Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans

RATIONALE: One of the most often reported cognitive deficits of acute cannabis administration is an impaired recall of previously learned information. OBJECTIVE: The aim of the present study was to determine whether cannabis-induced memory impairment in humans is mediated via glutamatergic or cholinergic pathways. METHODS: Fifteen occasional cannabis users participated in a double-blind, placebo-controlled, six-way cross-over study. On separate test days, subjects received combinations of pretreatment (placebo, vardenafil 20 mg or rivastigmine 3 mg) and treatment (placebo or 1,376 mg cannabis/kg body weight). Cognitive tests were administered immediately after inhalation of treatment was finished and included measures of memory (visual verbal learning task, prospective memory test, Sternberg memory test), perceptual-motor control (critical tracking task), attention (divided attention task) and motor impulsivity (stop signal task). RESULTS: The results of this study demonstrate that subjects under the influence of cannabis were impaired in all memory tasks, in critical tracking, divided attention and the stop signal task. Pretreatment with rivastigmine attenuated the effect of cannabis on delayed recall and showed a trend towards significance on immediate recall. When cannabis was given in combination with vardenafil, there were no significant interaction effects in any of the tasks. CONCLUSIONS: The present data therefore suggest that acetylcholine plays an important role in cannabis-induced memory impairment, whereas similar results for glutamate have not been demonstrated in this study

Therapeutic effect of an ayahuasca analogue in clinically depressed patients:a longitudinal observational study

RATIONALE: Studies have suggested mental health improvements following the use of the psychotropic plant concoction ayahuasca in non-clinical and clinical samples. OBJECTIVES: The present observational study assessed depressive symptomatology in 20 clinically depressed patients (symptom score > 13 on the Beck’s Depression Inventory) before attendance of an ayahuasca ceremony and 1 month and 1 year after. Secondary measures included ratings of altered states of consciousness and ego dissolution during the ayahuasca ceremony as well as global measures of mindfulness, satisfaction with life, depression, anxiety, and stress. RESULTS: Twenty participants completed baseline and 1-day follow-up, 19 completed measures at 1-month follow-up, and 17 completed measures at 1-year follow-up. BDI scores reduced from baseline (M = 22.7) to all post-ceremony measures (Ms 11.45, 12.89, and 8.88, for 1-day, 1-month, and 1-year follow-up, respectively). After 1 day, 12/20 participants were in remission (BDI < 13). Remission rates after 1 month and 1 year were 13/19 and 12/17, respectively. Three participants remained mildly depressed (BDI 14–19) at the 1-month and 1-year follow-up. Two participants did not respond and remained at a moderate/severe level of depression at 1-year follow-up. Reductions on the secondary mental health measures and increases in mindfulness and satisfaction with life were found up to 1 year post-ceremony. Improvements in clinical depression and mental health correlated with levels of experienced ego dissolution and oceanic boundlessness during the ceremony up to 1 month after the ceremony. Engagement in additional mental health treatments or use of another psychedelic during study participation may have contributed to improved mental health ratings at 1-year follow-up. CONCLUSION: Ayahuasca produces long-term mental health improvements in clinically depressed patients, which highlights its therapeutic potential. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00213-021-06046-9

Cannabis and tolerance: acute drug impairment as a function of cannabis use history

Contains fulltext : 167132.pdf (publisher's version ) (Open Access)Cannabis use history as predictor of neurocognitive response to cannabis intoxication remains subject to scientific and policy debates. The present study assessed the influence of cannabis on neurocognition in cannabis users whose cannabis use history ranged from infrequent to daily use. Drug users (N = 122) received acute doses of cannabis (300 mug/kg THC), cocaine HCl (300 mg) and placebo. Cocaine served as active control for demonstrating neurocognitive test sensitivity. Executive function, impulse control, attention, psychomotor function and subjective intoxication were significantly worse after cannabis administration relative to placebo. Cocaine improved psychomotor function and attention, impaired impulse control and increased feelings of intoxication. Acute effects of cannabis and cocaine on neurocognitive performance were similar across cannabis users irrespective of their cannabis use history. Absence of tolerance implies that that frequent cannabis use and intoxication can be expected to interfere with neurocognitive performance in many daily environments such as school, work or traffic

Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users

Performance impairment during Delta(9)-tetrahydrocannabinol (THC) intoxication has been well described in occasional cannabis users. It is less clear whether tolerance develops to the impairing effects of THC in heavy users of cannabis. The aim of the present study was to assess neurocognitive performance during acute THC intoxication in occasional and heavy users. Twenty-four subjects (12 occasional cannabis users and 12 heavy cannabis users) participated in a double-blind, placebo-controlled, two-way mixed model design. Both groups received single doses of THC placebo and 500 microg/kg THC by smoking. Performance tests were conducted at regular intervals between 0 and 8 h after smoking, and included measures of perceptual motor control (critical tracking task), dual task processing (divided attention task), motor inhibition (stop signal task) and cognition (Tower of London). THC significantly impaired performance of occasional cannabis users on critical tracking, divided attention and the stop signal task. THC did not affect the performance of heavy cannabis users except in the stop signal task, i.e. stop reaction time increased, particularly at high THC concentrations. Group comparisons of overall performance in occasional and heavy users did not reveal any persistent performance differences due to residual THC in heavy users. These data indicate that cannabis use history strongly determines the behavioural response to single doses of THC

Emotion recognition during cocaine intoxication

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Pharmacokinetic properties of delta9-tetrahydrocannabinol in oral fluid of occasional and chronic users

Saliva is of continuing interest in detecting the influence of drugs while driving. Commercial tests are currently available where cannabis detectability is a major challenge. The present study aids in the understanding of tetrahydrocannabinol (THC) pharmacokinetics in oral fluid. The oral fluid analyses exhibited no significant differences between 12 occasional users and 12 chronic users smoking a standardized cannabis joint, except for the maximum concentrations in the first samples (occasional users, 397- 6438 ng/g; chronic users 387-71,747 ng/g). THC was detectable in all samples with medians in the last samples (8 h) of 6.3 and 11.3 ng/g in occasional and chronic users, respectively. The elimination half-life in both groups was 1.6 +/- 0.4 h. A series of samples was obtained over a period of 8 h without actual drug use representing a later elimination phase. Of these oral fluid samples, only 4.3% were negative for THC despite positive serum, and 24.1% of serum samples were negative despite positive oral fluid. This confirms that THC is detectable for longer in oral fluid than in serum. The oral fluid-to-serum ratios were 0.3 to 425 (median 16.5) with no difference between chronic and occasional users. The large inter- and intraindividual variability observed precludes a reliable estimation of THC serum concentrations from oral fluid data using this collection device

Pharmacokinetic properties of delta9-tetrahydrocannabinol in serum and oral fluid

In a study on the effects of smoked cannabis (18.2 +/- 2.8 mg as low and 36.5 +/- 5.6 mg as high dose) paired blood and oral fluid samples were collected from 10 study participants up to 6 h after smoking and analyzed for the cannabinoids Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (THC-OH) and 11-nor-9-carboxy-THC (THCA) using gas chromatography-mass spectrometry. Highest concentrations in serum were 47.8 +/- 35.0 and 79.1 +/- 42.5 microg/L at the end of smoking (low and high dose, respectively) and decreased to less than 1 microg/L during 6 h with elimination half-lives of 1.4 +/- 0.1 h calculated from 1 to 6 h, which is shorter than reported previously. The elimination half-lives of THC-OH (2.0 +/- 0.3 h) and THCA (3.4 +/- 0.9 h) were significantly higher. The THC concentrations in oral fluid were highest with 900 +/- 589 and 1041 +/- 652 microg/L (low and high dose, respectively) in the first sample collected at 0.25 h and decreased to 18 +/- 12 microg/L over 6 h with elimination half-lives of 1.5 +/- 0.6 h. The elimination half-life of THC in serum and oral fluid and between the two doses did not significantly differ. Oral fluid/serum ratios were 46 +/- 27 and 36 +/- 20 (low and high dose, respectively), which are higher than previously reported and might be based on sample collection and/or analytical issues. In conclusion, despite similar elimination rates of THC in serum and oral fluid, which appear incidental, the high differences in oral fluid/serum ratios are not a reliable basis for correlating THC concentrations in oral fluid and serum. The oral compartment and its kinetics for drugs, particularly THC, are not yet satisfactorily understood

