronabinol contributed to significant relief of pain , reduced pain bothersomeness , and increased satisfaction compared with baseline . The incidence of side effects was dose-related . Overall , the use of dronabinol was found to result in additional analgesia among patients taking opioids for chronic noncancer pain . PERSPECTIVE This study examines the effect of adding a cannabinoid to the regimen of patients with chronic pain who report significant pain despite taking stable doses of opioids . The results of our preliminary study suggest that dronabinol , a synthetic THC , may have an additive effect on pain relief OBJECTIVES Young people are sleeping less . Short sleep duration has a range of negative consequences including a hypothesized link with psychological distress , which has yet to be studied DESIGN Prospect i ve cohort study SETTING Community-based sample from Australia PARTICIPANTS Twenty thous and ( 20,822 ) young adults ( aged 17 - 24 ) identified through the state vehicle licensing authority . A r and om sample ( n = 5000 ) was approached for follow-up 12 - 18 months later , with 2837 providing full data . MAIN OUTCOME MEASURE Psychological distress , determined by a Kessler 10 score > 21 , at baseline ; and as both onset and persistence of distress at follow-up . RESULTS Shorter sleep duration was linearly associated with prevalent psychological distress : relative risk ( RR ) 1.14 ( 95 % CI 1.12 to 1.15 ) . Only the very short ( < 5 h ) sleepers among those not distressed at baseline had an increased risk for onset of psychological distress ( RR 3.25 [ 95 % CI 1.84 , 5.75 ] ) . Of 945 cohort participants reporting psychological distress at baseline , 419 ( 44 % ) were distressed at follow-up . Each hour less of sleep increased the risk of psychological distress persisting after adjustment for potential confounding variables : RR 1.05 ( 95 % CI 1.01 to 1.10 ) . Long sleep duration showed no association with distress at any time point . CONCLUSIONS Self-reported shorter sleep duration is linearly associated with prevalent and persistent psychological distress in young adults . In contrast , only the very short sleepers had a raised risk of new onset of distress . Different approaches to sleep duration measurement yield different results and should guide any interventions to improve subjective sleep duration in young adults This study compared the efficacy of a tetrahydrocannabinol : cannabidiol ( THC : CBD ) extract , a nonopioid analgesic endocannabinoid system modulator , and a THC extract , with placebo , in relieving pain in patients with advanced cancer . In total , 177 patients with cancer pain , who experienced inadequate analgesia despite chronic opioid dosing , entered a two-week , multicenter , double-blind , r and omized , placebo-controlled , parallel-group trial . Patients were r and omized to THC : CBD extract ( n = 60 ) , THC extract ( n = 58 ) , or placebo ( n = 59 ) . The primary analysis of change from baseline in mean pain Numerical Rating Scale ( NRS ) score was statistically significantly in favor of THC : CBD compared with placebo ( improvement of -1.37 vs. -0.69 ) , whereas the THC group showed a nonsignificant change ( -1.01 vs. -0.69 ) . Twice as many patients taking THC : CBD showed a reduction of more than 30 % from baseline pain NRS score when compared with placebo ( 23 [ 43 % ] vs. 12 [ 21 % ] ) . The associated odds ratio was statistically significant , whereas the number of THC group responders was similar to placebo ( 12 [ 23 % ] vs. 12 [ 21 % ] ) and did not reach statistical significance . There was no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups . No significant group differences were found in the NRS sleep quality or nausea scores or the pain control assessment . However , the results from the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Question naire showed a worsening in nausea and vomiting with THC : CBD compared with placebo ( P = 0.02 ) , whereas THC had no difference ( P = 1.0 ) . Most drug-related adverse events were mild/moderate in severity . This study shows that THC : CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids Troubled sleep is a commonly cited consequence of adolescent drug use , but it has rarely been studied as a cause . Nor have there been any studies of the extent to which sleep behavior can spread in social networks from person to person to person . Here we map the social networks of 8,349 adolescents in order to study how sleep behavior spreads , how drug use behavior spreads , and how a friend 's sleep behavior influences one 's own drug use . We find clusters of poor sleep behavior and drug use that extend up to four degrees of separation ( to one 's friends ' friends ' friends ' friends ) in the social network . Prospect i ve regression models show that being central in the network negatively influences future sleep outcomes , but not vice versa . Moreover , if a friend sleeps ≤7 hours , it increases the likelihood a person sleeps ≤7 hours by 11 % . If a friend uses marijuana , it increases the likelihood of marijuana use by 110 % . Finally , the likelihood that an individual uses drugs increases by 19 % when a friend sleeps ≤7 hours , and a mediation analysis shows that 20 % of this effect results from the spread of sleep behavior from one person to another . This is the first study to suggest that the spread of one behavior in social networks influences the spread of another . The results indicate that interventions should focus on  healthy sleep to prevent drug use and targeting specific individuals may improve outcomes across the entire social network The objective was to determine whether a cannabis-based medicinal extract ( CBME ) benefits a range of symptoms due to multiple sclerosis ( MS ) . A parallel group , double-blind , r and omized , placebo-controlled study was undertaken in three centres , recruiting 160 out patients with MS experiencing significant problems from at least one of the following : spasticity , spasms , bladder problems , tremor or pain . The interventions were oromucosal sprays of matched placebo , or whole plant CBME containing equal amounts of delta-9- tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) at a dose of 2.5- 120 mg of each daily , in divided doses . The primary outcome measure was a Visual Analogue Scale ( VAS ) score for each patient ’s