Mateus M Bergamaschi of University of São Paulo, São Paulo (USP) with expertise in: Clinical Pharmacology, Clinical Trials and Clinical Chemistry. Read Mateus M Bergamaschi,1,2,3 Regina Helena Costa Queiroz,2,3 Marcos Hortes Nisihara Chagas,1,3 Danielle Chaves Gomes de Oliveira,1,3 Bruno Spinosa De . Mateus M. Bergamaschi,1,2 Erin L. Karschner,1 Robert S. Goodwin,1 Karl B. .. One participant (M) was THC negative from admission through discharge on.
Bergamaschi Mateus M
The anxiolytic effects of CBD had been extensively demonstrated in animal studies and in healthy volunteers submitted to anxiety induced by several procedures, including the simulation of public speaking Crippa et al , , However, there is only one published report of the anxiolytic effect of CBD in an anxiety disorder Crippa et al , , The SPECT analysis of this study and of a previous one with healthy volunteers Crippa et al , showed that the CBD effects were associated with the activity of the parahippocampal gyrus and hippocampus.
Moreover, CBD has shown to disrupt forward intrinsic connectivity between the amygdala and the anterior cingulate during the neural response to fearful faces Fusar-Poli et al , b. Taken together, these studies demonstrate the action of CBD in limbic and paralimbic brain areas, which are known to be associated with anxiety.
Additionally, CBD injected into the dorsolateral periaqueductal gray of rats produced anxiolytic-like effects in the elevated plus-maze and elevated T-maze, and these effects were prevented by a 5HT1A receptor antagonist Soares et al , ; Campos and Guimaraes, Another important observation of this study was that the increase of negative self-evaluation during public speaking was almost abolished by CBD.
In a previous study, we suggested that the negative self-evaluation during the phobic situation of public speaking would be important for the avoidance and impairment in social functioning that support the diagnosis of SAD Freitas-Ferrari et al , submitted. In that way, the observed effect of CBD for improving the self-evaluation during public speaking, which is one of the pivotal aspects of SAD, will influence the therapy of SAD patients.
Although physiological measures have not shown significant differences among the groups, the self-report of somatic symptoms BSS increased significantly only for the SAD patients who received placebo during the test.
Following the same rationale as above, it is well-known that more pronounced bodily symptoms may contribute to the clinical diagnosis of SAD, and this result suggests that CBD also protects the patients from their subjective physiological abnormalities induced by the SPST. The findings reported herein need to be interpreted with caution, given the limitations of the study. First, it would have been desirable to measure plasma levels of CBD and to relate such measurements to changes in the VAMS scores; however, it should be pointed out that previous investigations have not been able to confirm whether there is a direct relationship between plasma levels of cannabinoids, in particular CBD, and their clinical effects Agurell et al , Another limitation refers to the size of the sample included; however, the statistical power of the data from the VAMS and SSPS was shown to be relatively robust even with small subject numbers.
An extensive list of medications for the pharmacological treatment of SAD was made available in recent years, including selective serotonin reuptake inhibitors SSRIs , selective serotonin and norepinephrine reuptake inhibitor SSNRI , antidepressants and benzodiazepines Schneier, However, both SSRIs and SSNRIs have an initial activation and a long latency period of response, and benzodiazepines are limited by their potential to produce motor impairment, sedation, and to induce dependence and withdrawal symptoms following discontinuation Blanco et al , Conversely, CBD has important advantages in comparison with the currently available pharmacological agents for the treatment of SAD, such as an early onset of action and lack of important side effects both with acute and chronic administration to healthy subjects Crippa et al , , Moreover, it was shown that repeated treatment with CBD but not 9-THC does not develop tolerance or dependence Hayakawa et al , and possibly reduces drug-seeking behaviors Parker et al , ; Ren et al , ; Morgan et al , Thus, because of the absence of psychoactive or cognitive effects, to its safety and tolerability profiles, and to its broad pharmacological spectrum, CBD is possibly the cannabinoid that is most likely to have initial findings in anxiety translated into clinical practice.
