IMPORTANCE There are no medications approved for treating cannabis dependence or withdrawal. The cannabis extract nabiximols (Sativex), developed as a multiple sclerosis treatment, offers a potential agonist medication for cannabis withdrawal.OBJECTIVE To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal. DESIGN, SETTING, AND PARTICIPANTSA 2-site, double-blind randomized clinical inpatient trial with a 28-day follow-up was conducted in New South Wales, Australia. Participants included 51 DSM-IV-TR cannabis-dependent treatment seekers.INTERVENTIONS A 6-day regimen of nabiximols (maximum daily dose, 86.4 mg of Δ9-tetrahydrocannabinol and 80 mg of cannabidiol) or placebo with standardized psychosocial interventions during a 9-day admission.MAIN OUTCOMES AND MEASURES Severity of cannabis withdrawal and cravings (Cannabis Withdrawal Scale), retention in withdrawal treatment, and adverse events. Secondary outcomes include postwithdrawal cannabis use, health outcomes, and psychosocial outcomes.RESULTS Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal relative to placebo (F 8,377.97 = 2.39; P = .01), including effects on withdrawal-related irritability, depression, and cannabis cravings. Nabiximols had a more limited, but still positive, therapeutic benefit on sleep disturbance, anxiety, appetite loss, physical symptoms, and restlessness. Nabiximols patients remained in treatment longer during medication use (unadjusted hazard ratio, 3.66 [95% CI, 1.18-11.37]; P = .02), with 2.84 the number needed to treat to achieve successful retention in treatment. Participants could not reliably differentiate between nabiximols and placebo treatment (χ 2 1 = 0.79; P = .67), and those receiving nabiximols did not report greater intoxication (F 1,6 = 0.22; P = .97). The number (F 1,50 = 0.3; P = .59) and severity (F 1,50 = 2.69; P = .10) of adverse events did not differ significantly between groups. Both groups showed reduced cannabis use at follow-up, with no advantage of nabiximols over placebo for self-reported cannabis use (F 1,48 = 0.29; P = .75), cannabis-related problems (F 1,49 = 2.33; P = .14), or cannabis dependence (F 1,50 < 0.01; P = .89). CONCLUSIONS AND RELEVANCEIn a treatment-seeking cohort, nabiximols attenuated cannabis withdrawal symptoms and improved patient retention in treatment. However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use following medication cessation. The data support further evaluation of nabiximols for management of cannabis dependence and withdrawal in treatment-seeking populations.

Growth retardation as well as the development of Cushingoid features in adrenally insufficient patients treated with the currently accepted replacement dose of cortisol (33-41 mumol/day.m2; 12-15 mg/m2.day) prompted us to reevaluate the cortisol production rate (FPR) in normal subjects and patients with Cushing's syndrome, using a recently developed thermospray liquid chromatography-mass spectrometry method. The stable isotope [9,12,12-2H3]cortisol was infused continuously for 31 h at about 5% of the anticipated FPR. Blood samples were obtained at 20-min intervals for 24 h, spun, and pooled in 4-h groups. Tracer dilution in plasma was determined by liquid chromatography/mass spectrometry. The method was validated with controlled infusions in 6 patients with adrenal insufficiency. Results from 12 normal volunteers revealed a FPR of 27.3 +/- 7.5 mumol/day (9.9 +/- 2.7 mg/day) or 15.7 mumol/day.m2; 5.7 mg/m2. day). A previously unreported circadian variation in FPR was observed. Patients with Cushing's syndrome demonstrated unequivocal elevation of FPR and cortisol concentration correlated during each sample period in normal volunteers, indicating that cortisol secretion, rather than metabolism, is mainly responsible for changes in plasma cortisol. Our data suggest that the FPR in normal subjects may be lower than previously believed.