most troublesome symptom . Additional measures included VAS scores of other symptoms , and measures of disability , cognition , mood , sleep and fatigue . Following CBME the primary symptom score reduced from mean ( SE ) 74.36 ( 11.1 ) to 48.89 ( 22.0 ) following CBME and from 74.31 ( 12.5 ) to 54.79 ( 26.3 ) following placebo [ ns ] . Spasticity VAS scores were significantly reduced by CBME ( Sativex ) in comparison with placebo ( P- 0.001 ) . There were no significant adverse effects on cognition or mood and intoxication was generally mild Objective : To test the effectiveness and long term safety of cannabinoids in multiple sclerosis ( MS ) , in a follow up to the main Cannabinoids in Multiple Sclerosis ( CAMS ) study . Methods : In total , 630 patients with stable MS with muscle spasticity from 33 UK centres were r and omised to receive oral Δ9-tetrahydrocannabinol ( Δ9-THC ) , cannabis extract , or placebo in the main 15 week CAMS study . The primary outcome was change in the Ashworth spasticity scale . Secondary outcomes were the Rivermead Mobility Index , timed 10 metre walk , UK Neurological Disability Score , postal Barthel Index , General Health Question naire-30 , and a series of nine category rating scales . Following the main study , patients were invited to continue medication , double blinded , for up to12 months in the follow up study reported here . Results : Intention to treat analysis of data from the 80 % of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months ( Δ9-THC mean reduction 1·82 ( n = 154 , 95 % confidence interval ( CI ) 0.53 to 3.12 ) , cannabis extract 0.10 ( n = 172 , 95 % CI −0.99 to 1.19 ) , placebo −0.23 ( n = 176 , 95 % CI −1.41 to 0.94 ) ; p = 0.04 unadjusted for ambulatory status and centre , p = 0.01 adjusted ) . There was suggestive evidence for treatment effects of Δ9-THC on some aspects of disability . There were no major safety concerns . Overall , patients felt that these drugs were helpful in treating their disease . Conclusions : These data provide limited evidence for a longer term treatment effect of cannabinoids . A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS Background : Central pain in multiple sclerosis ( MS ) is common and often refractory to treatment . Methods : We conducted a single-center , 5-week ( 1-week run-in , 4-week treatment ) , r and omized , double-blind , placebo-controlled , parallel-group trial in 66 patients with MS and central pain states ( 59 dysesthetic , seven painful spasms ) of a whole-plant cannabis-based medicine ( CBM ) , containing delta-9-tetrahydrocannabinol : cannabidiol ( THC : CBD ) delivered via an oromucosal spray , as adjunctive analgesic treatment . Each spray delivered 2.7 mg of THC and 2.5 of CBD , and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours . Results : Sixty-four patients ( 97 % ) completed the trial , 34 received CBM . In week 4 , the mean number of daily sprays taken of CBM ( n = 32 ) was 9.6 ( range 2 to 25 , SD = 6.0 ) and of placebo ( n = 31 ) was 19.1 ( range 1 to 47 , SD = 12.9 ) . Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale . CBM was superior to placebo in reducing the mean intensity of pain ( CBM mean change −2.7 , 95 % CI : −3.4 to −2.0 , placebo –1.4 95 % CI : −2.0 to −0.8 , comparison between groups , p = 0.005 ) and sleep disturbance ( CBM mean change –2.5 , 95 % CI : −3.4 to −1.7 , placebo –0.8 , 95 % CI : −1.5 to −0.1 , comparison between groups , p = 0.003 ) . CBM was generally well tolerated , although more patients on CBM than placebo  reported dizziness , dry mouth , and somnolence . Cognitive side effects were limited to long-term memory storage . Conclusions : Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated BACKGROUND Spasticity is a disabling complication of multiple sclerosis , affecting many patients with the condition . We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design . METHODS A 19-week follow-up , multicentre , double-blind , r and omized , placebo-controlled , parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy . Subjects were treated with nabiximols , as add-on therapy , in a single-blind manner for 4weeks , after which those achieving an improvement in spasticity of ≥20 % progressed to a 12-week r and omized , placebo-controlled phase . RESULTS Of the 572 subjects enrolled , 272 achieved a ≥20 % improvement after 4weeks of single-blind treatment , and 241 were r and omized . The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale ( NRS ) in the r and omized , controlled phase of the study . Intention-to-treat ( ITT ) analysis showed a highly significant difference in favour of nabiximols ( P=0.0002 ) . Secondary end-points of responder analysis , Spasm Frequency Score , Sleep Disturbance NRS Patient , Carer and Clinician Global Impression of Change were all significant in favour of nabiximols . CONCLUSIONS The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice , by limiting exposure to those patients who are likely to benefit from it . Hence , the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment Abstract : The effects of cannabis extracts on nocturnal sleep , early-morning performance , memory , and sleepiness were studied in 8 healthy volunteers ( 4 males , 4 females ; 21 to 34 years ) . The study was double-blind and placebo-controlled with a 4-way crossover design . The 4 treatments were placebo , 15 mg Δ-9-tetrahydrocannabinol ( THC ) , 5 mg THC combined with 5 mg cannabidiol ( CBD ) , and 15 mg THC combined with 15 mg CBD . These were formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-minute period from 10 pm . The electroencephalogram  was recorded during the sleep period ( 11 pm to 7 am ) . Performance , sleep latency , and subjective assessment s of sleepiness and mood were measured from 8:30 am ( 10 hours after drug administration ) . There were no effects of 15 mg THC on nocturnal sleep . With the concomitant administration of the drugs ( 5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD ) , there was a decrease in stage 3 sleep , and with the higher dose combination , wakefulness was increased . The next day , with 15 mg THC , memory was impaired , sleep latency was reduced , and the subjects reported increased sleepiness and changes in mood . With the lower dose combination , reaction time was faster on the digit recall task , and with the higher dose combination , subjects reported increased sleepiness and changes in mood . Fifteen milligrams THC would appear to be sedative , while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counteracted the residual sedative activity of 15 mg THC Background : Chronic neuropathic pain affects 1%–2 % of the adult population and is often refractory to st and ard pharmacologic treatment . Patients with chronic pain have reported using smoked cannabis to relieve pain , improve sleep and improve mood . Methods : Adults with post-traumatic or postsurgical neuropathic pain were r and omly assigned to receive cannabis at four potencies ( 0 % , 2.5 % , 6 % and 9.4 % tetrahydrocannabinol ) over four 14-day periods in a crossover trial . Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle , followed by a nine-day washout period . Daily average pain intensity was measured using an 11-point numeric rating scale . We recorded effects on mood , sleep and quality of life , as well as adverse events . Results : We recruited 23 participants ( mean age 45.4 [ st and ard deviation 12.3 ] years , 12 women [ 52 % ] ) , of whom 21 completed the trial . The average daily pain intensity , measured on the 11-point numeric rating scale , was lower on the prespecified primary contrast of 9.4 % v. 0 % tetrahydrocannabinol ( 5.4 v. 6.1 , respectively ; difference = 0.7 , 95 % confidence interval [ CI ] 0.02–1.4 ) . Preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief . Participants receiving 9.4 % tetrahydrocannabinol reported improved ability to fall asleep ( easier , p = 0.001 ; faster , p < 0.001 ; more drowsy , p = 0.003 ) and improved quality of sleep ( less wakefulness , p = 0.01 ) relative to 0 % tetrahydrocannabinol . We found no differences in mood or quality of life . The most common drug-related adverse events during the period when participants received 9.4 % tetrahydrocannabinol were headache , dry eyes , burning sensation in areas of neuropathic pain , dizziness , numbness and cough . Conclusion : A single inhalation of 25 mg of 9.4 % tetrahydrocannabinol herbal cannabis three times daily for five days reduced the intensity of pain , improved sleep and was well tolerated . Further long-term safety and efficacy studies are indicated . ( International St and ard R and omised Controlled Trial Register no. IS RCT N68314063 Objective Multiple sclerosis ( MS ) is associated with chronic symptoms , including muscle stiffness , spasms , pain and insomnia . Here we report the results of the Multiple Sclerosis and Extract of Cannabis ( MUSEC ) study that aim ed to substantiate the patient based findings of previous studies . Patients and methods Patients with stable MS at 22 UK centres were r and omised to oral cannabis extract ( CE ) ( N=144 ) or  placebo ( N=135 ) , stratified by centre , walking ability and use of antispastic medication . This double blind , placebo controlled , phase III study had a screening period , a 2 week dose titration phase from 5 mg to a maximum of 25 mg of tetrahydrocannabinol daily and a 10 week maintenance phase . The primary outcome measure was a category rating scale ( CRS ) measuring patient reported change in muscle stiffness from baseline . Further CRSs assessed body pain , spasms and sleep quality . Three vali date d MS specific patient reported outcome measures assessed aspects of spasticity , physical and psychological impact , and walking ability . Results The rate of relief from muscle stiffness after 12 weeks was almost twice as high with CE than with placebo ( 29.4 % vs 15.7 % ; OR 2.26 ; 95 % CI 1.24 to 4.13 ; p=0.004 , one sided ) . Similar results were found after 4 weeks and 8 weeks , and also for all further CRSs . Results from the MS scales supported these findings . Conclusion The study met its primary objective to demonstrate the superiority of CE over placebo in the treatment of  muscle stiffness in MS . This was supported by results for secondary efficacy variables . Adverse events in participants treated with CE were consistent with the known side effects of cannabinoids . No new safety concerns were observed . Trial registration number NCT00552604 BACKGROUND : Sleep disorders affect many patients with chronic pain conditions . Cannabis has been reported by several patient population s to help sleep . We evaluated the safety and efficacy of nabilone , a synthetic cannabinoid , on sleep disturbance in fibromyalgia ( FM ) , a disease characterized by widespread chronic pain and insomnia . METHODS : We conducted a r and omized , double-blind , active-control , equivalency crossover trial to compare nabilone ( 0.5–1.0 mg before bedtime ) to amitriptyline ( 10–20 mg before bedtime ) in patients with FM with chronic insomnia . Subjects received each drug for 2 wk with a 2-wk washout period . The primary outcome was sleep quality , measured by the Insomnia Severity Index and the Leeds Sleep Evaluation Question naire . Secondary outcomes included pain , mood , quality of life , and adverse events ( AEs ) . RESULTS : Thirty-one subjects were enrolled and 29 completed the trial ( 26 women , mean age 49.5 yr ) . Although sleep was improved by both amitriptyline and nabilone , nabilone was superior to amitriptyline ( Insomnia Severity Index difference = 3.2 ; 95 % confidence interval = 1.2–5.3 ) . Nabilone was marginally better on the restfulness ( Leeds Sleep Evaluation Question naire difference = 0.5 [ 0.0–1.0 ] ) but not on wakefulness ( difference = 0.3 [ −0.2 to 0.8 ] ) . No effects on pain , mood , or quality of life were observed . AEs were mostly mild to moderate and were more frequent with nabilone . The most common AEs for nabilone were dizziness , nausea , and dry mouth . CONCLUSIONS : Nabilone is effective in improving sleep in patients with FM and is well tolerated . Low-dose nabilone given once daily at bedtime may be considered as an alternative to amitriptyline . Longer trials are needed to determine the duration of effect and to characterize long-term safety BACKGROUND Multiple sclerosis is associated with muscle stiffness , spasms , pain , and tremor . Much anecdotal evidence suggests that cannabinoids could help these symptoms . Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis . METHODS We did a r and omised , placebo-controlled trial , to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity . 