Cannabinoids in the Treatment of Cannabis Use Disorder: Systematic Review of Randomized Controlled Trials.

Background: The prevalence of cannabis use and cannabis use disorders (CUD) has significantly increased over time. However, there are no approved pharmacological treatments for CUD. The aim of this study was to determine the efficacy and safety of various medical cannabinoids in the treatment of CUD. Methods: We conducted a systematic review of randomized controlled trials which evaluated the therapeutic potential of medical cannabinoids in individuals with CUD and summarized the main study outcomes in terms of cannabis use, abstinence, withdrawal symptoms, craving, retention in treatment and adverse events. Results: We identified eight trials with a total of 667 study participants. Dronabinol reduced cannabis withdrawal symptoms whereas nabiximols, cannabidiol and PF-04457845, a fatty acid amide inhibitor, also reduced cannabis use and improved abstinence, compared to placebo. Nabilone failed to demonstrate efficacy in the treatment of CUD. All medications were well-tolerated. Conclusions: Cannabinoid receptor agonists, i.e., dronabinol and nabilone, showed only limited or no therapeutic potential in the treatment of CUD. In contrast, modulators of endocannabinoid activity, i.e., nabiximols, cannabidiol and PF-04457845, demonstrated broader efficacy which covered almost all aspects of CUD. Endocannabinoid modulation appears to be a promising treatment approach in CUD, but the evidence to support this strategy is still small and future research in this direction is needed.

Impact of Chronic Cannabis Use on Auditory Mismatch Negativity Generation in Schizophrenia Patients.

INTRODUCTION: Cannabis use disorders (CUD) are highly prevalent among patients with schizophrenia (SCZ). Deficient mismatch negativity (MMN) generation is a characteristic finding in SCZ patients and cannabis users. This study therefore examined the effects of CUD on MMN generation in SCZ patients. METHODS: Twenty SCZ - CUD patients, 21 SCZ+CUD patients, and 20 healthy controls (HC) were included in this study. MMN to frequency and duration deviants was elicited within an auditory oddball paradigm and recorded by 32 channel EEG. RESULTS: As expected, SCZ - CUD patients showed reduced frontocentral MMN amplitudes to duration deviants compared to HC. Interestingly, SCZ+CUD patients demonstrated greater MMN amplitudes to duration deviants compared to SCZ - CUD patients at central electrodes with no differences compared to HC. DISCUSSION: These results demonstrate that comorbid cannabis use in SCZ patients might be associated with superior cognitive functioning. It can be assumed that the association between cannabis use and better cognitive performance may be due to a subgroup of cognitively less impaired SCZ patients characterized by lower genetic vulnerability for psychosis.

Pure delta-9-tetrahydrocannabinol and its combination with cannabidiol in treatment-resistant Tourette syndrome: A case report.

OBJECTIVES: Anecdotal reports and preliminary studies suggest a therapeutic potential of cannabis in Tourette syndrome. We report the case of a female patient suffering from treatment-resistant Tourette syndrome. METHODS: Guideline-directed antipsychotic treatment with risperidone and aripiprazole as well as pure delta-9-tetrahydrocannabinol had no significant effect on Tourette syndrome symptomatology. RESULTS: Following administration of a daily dosage of 10 mg delta-9-tetrahydrocannabinol combined with 20 mg cannabidiol (CBD), the patient showed a rapid and highly significant improvement in the Yale Global Tic Severity Scale. CONCLUSIONS: It can be speculated whether the beneficial effects may rely on the pharmacological properties of cannabidiol.

Serotonergic modulation of orbitofrontal activity and its relevance for decision making and impulsivity.