On two separate occasions, eight subjects controlled speed to run the greatest distance possible in 30 min in a hot, humid environment (ambient temperature 32 degrees C, relative humidity 60%). For the experimental test (precooling), exercise was preceeded by cold-water immersion. Precooling increased the distance run by 304 +/- 166 m (P < 0.05). Precooling decreased the pre-exercise rectal and mean skin temperature by 0.7 degrees C and 5.9 degrees C, respectively (P < 0.05). Rectal and mean skin temperature were decreased up to 20 and 25 min during exercise, respectively (P < 0.05). Mean body temperature decreased from 36.5 +/- 0.1 degrees C to 33.8 +/- 0.2 degrees C following precooling (P < 0.05) and remained lower throughout exercise (P < 0.01) and at the end of exercise (by 0.8 degrees C; P < 0.05). The rate of heat storage at the end of exercise increased from 113 +/- 45 to 249 +/- 55 W.m-2 (P < 0.005). Precooling lowered the heart rate at rest (13%), 5 (9%), and 10 min (10%) exercise (P < 0.05) and increased the end of exercise blood lactate from 4.9 +/- 0.5 to 7.4 +/- 0.9 mmol.L-1 (P < 0.01). The VO2 at 10 and 20 min of exercise and total body sweating are not different between tests. In conclusion, water immersion precooling increased exercise endurance in hot, humid conditions with an enhanced rate of heat storage and decreased thermoregulatory strain.

The effects of sprint training on muscle metabolism and ion regulation during intense exercise remain controversial. We employed a rigorous methodological approach, contrasting these responses during exercise to exhaustion and during identical work before and after training. Seven untrained men undertook 7 wk of sprint training. Subjects cycled to exhaustion at 130% pretraining peak oxygen uptake before (PreExh) and after training (PostExh), as well as performing another posttraining test identical to PreExh (PostMatch). Biopsies were taken at rest and immediately postexercise. After training in PostMatch, muscle and plasma lactate (Lac(-)) and H(+) concentrations, anaerobic ATP production rate, glycogen and ATP degradation, IMP accumulation, and peak plasma K(+) and norepinephrine concentrations were reduced (P<0.05). In PostExh, time to exhaustion was 21% greater than PreExh (P<0.001); however, muscle Lac(-) accumulation was unchanged; muscle H(+) concentration, ATP degradation, IMP accumulation, and anaerobic ATP production rate were reduced; and plasma Lac(-), norepinephrine, and H(+) concentrations were higher (P<0.05). Sprint training resulted in reduced anaerobic ATP generation during intense exercise, suggesting that aerobic metabolism was enhanced, which may allow increased time to fatigue.

could be the result of repeated isometric contractions, particularly from the arm and forearm muscles. (Br J Sports Med 1999;33:14-18) Keywords: rock climbing; performance; oxygen uptake; heart rate; lactate Sport climbing is a discipline of rock climbing which is performed indoors and outdoors. Indoor sport climbing is characterised by gymnastic type movements on walls fitted with artificial hand and foot holds and is an internationally contested event. Outdoor sport climbing requires similar movements with the climber guarded from injury during a fall by protection fixed in the rock before ascent. This style of rock climbing and the increased popularity of climbing in recent years have contributed to an increase in the number and difficulty of rock climbing ascents.Although climbers are characterised by low body fat, exceptional power to weight ratios, 1 2 and forearm circulatory adaptations favouring the performance of isometric work, 3 the physiological factors related to sport climbing remain essentially undefined. Previous research suggests that indoor sport climbing is highly anaerobic in nature given the low fraction (∼46%) of running maximum oxygen uptake (Ṽ O 2max ) required for ascents of three to five minutes' duration. 4 However, no study has reported Ṽ O 2 in well trained climbers at diVerent climbing velocities or Ṽ O 2 as peak oxygen uptake (Ṽ O 2climb-peak ) determined during a specific incremental climbing test to exhaustion. Furthermore, no study has reported Ṽ O 2 during an outdoor sport climb or expressed Ṽ O 2 as a percentage of Ṽ O 2climb-peak .Therefore, the purpose of this study was to investigate oxygen consumption during indoor and outdoor sport climbing. During indoor climbing a rock climbing specific ergometer fitted with artificial hand/foot holds was used and climbing velocity incremented until exhaustion to determine Ṽ O 2climb-peak . During the outdoor climb oxygen uptake and the fractional use of a peak oxygen uptake (%Ṽ O 2climb-peak) were investigated. In addition, HR and blood lactate concentrations ([La b ]) were measured. Methods SUBJECTS AND STUDY DESIGNSix men and one woman volunteered as subjects and were all in good health as reported by a medical screening questionnaire. Table 1 gives descriptive characteristics of the subjects. The mean climbing experience of the group was 8.9 (SE 1.2) years, and for individuals the most diYcult outdoor ascent made without preview or fall (on sight ascent) ranged from 6b to 7a. With the numerical scale for climbing diYculty ranging from 5a (novice) to 7c (expert) (UK grading system) the subject sample comprised highly skilled climbers.On one occasion anthropometric measurements were taken, a capillary (finger prick)