630 participants were treated at 33 UK centres with oral cannabis extract ( n=211 ) , Delta9-tetrahydrocannabinol ( Delta9-THC ; n=206 ) , or placebo ( n=213 ) . Trial duration was 15 weeks . Our primary outcome measure was change in overall spasticity scores , using the Ashworth scale . Analysis was by intention to treat . FINDINGS 611 of 630 patients were followed up for the primary endpoint . We noted no treatment effect of cannabinoids on the primary outcome ( p=0.40 ) . The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 ( 95 % CI -1.04 to 1.67 ) , and for those taking Delta9-THC versus placebo it was 0.94 ( -0.44 to 2.31 ) . There was evidence of a treatment effect on patient-reported spasticity and pain ( p=0.003 ) , with improvement in spasticity reported in 61 % ( n=121 , 95 % CI 54.6 - 68.2 ) , 60 % ( n=108 , 52.5 - 66.8 ) , and 46 % ( n=91 , 39.0 - 52.9 ) of participants on cannabis extract , Delta9-THC , and placebo , respectively . INTERPRETATION Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale . However , though there was a degree of unmasking among the patients in the active treatment groups , objective improvement in mobility and patients ' opinion of an improvement in pain suggest cannabinoids might be clinical ly useful & NA ; The objective was to investigate the effectiveness of cannabis‐based medicines for treatment of  chronic pain associated with brachial plexus root avulsion . This condition is an excellent human model of central neuropathic pain as it represents an unusually homogenous group in terms of anatomical location of injury , pain descriptions and patient demographics . Forty‐eight patients with at least one avulsed root and baseline pain score of four or more on an 11‐point ordinate scale participated in a r and omised , double‐blind , placebo‐controlled , three period crossover study . All patients had intractable symptoms regardless of current analgesic therapy . Patients entered a baseline period of 2 weeks , followed by three , 2‐week treatment periods during each of which they received one of three oromucosal spray preparations . These were placebo and two whole plant extracts of Cannabis sativa L. : GW‐1000‐02 ( Sativex ® ) , containing Δ9tetrahydrocannabinol (THC):cannabidiol ( CBD ) in an approximate 1:1 ratio and GW‐2000‐02 , containing primarily THC . The primary outcome measure was the mean pain severity score during the last 7 days of treatment . Secondary outcome measures included pain related quality of life assessment s. The primary outcome measure failed to fall by the two points defined in our hypothesis . However , both this measure and measures of sleep showed statistically significant improvements . The study medications were generally well tolerated with the majority of adverse events , including intoxication type reactions , being mild to moderate in severity and resolving spontaneously . Studies of longer duration in neuropathic pain are required to confirm a clinical ly relevant , improvement in the treatment of this condition Rationale Dronabinol ( Δ9tetrahydrocannabinol ) is approved for HIV-related anorexia , yet , little is known about its effects in HIV-positive marijuana smokers . HIV-negative marijuana smokers require higher than recommended dronabinol doses to experience expected effects . Objectives Employing a within-subjects , double-blind , placebo-controlled design , we assessed the effects of repeated high-dose dronabinol in HIV-positive marijuana smokers taking antiretroviral medication . Methods Participants ( N = 7 ) , who smoked marijuana 4.2 ± 2.3 days/week , resided in a residential laboratory for two 16-day stays , receiving  dronabinol  ( 10 mg QID ) in one stay and placebo in the other . Efficacy was assessed with objective ly verified food intake and body weight . Tolerability was measured with sleep , subjective , and cognitive assessment s. For analyses , each inpatient stay was divided into two phases , days 1–8 and 9–16 ; we compared dronabinol ’s effects with placebo in each 8-day phase to investigate tolerance . Results Despite sustained increases in self-reported food cravings  , dronabinol only increased caloric intake in the initial 8 days of dosing . Similarly , sleep quality was improved only in the first 8 days of dosing  .  Dronabinol ’s mood-enhancing effects were sustained across the 16-day inpatient stay . Dronabinol was well tolerated , causing few negative subjective or cognitive effects . Conclusions In HIV-positive marijuana smokers , high dronabinol doses safely and effectively increased caloric intake . However , repeated high-dose dronabinol appeared to result in selective tolerance to these effects . These findings indicate that HIV-positive individuals who smoke marijuana may require higher dronabinol doses than are recommended by the FDA . Future research to establish optimal dosing regimens , and reduce the development of tolerance , is required OBJECTIVES To assess the efficacy of a cannabis-based medicine ( CBM ) in the treatment of  pain due to rheumatoid arthritis ( RA ) . METHODS We compared a CBM ( Sativex ) with placebo in a r and omized , double-blind , parallel group study in 58 patients over 5 weeks of treatment . The CBM was administered by oromucosal spray in the evening and assessment s were made the following morning . Efficacy outcomes assessed were pain on movement , pain at rest , morning stiffness and sleep quality measured by a numerical rating scale , the Short-Form McGill Pain Question naire ( SF-MPQ ) and the DAS28 measure of disease activity . RESULTS Seventy-five patients were screened and 58 met the eligibility criteria . Thirty-one were r and omized to the CBM and 27 to placebo .  