BACKGROUND: The orbitofrontal cortex seems to play a crucial role in reward-guided learning and decision making, especially for impulsive choice procedures including delayed reward discounting. The central serotonergic system is closely involved in the regulation of impulsivity, but how the serotonergic firing rate and release, best investigated by the loudness dependence of auditory evoked potentials (LDAEP), interact with orbitofrontal activity is still unknown. METHODS: Twenty healthy volunteers (11 males, 9 females, 31.3 ± 10.6 years old) were studied in a 3T MRI scanner (Philips, Hamburg, Germany) during a delay discounting task, after their LDAEP was recorded using a 32 electrodes EEG machine (Brain Products, Munich, Germany). RESULTS: Significant positive correlations were only found between the LDAEP and the medial orbitofrontal part of the superior frontal gyrus (SFG/MO) [Δ immediate reward - delayed reward] for the right (r = 0.519; P = 0.019) and left side (r = 0.478; P = 0.033). This relationship was stronger for females compared with males. Orbitofrontal activity was also related to the Barratt Impulsivity Scale. CONCLUSIONS: This study revealed that low serotonergic activity as measured by a strong LDAEP was related to a high fMRI signal intensity of SFG/MO during immediate reward behavior which is related to impulsivity. Since this relationship was only found for the infralimbic medial and not for the middle or lateral part of the orbitofrontal cortex, an exclusive projection tract of the serotonergic system to this cortical region can be assumed to regulate impulsive reward-orientated decision making. Hum Brain Mapp 38:1507-1517, 2017. © 2016 Wiley Periodicals, Inc.

The problems of long-term treatment with benzodiazepines and related substances.

BACKGROUND: Benzodiazepine abuse and dependence have been recognized and widely discussed for more than 40 years. With more than 230 million daily doses prescribed in Germany per year, the burden of reimbursement on the statutory health insurance carriers is high, albeit with a slight decline from year to year. At present, about 50% of all prescriptions in Germany are issued privately, even for patients who have statutory health insurance. METHODS: We selectively review the literature on the epidemiology and treatment of benzodiazepine dependence and abuse in Germany. RESULTS: Estimates of the number of benzodiazepine-dependent persons in Germany range from 128 000 to 1.6 million. Most estimates take no account of the large number of private prescriptions (i.e., those that are not reimbursed by the statutory health insurance scheme), while many exclude prescriptions for elderly persons, for whom these drugs are frequently prescribed. For the outpatient treatment of benzodiazepine withdrawal, it is recommended that the drug should first be switched to an equivalent dose of another benzodiazepine with an intermediate or long-acting effect; the dose should then, in general, be reduced weekly. In case of consumption of a high dose (≥ 20 mg diazepam equivalent), hospitalization and the additional administration of carbamazepine or valproic acid are recommended. Flumazenil treatment can improve with - drawal symptoms and leads to higher abstinence rates. Antidepressants should be given only if the patient is depressed. The dependence potential of nonbenzodiazepine drugs such as zolpidem and zopiclon must also be borne in mind. CONCLUSION: Benzodiazepines are generally highly effective when first given, but they should generally be given only for strict indications and for a limited time. If these drugs still need to be given beyond the short term, timely referral to a specialist is indicated, and possibly also contact with the addiction aid system.

Antipsychotic-like effects of cannabidiol and rimonabant: systematic review of animal and human studies.

Several lines of experimental and clinical evidence point to a close relationship between cannabis, the endogenous cannabinoid system, and schizophrenia. A variety of animal and human studies found a dysregulation of endocannabinoid signalling in psychosis. Elevated anandamide levels in schizophrenia patients that are negatively correlated with psychotic symptomatology indicate a protective role, whereas 2-arachidonoylglycerol appears to counteract psychosis-related cognitive impairments. Thus, pharmacological manipulation of the endogenous cannabinoid system might be associated with potential antipsychotic properties. In the present systematic review, both preclinical studies using different animal models of psychosis as well as clinical trials investigating the antipsychotic effects of both cannabidiol and rimonabant are presented together with the possible underlying mechanisms of action. The results predominantly confirm the hypothesis of an antipsychotic activity of both cannabinoids. In comparison, cannabidiol appears to be superior to rimonabant with a pharmacological profile similar to atypical antipsychotic drugs.

Association between a cannabinoid receptor gene (CNR1) polymorphism and cannabinoid-induced alterations of the auditory event-related P300 potential.