Therefore, the effects of a single dose of CBD, observed in this study in the face of one of the main SAD's phobic stimuli, is a promising indication of a rapid onset of therapeutic effect in patients with SAD. However, randomized, double-blind, placebo-controlled, clinical trials with larger samples and chronic use are still needed to confirm these statements.
Likewise, because CBD effects are biphasic, the determination of adequate treatment ranges for each disorder remains a challenge. Further research to determine the precise mechanisms of action of CBD in the different anxiety disorders is desirable and opportune.
National Center for Biotechnology Information , U. Journal List Neuropsychopharmacology v. Published online Feb 9. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Physiological Measurements Skin conductance A computer-controlled, voltage-constant 0. Heart rate Heart rate HR was estimated by manually counting the pulse rate.
Table 1 Timetable of the Experimental Session. Open in a separate window. Statistical Analysis Clinical and demographical characteristics were analyzed with the non-parametric tests gender and socioeconomic level and by the analysis of variance for one factor ANOVA , followed by post-hoc Bonferroni's test for multiple comparisons age, age of SAD onset and SPIN.
Table 2 Clinical and Demographical Characteristics of the Groups. Interactions of delta 1-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man. Assay of cannabinol and cannabidiol by mass fragmentography. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacotherapy of social anxiety disorder. Neural basis of Deltatetrahydrocannabinol and cannabidiol: Specificity of social anxiety disorder as a risk factor for alcohol and cannabis dependence.
Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats.
Management of anxiety disorders. Guidelines of the Brazilian medical Association for the diagnosis and differential diagnosis of social anxiety disorder. Comparability between telephone and face-to-face structured clinical interview for DSM-IV in assessing social anxiety disorder. Neural basis of anxiolytic effects of cannabidiol CBD in generalized social anxiety disorder—a preliminary report. Are there differences between early- and late-onset social anxiety disorder.
Grey matter correlates of cognitive measures of the simulated public speaking test in social anxiety spectrum: Censored data represented by the small vertical ticks on the plotted lines are study participants who left the study before achieving negative THC or negative OH-THC results on 4 or 2 consecutive days, respectively. To our knowledge, these are the first blood cannabinoid concentrations in chronic daily cannabis smokers during extended up to 33 days continuously monitored abstinence.
These data are critical for understanding cannabinoid pharmacokinetics in this population, and for interpreting blood cannabinoid tests. In contrast, the active THC metabolite, OH-THC, had a maximum detection window of 72 h after admission, shorter than the 7 days reported in a previous study of cannabis smokers under monitored abstinence for 1 week The variable THC detection rate throughout the study, with positive samples interspersed with negatives ones e.
For instance, 2 participants with THC-positive samples on days 24 and 26, followed by negative samples, were THC-positive again on day 30 at 0. This increased the detection rate on day 30, as shown in Fig. Persistence of THC impairment was shown in multiple studies for at least several weeks after initiation of abstinence 8 — 10 , Thus, our findings suggest an association between residual cannabinoid concentrations and impairment over the initial few weeks of abstinence, consistent with the approach of per se drugged driving laws.
However, additional research is warranted on development of and dissipation of pharmacodynamic tolerance 33 — 35 , acute cannabis withdrawal which may also impair performance 36 , 37 , and the relationship between concentrations in blood and brain the site of action of impairment Sweden and Australia have zero tolerance for illegal drugs in drivers.
In our study sample, 1 of 21 participants 4. The state of Colorado is currently considering a per se limit of 5. THC-glucuronide, cannabinol, and cannabidiol concentrations in blood may also indicate recent cannabis smoking This study has several limitations.
Time of last cannabis smoking was based on participant self-report. However, our data report objective data from admission and document drug detection over days to weeks. If participants actually abstained from cannabis smoking immediately before admission, the length of detection could only be longer than times reported. In conclusion, our results demonstrate, for the first time as far as we are aware, that cannabinoids can be detected in blood of chronic daily cannabis smokers during a month of sustained abstinence.