Mean ( S.D. ) daily dose achieved in the final treatment week was 5.4 ( 0.84 ) actuations for the CBM and 5.3 ( 1.18 ) for placebo . In comparison with placebo , the CBM produced statistically significant improvements in pain on movement , pain at rest , quality of sleep , DAS28 and the SF-MPQ pain at present component . There was no effect on morning stiffness but baseline scores were low . The large majority of adverse effects were mild or moderate , and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group . CONCLUSIONS In the first ever controlled trial of a CBM in RA , a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment . Whilst the differences are small and variable across the population , they represent benefits of clinical relevance and show the need for more detailed investigation in this indication Three Cannabis Based Medicinal Extracts ( CBMEs ) for sublingual use became available in 2000 . A total of 34 ‘ N of 1 ’ studies were undertaken using this novel therapy for patients with chronic , mainly neuropathic , pain and associated symptoms to explore efficacy , tolerability , safety and dosages . Three CBMEs ( Δ9 Tetrahydrocannabinol ( THC ) , Cannabidiol ( CBD ) and a 1 : 1 mixture of them both ) were given over a 12‐week period . After an initial open‐label period , the CBMEs were used in a r and omised , double‐blind , placebo controlled , crossover trial . Extracts which contained THC proved most effective in symptom control . Regimens for the use of the sublingual spray emerged and a wide range of dosing requirements was observed . Side‐effects were common , reflecting a learning curve for both patient and study team . These were generally acceptable and little different to those seen when other psycho‐active agents are used for chronic pain . These initial experiences with CBME open the way to more detailed and extensive studies Background Many patients with amyotrophic lateral sclerosis ( ALS ) experience cramps during the course of the disease but so far , none of the medications used has been of proven benefit . The objective was to determine the effect of orally administered tetrahydrocannabinol ( THC ) on cramps in ALS patients . Methods The authors conducted a r and omised , double-blind , placebo-controlled crossover trial in 27 ALS patients suffering from moderate to severe ( visual analogue scale ( VAS ) ; VAS≥4 ) daily cramps . There were 7 women and 20 men with a mean age of 57 years and a mean functional ALS score ( ALSFRS-R ) of 38.4 . Patients were r and omly assigned to receive 5 mg THC twice daily followed by placebo or vice versa . Each treatment period lasted for 2 weeks and was preceded by a 2-week drug-free observation period ( run-in , wash-out period respectively ) . The primary outcome measure was change in cramp intensity as assessed by a VAS . Secondary outcome measures included the number of cramps per day , number of cramps during daytime and bedtime , intensity of fasciculations ( VAS ) as well as vali date d measures of quality of life ( ALSAQ-40 ) , quality of sleep ( SDQ ) , appetite ( FAACT ) and depression ( HADS ) . Results Complete data were available from 22 patients . THC was well tolerated . There was no evidence for a treatment effect on cramp intensity , number of cramps , fasciculation intensity or any of the other secondary outcome measures . Conclusions This interventional study with orally administered THC 5 mg twice daily did not demonstrate subjective improvement of cramp intensity in ALS patients The duration of behavioral impairment after marijuana smoking remains a matter of some debate . Alcohol and marijuana are frequently used together , but there has been little study of the effects of this drug combination on mood and behavior the day after use . The present study was design ed to address these issues . Fourteen male and female subjects were each studied under four conditions :  alcohol alone , marijuana alone , alcohol and marijuana in combination , and no active treatment .  Mood and performance assessment s were made during acute intoxication and twice the following day ( morning and mid-afternoon ) . Acutely , each drug alone produced moderate levels of subjective intoxication and some degree of behavioral impairment . The drug combination produced the greatest level of impairment on most tasks and “ strong ” overall subjective ratings . There were few significant interactions between the two drugs , indicating that their effects tended to be additive . Only weak evidence was obtained for subjective or behavioral effects the day after active drug treatments , although consistent time-of-day effects ( morning versus afternoon ) were observed on several subjective and behavioral measures . In sum , this study provided little evidence that moderate doses of alcohol and marijuana , consumed either alone or in combination , produce behavioral or subjective impairment the following day Objective To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain . Design R and omised , double blind , crossover trial of 14 weeks ’ duration comparing dihydrocodeine and nabilone . Setting Outpatient units of three hospitals in the United Kingdom . Participants 96 patients with chronic neuropathic pain , aged 23 - 84 years . Main outcome measures The primary outcome was difference between nabilone and dihydrocodeine in pain , as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period . Secondary outcomes were changes in mood , quality of life , sleep , and psychometric function . Side effects were measured by a question naire . Intervention Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks . Treatment periods were separated by a 2 week washout period . Results Mean baseline visual analogue score was 69.6 mm ( range 29.4 - 95.2 ) on a 0 - 100 mm scale . 73 patients were included in the available case analysis and 64 patients in the per protocol analysis . The mean score was 6.0 mm longer for nabilone than for dihydrocodeine ( 95 % confidence interval 1.4 to 10.5 ) in the available case analysis and 5.6 mm ( 10.3 to 0.8 ) in the per protocol analysis . Side effects were more frequent with nabilone . Conclusion Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects , although no major adverse events occurred for either drug . Trial registration Current Controlled Trials IS RCT N15330757 UNLABELLED Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge . Nabiximols ( Nabiximols is the U.S. Adopted Name [ USAN ] for Sativex [ GW Pharma Ltd , Wiltshire , U.K. ] , which does not yet have an INN ) , a novel cannabinoid formulation , is undergoing investigation as add-on therapy for this population . In a r and omized , double-blind , placebo-controlled , grade d-dose study , patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose ( 1 - 4 sprays/day ) , medium dose ( 6 - 10 sprays/day ) , or high dose ( 11 - 16 sprays/day ) . Average pain , worst pain and sleep disruption were measured daily during 5 weeks of treatment ; other question naires measured quality of life and mood .  