Emotion recognition during cocaine intoxication

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Comparison of cannabinoid pharmacokinetic properties in occasional and heavy users smoking a marijuana or placebo joint

Cannabinoid pharmacokinetics in occasional users is well studied, but the interpretation of data from heavy users is difficult. In the present study, blood pharmacokinetic properties were investigated in occasional and heavy users in cannabis and placebo conditions. The results obtained with occasional users were in contrast to those of the heavy users who admitted cannabis use on 4-25 occasions during the previous week. Of the 12 heavy users, 10 exhibited up to 12.3 microg/L Delta(9)-tetrahydrocannabinol (THC) prior to smoking. During the 8 h after smoking, the distribution and elimination patterns were comparable to those of the occasional users and the concentrations returned to 68-196% (median 110%) of the initial values. However, the maximal concentration and the areas under the curves were significantly higher with marked interindividual variation. In contrast to the cannabis conditions, the THC concentrations in the placebo phase decreased more slowly (elimination half-life 17.5-43.5 h vs. 1.0-5.9 h) in accordance with a late elimination phase. The elimination half-lives of 11-hydroxy-THC and 11-nor-9-carboxy-THC in th cannabis conditions (medians 3.1 h and 6.2 h, respectively) were longer than those of THC, which was different in the placebo phase (medians 7.2 h and 13.0 h, respectively). From the results, it must be cautioned that cannabinoid blood concentrations from heavy users in a late elimination phase may be difficult to distinguish from concentrations measured in occasional users after acute cannabis use

Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes

Contains fulltext : 162797.pdf (publisher's version ) (Open Access)The dopamine beta-hydroxylase (DbetaH) enzyme transforms dopamine into noradrenaline. We hypothesized that individuals with low activity DBH genotypes (rs1611115 CT/TT) are more sensitive to the influence of cannabis and cocaine on cognitive impulse control and functional connectivity in the limbic 'reward' circuit because they experience a drug induced hyperdopaminergic state compared to individuals with high activity DBH genotypes (rs1611115 CC). Regular drug users (N = 122) received acute doses of cannabis (450 mug/kg THC), cocaine HCl 300 mg and placebo. Cognitive impulse control was assessed by means of the Matching Familiar Figures Test (MFFT). Resting state fMRI was measured in a subset of participants to determine functional connectivity between the nucleus accumbens (NAc) and (sub)cortical areas. The influence of cannabis and cocaine on impulsivity and functional connectivity significantly interacted with DBH genotype. Both drugs increased cognitive impulsivity in participants with CT/TT genotypes but not in CC participants. Both drugs also reduced functional connectivity between the NAc and the limbic lobe, prefrontal cortex, striatum and thalamus and primarily in individuals with CT/TT genotypes. Correlational analysis indicated a significant negative association between cognitive impulsivity and functional connectivity in subcortical areas of the brain. It is concluded that interference of cannabis and cocaine with cognitive impulse control and functional corticostriatal connectivity depends on DBH genotype. The present data provide a neural substrate and behavioral mechanism by which drug users can progress to drug seeking and may also offer a rationale for targeted pharmacotherapy in chronic drug users with high risk DBH genotypes.10 p