Numerous studies demonstrated a close relationship between cannabis abuse and schizophrenia with similar impairments in cognitive processing, particularly in P300 generation. Recently, an (AAT)n triplet repeat polymorphism within the cannabinoid receptor gene CNR1 has been found to be associated with both schizophrenia and substance dependence, and to modulate the P300 potential. As previously reported, both acute oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the main psychoactive constituent of cannabis, and standardized cannabis extract containing Δ(9)-THC and cannabidiol (CBD) revealed a significant reduction of P300 amplitudes in healthy subjects but did not show any differences among each other. The aim of this study was to investigate whether the (AAT)n polymorphism differentially modulates the effects of Δ(9)-THC and cannabis extract on P300 generation in 20 healthy volunteers during an auditory choice reaction task. For the >10/>10 genotype, there was a significant decrease of P300 amplitude as well as a significant prolongation of P300 latency under pure Δ(9)-THC but not under cannabis extract. Moreover, we found a significant correlation between the number of AAT repeats and P300 variables for the Δ(9)-THC condition. Our data thus indicate that the CNR1 gene seems to be involved in the regulation of the P300 wave as a marker of selective attention and working memory. Moreover, it appears that variations within CNR1 may differentially alter the sensitivity to the acute effects of cannabinoids on P300 generation in healthy subjects.

Auditory mismatch negativity deficits in long-term heavy cannabis users.

Mismatch negativity (MMN) is an auditory event-related potential indicating auditory sensory memory and information processing. The present study tested the hypothesis that chronic cannabis use is associated with deficient MMN generation. MMN was investigated in age- and gender-matched chronic cannabis users (n = 30) and nonuser controls (n = 30). The cannabis users were divided into two groups according to duration and quantity of cannabis consumption. The MMNs resulting from a pseudorandomized sequence of 2 × 900 auditory stimuli were recorded by 32-channel EEG. The standard stimuli were 1,000 Hz, 80 dB SPL and 90 ms duration. The deviant stimuli differed in duration (50 ms) or frequency (1,200 Hz). There were no significant differences in MMN values between cannabis users and nonuser controls in both deviance conditions. With regard to subgroups, reduced amplitudes of frequency MMN at frontal electrodes were found in long-term (≥8 years of use) and heavy (≥15 joints/week) users compared to short-term and light users. The results indicate that chronic cannabis use may cause a specific impairment of auditory information processing. In particular, duration and quantity of cannabis use could be identified as important factors of deficient MMN generation.

No association between chronic cannabis use and loudness dependence of auditory evoked potentials as indicator of central serotonergic neurotransmission.

Chronic cannabis use has been found to be associated with major depression. It is suggested that cannabis use induces changes in neurotransmitter systems involved in the pathogenesis of depressive disorders, particularly in the serotonergic system. The analysis of the loudness dependence of auditory evoked potentials (LDAEP) is a valid non-invasive indicator of central serotonergic activity in animals and humans. In the present study, we investigated the effects of chronic cannabis use on LDAEP in 30 psychiatrically unaffected users compared to 30 non-user controls. Users were required to abstain from cannabis for at least 24 h before testing. Putative depressive symptoms were assessed by using the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-21). LDAEP as well as BDI and HAMD-21 scores did not differ between cannabis users and controls. Moreover, LDAEP neither correlate with duration and quantity of cannabis use nor with psychometric assessments. These results indicate that chronic cannabis use had no influence on the LDAEP in this study sample. It can be suggested that significant alterations in serotonergic systems may rather be related to acute activation of the endogenous cannabinoid system or to cannabis dependence accompanied by manifest depressive symptoms.

Psychomotor performance in relation to acute oral administration of Delta9-tetrahydrocannabinol and standardized cannabis extract in healthy human subjects.