A total of 360 patients were r and omized ; 263 completed . There were no baseline differences across groups . The 30 % responder rate primary analysis was not significant for nabiximols versus placebo ( overall P = .59 ) . A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall ( P = .035 ) , and specifically in the low-dose ( P = .008 ) and medium-dose ( P = .039 ) groups . In the low-dose group , results were similar for mean average pain ( P = .006 ) , mean worst pain ( P = .011 ) , and mean sleep disruption ( P = .003 ) . Other question naires showed no significant group differences . Adverse events were dose-related and only the high-dose group compared unfavorably with placebo . This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials . PERSPECTIVE Nabiximols , a novel cannabinoid formulation , may be a useful add-on analgesic for patients with opioid-refractory cancer pain . A r and omized , double-blind , placebo-controlled , grade d-dose study demonstrated efficacy and safety at low and medium doses Abstract Cannabinoids are known to have analgesic properties . We evaluated the effect of oro‐mucosal sativex , ( THC : CBD ) , an endocannabinoid system modulator , on pain and allodynia , in 125 patients with neuropathic pain of peripheral origin in a five‐week , r and omised , double‐blind , placebo‐controlled , parallel design trial . Patients remained on their existing stable analgesia . A self‐titrating regimen was used to optimise drug administration . Sixty‐three patients were r and omised to receive sativex and 62 placebo .  The mean reduction in pain intensity scores ( primary outcome measure ) was greater in patients receiving sativex than placebo ( mean adjusted scores −1.48 points vs. −0.52 points on a 0–10 Numerical Rating Scale ( p = 0.004 ; 95 % CI : −1.59 , −0.32 ) . Improvements in Neuropathic Pain Scale composite score ( p = 0.007 ) , sleep NRS ( p = 0.001 ) , dynamic allodynia ( p = 0.042 ) , punctate allodynia ( p = 0.021 ) , Pain Disability Index ( p = 0.003 ) and Patient ’s Global Impression of Change ( p < 0.001 ) were similarly greater on sativex vs. placebo . Sedative and gastrointestinal side effects were reported more commonly by patients on active medication . Of all participants , 18 % on sativex and 3 % on placebo withdrew during the study . An open‐label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks Objectives : Individuals with HIV constitute the largest group using cannabinoids for medicinal reasons ; yet , no studies have directly compared the tolerability and efficacy of smoked marijuana and oral dronabinol maintenance in HIV-positive marijuana smokers . This placebo-controlled within-subjects study evaluated marijuana and dronabinol across a range of behaviors : eating topography , mood , cognitive performance , physiologic measures , and sleep . Methods : HIV-positive marijuana smokers ( n = 10 ) completed 2 16-day inpatient phases . Each dronabinol ( 5 and 10 mg ) and marijuana ( 2.0 % and 3.9 % Δ9-tetrahydrocannabinol [ THC ] ) dose was administered 4 times daily for 4 days , but only 1 drug was active per day , thereby maintaining double-blind dosing . Four days of placebo washout separated each active cannabinoid condition . Results : As compared with placebo , marijuana and dronabinol dose dependently increased daily caloric intake and body weight in HIV-positive marijuana smokers . All cannabinoid conditions produced significant intoxication , except for low-dose dronabinol ( 5 mg ) ; the intoxication was rated positively ( eg , “ good drug effect ” ) with little evidence of discomfort and no impairment of cognitive performance . Effects of marijuana and dronabinol were comparable , except that only marijuana ( 3.9 % THC ) improved ratings of sleep . Conclusions : These data suggest that for HIV-positive marijuana smokers , both dronabinol ( at doses 8 times current recommendations ) and marijuana were well tolerated and produced substantial and comparable increases in food intake Neuropathic pain ( NeP ) is prevalent in patients with peripheral neuropathy ( PN ) , regardless of etiology . We sought to compare the efficacy of the cannabinoid nabilone as either monotherapy or adjuvant therapy with a first-line medication for NeP , gabapentin , in a patient population with PN-NeP. Patients diagnosed with PN-NeP were permitted to initiate monotherapy ( nabilone or gabapentin ) or add one of these two medications ( adjuvant therapy ) to their existing NeP treatment regimen in a non-r and omized open-label nature . Baseline data collected included a primary outcome ( visual analog scores [ VAS ] of pain ) and secondary outcomes ( quality of life [ EuroQol 5 Domains and Short-Form 36 ] assessment s and assessment s of sleep [ Medical Outcomes Sleep Study Scale { MOSSS } ] , anxiety and depression [ Hospital Anxiety and Depression Scale ] , and pain [ Brief Pain Inventory ] ) . Re assessment and modulation of dosing and /or medications occurred at 3- and 6-month intervals . Medication adverse effects and drug efficacy , as well as question naires , were assessed at 6 months . Matched analysis of variance testing was performed to compare 3- and 6-month scores with baseline , as well as to compare therapies at equal time points . Significant improvements in pain VAS were seen in all treatment groups at 6 months . Numerous sleep parameters within MOSSS , Brief Pain Inventory , and Short-Form 36 improved in patients receiving nabilone or gabapentin either as monotherapy or adjuvant treatment . Hospital Anxiety and Depression Scale-A scores were significantly improved in all treatment groups . Sleep adequacy and the sleep problems index within the MOSSS improved in nabilone monotherapy patients in particular . The benefits of monotherapy or adjuvant therapy with nabilone appear comparable to gabapentin for management of NeP. We advocate for head-to-head r and omized , double-blind studies for current therapies for NeP in order to determine potential advantages beneficial in this patient population TOC summary This enriched‐enrollment , r and omized , double‐blind , placebo‐controlled , flexible‐dose adjuvant study demonstrated that nabilone provided improvements in pain , anxiety , quality of life and patient satisfaction for patients with diabetic neuropathic pain . ABSTRACT Cannabinoids are emerging as potential options for neuropathic pain treatment . This study evaluated an oral cannabinoid , nabilone , in the treatment of refractory human diabetic peripheral neuropathic pain ( DPN ) . We performed a single‐center , r and omized , double‐blind , placebo‐controlled , flexible‐dose study with an enriched enrolment r and omized withdrawal design . DPN subjects with a pain score ⩾4 ( 0‐10 scale ) continued regular pain medications and were administered single‐blinded adjuvant nabilone for 4 weeks . Subjects achieving ⩾30 % pain relief ( 26/37 ) were then r and omized and treated with either flexible‐dose nabilone 1‐4 mg/day ( n = 13 ) or placebo ( n = 13 ) in a further 5‐week double‐blind treatment period , with 30 % ( 11/37 ) of subjects deemed run‐in‐phase nabilone nonresponders . For nabilone run‐in‐phase responders , there was an improvement in the change in mean end‐point neuropathic pain  vs placebo ( mean treatment reduction of 1.27 ; 95 % confidence interval 2.29‐0.25 , P = 0.02 ) , with an average nabilone dose at end point of 2.9 ± 1.1 mg/day , and improvements from baseline for the anxiety subscale of the Hospital Anxiety and Depression Scale , the Medical Outcomes Study sleep scale problems index , and the European Quality of Life‐5‐Domains index score ( each P < 0.05 ) . Nabilone run‐in‐phase responders reported greater global end‐point improvement with nabilone than with placebo ( 100 % vs 31 % ; P < 0.05 ) . Medication‐related confusion led to discontinuation in 2/37 subjects during single‐blind nabilone treatment . Potential unmasking occurred in 62 % of both groups . Flexible‐dose nabilone 1‐4 mg/day was effective in relieving DPN symptoms , improving disturbed sleep , quality of life , and overall patient status . Nabilone was well tolerated and successful as adjuvant in patients with DPN Cannabinoids have been used for pain relief for centuries and recent studies have investigated their analgesic and anti-inflammatory mechanisms , as well as clinical efficacy , in treating chronic pain . We report an open-label study addressed to evaluate the effect and adverse events of orally administered Δ -9-tetrahydrocannabinol ( Δ -9-THC ) in 13 patients with chronic nonmalignant pain ( CNMP ) unresponsive to conventional pharmacotherapy . The effect of the treatment was assessed on an eight-item HRQoL question naire . Five out of 13 patients reported adequate response to the treatment while eight patients reported inadequate or no response . Seven patients did not experience any adverse events ( AEs ) , six patients reported AEs , two of which discontinued the treatment . We conclude that oral THC may be a valuable therapeutic option for selected patients with CNMP that are unresponsive to previous treatments , though further research is warranted to characterize those patients The reinforcing and subjective effects of oral delta-9-tetrahydrocannabinol ( THC ) and smoked marijuana were studied in two groups of regular marijuana users . One group ( N = 10 ) was tested with smoked marijuana and the other ( N = 11 ) with oral THC .  Reinforcing effects were measured with a discrete-trial choice procedure which allowed subjects to choose between the self-administration of active drug or placebo on two independent occasions . Subjective effects and heart rate were measured before and after drug administration . Smoked active marijuana was chosen over placebo on both choice occasions by all subjects . Similarly , oral THC was chosen over placebo on both occasions by all but one subject . Both active drug treatments produced qualitatively and quantitatively similar subjective effects , and both significantly increased heart rate , although the time course of effects differed substantially between the two treatments . The results demonstrate that both smoked marijuana and oral THC can serve as positive reinforcers in human subjects under laboratory conditions . The experimental paradigm used here should prove useful for identifying factors that influence the self-administration of marijuana and other cannabinoids by humans Purpose Cannabinoids have been shown to have analgesic properties in animal studies , but a potential role for these drugs in acute pain management has not been established . It was hypothesized that nabilone , an oral cannabinoid synthetic tetrahydrocannabinol analogue , decreases morphine consumption , pain scores , nausea and vomiting following major surgery . Methods A double-blind , r and omized , placebo-controlled , parallel-group pilot trial compared the effects of two different doses , 1 mg ( n = 11 ) and 2 mg ( n = 9 ) of nabilone , ketoprofen 50 mg ( n = 11 ) or placebo ( n = 10 ) , given at eight-hour intervals for 24 hr . Outcomes included morphine consumption , pain scores and emesis after major surgery . Secondary outcomes included patient tolerability of the study medication . Results Forty-one patients ( mean age 52 ± 2 yr ) undergoing gynecologic ( 46 % ) , orthopedic ( 44 % ) , or other ( 10 % ) surgery were recruited . Cumulative 24-hr morphine consumption was not different between the four groups , but pain scores at rest and on movement were significantly higher in the 2 mg nabilone group compared to the other groups . There were no significant differences between groups with respect to episodes of nausea and vomiting , quality of sleep , sedation , euphoria , pruritus , or the number and severity of adverse events . No serious adverse event was recorded . Conclusions Contrary to the main hypothesis , high dose nabilone in the presence of morphine patient controlled analgesia is associated with an increase in pain scores in patients undergoing major surgery . RésuméObjectifLes propriétés analgésiques des cannabinoïdes ont été démontrées chez des animaux , mais leur rôle possible sur le contrôle de la douleur aiguë n’a pas été établi . Notre hypothèse voulait que la nabilone , analogue synthétique oral du cannabinoïde tétrahydrocannabinol , diminue la consommation de morphine , les scores de douleur , les nausées et les vomissements à la suite d’une opération chirurgicale majeure . MéthodeDans une étude pilote de groupes parallèles , r and omisée , à double insu et contrôlée contre placebo , les effets de deux doses de nabilone , 1 mg ( n = 11 ) et 2 mg ( n = 9 ) , de 50 mg de kétoprofène ( n = 11 ) ou d’un placebo  ( n = 10 ) , administrés à 8 h d’intervalle pendant 24 h , ont été comparés . La consommation de  morphine , les scores de