This is consistent with the time course of persisting neurocognitive impairment reported in recent studies 9 , 10 , 26 , There is a strong public safety need to reduce morbidity and mortality from cannabis-impaired driving. Extended residual THC excretion in chronic daily cannabis smokers complicates prosecution. Establishment of per se THC legislation might achieve such a reduction in motor vehicle injuries and deaths.
Per se alcohol legislation improved prosecution of drunk drivers and dramatically reduced alcohol-related deaths. By analogy, one way to protect the public from drugged drivers is to establish legislation making it illegal to smoke cannabis and drive. The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
Gorelick for editing assistance and Allan Barnes for assistance with sample analysis. Upon manuscript submission, all authors completed the author disclosure form. All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: National Center for Biotechnology Information , U. Author manuscript; available in PMC Mar 1. Bergamaschi , 1, 2 Erin L. Karschner , 1 Robert S. Goodwin , 1 Karl B.
Scheidweiler , 1 Jussi Hirvonen , 3 Regina H. Queiroz , 2 and Marilyn A. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available free at Clin Chem. See other articles in PMC that cite the published article. Results Thirty male chronic daily cannabis smokers participated [26 African American, 3 white, 1 mixed race; mean SD age Table 1 Demographic characteristics and self-reported cannabis use for 30 male participants.
Open in a separate window. Discussion To our knowledge, these are the first blood cannabinoid concentrations in chronic daily cannabis smokers during extended up to 33 days continuously monitored abstinence.
Acknowledgments Role of Sponsor: Footnotes 4 Nonstandard abbreviations: Consultant or Advisory Role: Marijuana neurobiology and treatment. Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. Acute marijuana effects on human risk taking. Vandrey R, Haney M. Pharmacotherapy for cannabis dependence: Briefly, 3mL of ice-cold acetonitrile was added to 1mL plasma to precipitate proteins. After mixing, samples were centrifuged and supernatant added to preconditioned solid phase extraction SPE columns.
Limits of quantification LOQ were 0. CBD was linear from 2. Assay limit of quantification was 0. The GI is an open-ended inquiry about any physical or health problems and its impact on functioning. The SI is a detailed and systematic inquiry regarding 78 adverse effects divided into 23 categories corresponding to organ systems or body parts Watson et al. Peak plasma concentration C max , time to peak plasma concentration t max and area under the curve AUC were calculated from CBD plasma concentrations.
Urine sampling allowed estimation of clearance, calculated as percent of dose excreted over 8h. Cortisol plasma levels and AUC differences between groups also were examined. Plasma and urine AUC were calculated by the following equation: Interaction between fentanyl dose and both i plasma CBD concentrations as well as ii urinary CBD clearance was assessed using mixed linear models.
Anxiety was assessed with a visual analog scale VAS. All scales were administered in less than 10 min. Vital signs blood pressure, heart rate, respiratory rate, oxygen saturation, and body temperature , respiratory function inspired and expired oxygen and carbon dioxide concentrations, arterial hemoglobin—oxygen saturation and respiratory rate and EKG were continuously monitored throughout the session.
Vital signs were recorded as in Figure 1. CBD pharmacokinetics and subjective measures were first analyzed for skew and kurtosis, then analyzed for repeated measures analysis using either general or mixed linear models. All subjects had a prior history of opioid exposure the majority had received either hydrocodone, oxycodone or codeine in association with post-surgical care to minimize any potential negative opioid response and were prescreened to assure absence of opioids via toxicology screens.
There were no serious adverse events such as respiratory depression or cardiovascular compromise in any subject. Minor adverse events reported by subjects during and immediately after sessions were recorded as dichotomous variables in descending number of occurrences: One subject developed itching and a rash that resolved after treatment with diphenhydramine.
Clinical monitoring of vital signs temperature, heart rate, respiratory rate, blood pressure, oxygen saturation occurred continuously and was analyzed at time points according to Figure 1 using AUC between groups.
Higher fentanyl dose 1. CBD dose 0 vs. Plasma CBD concentrations were measured at baseline and at selected time points according to the protocol outlined in Figure 1. Group 1 placebo measurements served as the negative control. None of the subjects in either the placebo or CBD groups showed detectable plasma fentanyl concentrations. Mean plasma cortisol concentrations in Group 1 placebo in Sessions 1 and 2 were There were no significant main effects for CBD for any of the subjective measures Table 3.