Abnormalities in psychomotor performance are a consistent finding in schizophrenic patients as well as in chronic cannabis users. The high levels of central cannabinoid (CB(1)) receptors in the basal ganglia, the cerebral cortex and the cerebellum indicate their implication in the regulation of motor activity. Based on the close relationship between cannabis use, the endogenous cannabinoid system and motor disturbances found in schizophrenia, we expected that administration of cannabinoids may change pattern of psychomotor activity like in schizophrenic patients. This prospective, double-blind, placebo-controlled cross-over study investigated the acute effects of cannabinoids on psychomotor performance in 24 healthy right-handed volunteers (age 27.9 +/- 2.9 years, 12 male) by comparing Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and standardized cannabis extract containing Delta(9)-THC and cannabidiol. Psychomotor performance was assessed by using a finger tapping test series. Cannabis extract, but not Delta(9)-THC, revealed a significant reduction of right-hand tapping frequencies that was also found in schizophrenia. As to the pure Delta(9)-THC condition, left-hand tapping frequencies were correlated with the plasma concentrations of the Delta(9)-THC metabolite 11-OH-THC. These effects are thought to be related to cannabinoid actions on CB(1) receptors in the basal ganglia, the cerebral cortex and the cerebellum. Our data further demonstrate that acute CB(1) receptor activation under the cannabis extract condition may also affect intermanual coordination (IMC) as an index of interhemispheric transfer. AIR-Scale scores as a measure of subjective perception of intoxication were dose-dependently related to IMC which was shown by an inverted U-curve. This result may be due to functional changes involving GABAergic and glutamatergic neurotransmission within the corpus callosum.

Effects of acute oral Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers.

Reduced amplitudes of auditory evoked P300 are a robust finding in schizophrenic patients, indicating deficient attentional resource allocation and active working memory. Delta9-Tetrahydrocannabinol (Delta9-THC), the main active constituent of Cannabis sativa, has been known to acutely impair cognitive abilities in several domains, particularly in memory and attention. Given the psychotic-like effects of Delta9-THC, a cannabinoid hypothesis of schizophrenia has been proposed. This prospective, double-blind, placebo-controlled cross-over study investigated the acute effects of cannabinoids on P300 amplitude in 20 healthy volunteers (age 28.2+/-3.1 years, 10 male) by comparing Delta9-THC and standardized cannabis extract containing Delta9-THC and cannabidiol (CBD). P300 waves were recorded during a choice reaction task. As expected, Delta9-THC revealed a significant reduction of P300 amplitude at midline frontal, central, and parietal electrodes. CBD has been known to abolish many of the psychotropic effects of Delta9-THC, but, unexpectedly, failed to demonstrate a reversal of Delta9-THC-induced P300 reduction. Moreover, there were no correlations between cannabinoid plasma concentrations and P300 parameters. These data suggest that Delta(9)-THC may lead to acute impairment of attentional functioning and working memory. It can be speculated whether the lack of effect of CBD may be due to an insufficient dose used or to an involvement of neurotransmitter systems in P300 generation which are not influenced by CBD.

Acute effects of Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity.

Reduced amplitudes of auditory evoked mismatch negativity (MMN) have often been found in schizophrenic patients, indicating deficient auditory information processing and working memory. Cannabis-induced psychotic states may resemble schizophrenia. Currently, there are discussions focusing on the close relationship between cannabis, the endocannabinoid and dopaminergic system, and the onset of schizophrenic psychosis. This study investigated the effects of cannabis on MMN amplitude in 22 healthy volunteers (age 28+/-6 years, 11 male) by comparing Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and standardized cannabis extract containing Delta(9)-THC and cannabidiol (CBD) in a prospective, double-blind, placebo-controlled cross-over design. The MMNs resulting from 1000 auditory stimuli were recorded by 32 channel EEG. The standard stimuli were 1000 Hz, 80 dB SPL, and 100 ms duration. The deviant stimuli differed in frequency (1500 Hz). Significantly greater MMN amplitude values at central electrodes were found under cannabis extract, but not under Delta(9)-THC. There were no significant differences between MMN amplitudes at frontal electrodes. MMN amplitudes at central electrodes were significantly correlated with 11-OH-THC concentration, the most important psychoactive metabolite of Delta(9)-THC. Since the main difference between Delta(9)-THC and standardized cannabis extract is CBD, which seems to have neuroprotective and anti-psychotic properties, it can be speculated whether the greater MMN amplitude that may imply higher cortical activation and cognitive performance is related to the positive effects of CBD. This effect may be relevant for auditory cortex activity in particular because only MMN amplitudes at the central, but not at the frontal electrodes were enhanced under cannabis.