douleur et les vomissements ont été notés après une chirurgie majeure . Les effets de la médication sur le patient étaient également étudiés . RésultatsQuarante et un patients ( moyenne d’âge de 52 ± 2 ans ) subissant une intervention gynécologique ( 46 % ) , orthopédique ( 44 % ) ou autre ( 10 % ) ont été recrutés . La consommation cumulative de morphine  sur 24 h était similaire dans les quatre groupes , mais les scores de douleur au repos et au mouvement ont été significativement plus élevés dans le groupe nabilone 2 mg . Aucune différence intergroupe significative n’est apparue quant aux épisodes de nausées et de vomissements , la qualité du sommeil , la sédation , l’euphorie , le prurit ou le nombre et la sévérité des événements indésirables . Aucun incident sérieux n’a été enregistré . Conclusion Contrairement à notre hypothèse , une forte dose de nabilone , en présence de morphine administrée comme analgésie auto-contrôlée , est associée à une hausse des scores de douleur chez les patients qui subissent une chirurgie majeure Δ9-Tetrahydrocannabinol ( Δ9-THC ) , the most prominent psychoactive cannabinoid in Cannabis sativa L. ( marijuana ) , has been reported to have properties of appetite stimulation , promotion of weight gain , and antiemetic efficacy in selected patient population s. In this 4-week , double-blind , crossover study , 11 female patients with primary anorexia nervosa ( PAN ) were evaluated on Δ9-THC and on an active placebo , diazepam . All patients participated in a st and ardized behavior modification treatment program . The following data were obtained : ( 1 ) daily weight , ( 2 ) daily caloric intake , and ( 3 ) weekly psychiatric assessment s. The two groups were comparable on all measures at baseline except for two items on the behavioral rating scales . The only significant differences found between the changes over time on Δ9-THC versus diazepam were more pathology on Δ9-THC for somatization , interpersonal sensitivity , and sleep disturbance . Three patients experienced severe dysphoric reactions consisting of paranoid ideation and feelings of loss of control during Δ9-THC administration . One week after the study ended , each subject was given the highest dose level of Δ8-THC achieved in the study , and periodic blood sample s were obtained coincident with self-rated “ subjective high ” assessment s and pulse measurements . Quantitative analyses of these sample s indicated peak times of 1 to 5 hours postdose for Δ9- THC and for its primary active metabolite , 11-hydroxy-THC , which generally coincided with peak times for “ subjective high ” and pulse rate . The results of this clinical investigation suggest that Δ9-THC is not efficacious , in short-term administration , in the treatment of primary anorexia nervosa and is associated with significant psychic disturbance in some PAN patients Abstract Background : Muscle spasticity is common in multiple sclerosis ( MS ) , occurring in more than 60 % of patients . Objective : To compare Sativex with placebo in relieving symptoms of spasticity due to MS . Methods : A 15-week , multicenter , double-blind , r and omized , placebo-controlled , parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy . Results : The primary endpoint was a spasticity 0–10 numeric rating scale ( NRS ) . Intention-to-treat ( ITT ) analysis showed a non-significant improvement in NRS score , in favor of Sativex . The per protocol ( PP ) population ( 79 % of subjects ) change in NRS score and responder analyses ( ≥30 % improvement from baseline ) were both significantly superior for Sativex , compared with placebo : −1·3 versus −0·8 points ( change from baseline , p=0·035 ) ; and 36 % versus 24 % ( responders , p=0·040 ) . These were supported by the time to response ( ITT : p=0·068 ; PP : p=0·025 ) analyses , carer global impression of change assessment ( p=0·013 ) and timed 10-meter walk ( p=0·042 ) . Among the subjects who achieved a ≥30 % response in spasticity  with Sativex , 98 , 94 and 73 % reported improvements of 10 , 20 and 30 % , respectively , at least once during the first 4 weeks of treatment . Sativex was generally well tolerated , with most adverse events reported being mild-to-moderate in severity . Discussion and conclusions : The 0–10 NRS and responder PP analyses demonstrated that Sativex treatment result ed in a significant reduction in treatment-resistant spasticity , in subjects with advanced MS and severe spasticity . The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status BACKGROUND Very few prospect i ve studies examine the relationship between childhood sleep problems  and subsequent substance use . In this study , we examined how sleep problems at ages 3 - 8 predicted onset of alcohol , cigarette , and marijuana use in adolescence . We also investigated the relationships between childhood sleep problems and adolescent internalizing and externalizing problems . METHODS Study participants were 292 boys and 94 girls from a community sample of high risk families and controls in an ongoing longitudinal study . RESULTS Controlling for parental alcoholism , sleep problems at ages 3 - 8 predicted onset of alcohol , cigarette , and marijuana use among boys and onset of alcohol use among girls . Childhood sleep problems were related to maternal ratings of internalizing and externalizing problems during adolescence for both boys and girls . Adjusting for these problems did not weaken the effects of sleep problems on onset of substance use . CONCLUSIONS This is to our knowledge the first study that prospect ively examines gender differences in the relationship between sleep problems and early onset of substance use . Childhood sleep problems predicted early onset of substance use for boys but not girls . If childhood sleep problems indeed increase the probability of substance use onset , greater attention by parents to  sleep problems in children and adolescents would potentially have ameliorative long-term effects . Parents are encouraged to explore different ways to help their children sleep better , including obtaining information and suggestions from their primary care physicians
target: Findings were mixed and showed various effects of cannabinoid administration on several aspects of sleep .
background: This paper review s the literature regarding the effects of cannabinoid administration on  sleep in humans .