Plasma CBD C max and t max were not significantly altered by fentanyl co-administration. Similarly, no effect was evident for urinary CBD and metabolite excretion except at the higher fentanyl dose in which CBD clearance was reduced. Importantly, fentanyl co-administration did not produce respiratory depression or cardiovascular complications during the test sessions and CBD did not potentiate fentanyl effects. Furthermore, CBD clearance did not differ when co-administered with opioids.
Our results add to the growing body of literature evaluating the safety of CBD administration in humans. Together with prior safety studies Consroe et al. The results suggest that CBD at the doses examined do not markedly alter affect, consistent with other reports Fusar-Poli et al. Further studies are necessary in larger populations to fully discern CBD effects on mood across a large dose range. The potential to examine CBD in human opiate abusers is intriguing based on results from our preclinical animal data Ren et al.
It is predicted that CBD would have a significant effect on inhibiting heroin-seeking behavior. However, there are still large gaps of knowledge regarding CBD actions in the brain, as this phytocannabinoid is much less studied than THC. It was previously demonstrated that CBD did not affect brain morphine and methadone concentrations in mice Reid and Bornheim, However, it was suggested that that although CBD has weak activity at CB 1 and CB 2 receptors, it may act as an inverse agonist at these receptors Pertwee et al.
CBD also was reported to alter the hydrolysis and cellular uptake of the endocannabinoid anandamide Bisogno et al. Given the growing clinical interest in CBD, and in relation to addictive disorders, future studies are needed to further explore the molecular mechanisms by which CBD may inhibit opioid-seeking behaviors and endogenous opioid mediated reward pathways.
There are limitations that must be considered with these results. Our experimental design was subject to some degree of selection bias due to not studying pharmacokinetic properties across all ages, gender and ethnic backgrounds; however, the pharmacokinetic properties of CBD have already been examined and the main objective of this study was to assess CBD safety in combination with an opioid agonist.
Moreover, whether these effects generalize to opioid dependent individuals and other relevant clinical populations are important to assess in the next phase of investigation. Self-report may have led to bias via distortion of information either intentionally or unintentionally, but our combination of self-report e. Finally, we studied relatively low to moderate doses of CBD and fentanyl and only included participants who were not opioid dependent out of concerns associated with development of drug abuse behaviors following administration in large doses.
While we cannot generalize our results to opioid dependent patients, the tolerance to opiates that characterize such individuals may actually decrease the risk associated with opioid intoxication compared to subjects with limited opioid exposure such as those included in this study.
In conclusion, capsules of and mg CBD did not exacerbate adverse effects associated with IV fentanyl administration. Co-administration of CBD and opioid is safe and well tolerated. The results of this study pave the way for future studies to examine the effect of CBD on opioid craving in association with opioid dependence in humans. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.
Participants were healthy volunteers aged 21 to 65 years with prior opioid exposure, regardless of the route. Blood samples were obtained before and after or mg of CBD pretreatment, followed by a single 0. CBD peak plasma concentrations, time to reach peak plasma concentrations tmax , and area under the curve AUC were measured. After low-dose CBD, tmax occurred at 3 and 1. After high-dose CBD, tmax occurred at 3 and 4 hours in sessions 1 and 2, respectively.
Cannabidiol does not exacerbate adverse effects associated with intravenous fentanyl administration. Coadministration of CBD and opioids was safe and well tolerated. The snippet could not be located in the article text.
Plasma cannabinoid concentrations during dronabinol pharmacotherapy for cannabis dependence
Safety and side effects of cannabidiol, a Cannabis sativa constituent. M Machado Bergamaschi, R Helena Costa Queiroz, A Waldo Zuardi, Current drug safety. Mateus M. Bergamaschi, Erin L. Karschner, Robert S. Goodwin, Karl B. Scheidweiler, Jussi Hirvonen, Regina H.C. Queiroz, Marilyn A. Huestis. Optical microscope and centrifugation were used to observe the structure change during evaporation of three different commercial emulsions of unknown.