Simultaneous and sensitive analysis of THC, 11-OH-THC, THC-COOH, CBD, and CBN by GC-MS in plasma after oral application of small doses of THC and cannabis extract.

Besides the psychoactive Delta(9)-tetrahydrocannabinol (THC), hashish and marijuana as well as cannabis-based medicine extracts contain varying amounts of cannabidiol (CBD) and of the degradation product cannabinol (CBN). The additional determination of these compounds is interesting from forensic and medical points of view because it can be used for further proof of cannabis exposure and because CBD is known to modify the effects of THC. Therefore, a method for the simultaneous quantitative determination of THC, its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH), CBD and CBN from plasma was developed. The method was based on automatic solid-phase extraction with C(18) ec columns, derivatization with N,O-bistrimethylsilyltrifluoroacetamide (BSTFA), and gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS) with deuterated standards. The limits of detection were between 0.15 and 0.29 ng/mL for THC, 11-OH-THC, THC-COOH, and CBD and 1.1 ng/mL for CBN. The method was applied in a prospective pharmacokinetic study after single oral administration of 10 mg THC alone or together with 5.4 mg CBD in cannabis extract. The maximum plasma concentrations after cannabis extract administration ranged between 1.2 and 10.3 ng/mL (mean 4.05 ng/mL) for THC, 1.8 and 12.3 ng/mL (mean 4.9 ng/mL) for 11-OH-THC, 19 and 71 ng/mL (mean 35 ng/mL) for THC-COOH, and 0.2 and 2.6 ng/mL (mean 0.95 ng/mg) for CBD. The peak concentrations (mean values) of THC, 11-OH-THC, THC-COOH, and CBD were observed at 56, 82, 115, and 60 min, respectively, after intake. CBN was not detected. Caused by the strong first-pass metabolism, the concentrations of the metabolites were increased during the first hours after drug administration when compared to literature data for smoking. Therefore, the concentration ratio 11-OH-THC/THC was discussed as a criterion for distinguishing oral from inhalative cannabis consumption.

Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract.

Cannabidiol (CBD) is known to modify the effects of Delta-tetrahydrocannabinol (THC) by decreasing anxiety and antagonizing other THC-effects. As a reason, pharmacodynamic as well as pharmacokinetic mechanisms were suggested. In context of the use of cannabis-based medicine extracts for therapeutic purposes, a study was performed in a double-blind and placebo-controlled cross-over design in which each of 24 volunteers (12 male and 12 female, age 18-45 years) obtained soft-gelatin capsules with 10 mg THC (THC-set), cannabis extract containing 10 mg THC +5.4 mg CBD (CAN-set) or placebo in weekly intervals. Blood samples were taken 30 minutes before and 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours and 24 hours after the intake. The concentrations of THC, of its metabolites 11-OH-THC, THC-COOH and of CBD in the plasma samples were determined by automatic solid phase extraction, derivatization with N,O-bis(trimethylsilyl)triflouroacetamide and gas chromatography-mass spectrometry. The concentration versus time curves (maximum concentrations Cmax, corresponding time tmax and areas under the curves AUC) were evaluated by statistical methods with respect to equivalence or differences between the CAN-set and the THC-set. Furthermore, the intra-individual ratios of Cmax and AUC for 11-OH-THC/THC, THC-COOH/THC and THC-COOH/11-OH-THC were compared between the THC-set and the CAN-set. Despite the large variation of the data, evidence emerged from the total of the results that CBD partially inhibits the CYP 2C catalyzed hydroxylation of THC to 11-OH-THC. The probability for this inhibition is particularly high for oral intake because THC and CBD attain relatively high concentrations in the liver and because of the high first-pass metabolism of THC. However, the effect of CBD is small in comparison to the variability caused by other factors. Therefore, a pharmacokinetic reason for the differences determined between pure THC and cannabis extract is improbable at the doses chosen in this study. Significantly higher AUC and Cmax and shorter tmax were found for females as compared with males.