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LANSING – One of the men charged with creating fictitious documents while contracted to service law enforcement alcohol testing instruments faces prison after being convicted by a jury, Michigan Attorney General Dana Nessel announced today.
The instrument, DataMaster DMT (DataMaster Transportable), is more commonly referred to as a breathalyzer and measures the driver’s breath alcohol concentration after they have been arrested for suspicion of drunk driving.
In 2020, Nessel filed charges against Andrew Clark and David John for falsifying service records related to certain diagnostic tests and repairs on DataMaster DMTs. A four-month investigation led by the Attorney General’s Public Integrity Unit (PIU) and the Michigan State Police (MSP) led to the criminal cases.
Clark opted for trial, which began Monday in Eaton County 56th Circuit Court.
The charges against Clark are:
two counts, forgery of a public record, a 14-year felony charge;
two counts, uttering and publishing, a 14-year felony charge; and
two counts, use of a computer to commit a crime, a 10-year felony charge.
After spending four hours deliberating, a jury convicted Clark late Thursday afternoon on all counts.
“The crimes perpetrated in this case compromised the public’s faith and confidence in the criminal justice system,” Nessel said. “I extend my appreciation to the jury and I remain grateful for the work of our PIU in coordination with MSP that brought this case to court.”
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Effects of Δ-THC on Working Memory: Implications for Schizophrenia
Summary of this paper
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Introduction
Therefore, an examination of the effects of marijuana on working memory may shed light on the link between marijuana abuse and schizophrenia. In this article, working memory will first be defined, and theory and findings regarding working memory performance in schizophrenia patients and marijuana smokers will be briefly examined. Second, the association between marijuana smoking and schizophrenia will be considered.
Working Memory And Marijuana Use
The relationship between marijuana use and working memory deficits in the nonpsychiatric population is complex. Reviews 21,22 of working memory function in psychiatrically healthy individuals who smoke marijuana regularly concluded that such individuals exhibit performance impairment on primary and secondary working memory tasks relative to healthy controls, and such impairments have been found to be associated with the self-reported frequency of marijuana smoking. 23, However, such deficits have been found less consistently than in participants with schizophrenia only.
Marijuana Use And Schizophrenia
39, However, knowledge of the direct effects of Δ 9 -THC on the component processes of schizophrenia, such as working memory, may help to clarify the causal relationships between these variables. For example, if Δ 9 -THC were found to acutely decrease working memory performance, this would be consistent with a causal link between regular marijuana smoking and impairment of a cognitive function centrally related to schizophrenia. However, a finding that Δ 9 -THC had a negligible or beneficial impact on working memory performance would be inconsistent with such a role.
Acute Effects Of Δ 9 -Thc On Working Memory
All smoked marijuana studies employed some form of standardized marijuana smoking (eg, paced puffing). The Figure 47 shows typical acute subjective and cardiovascular effects of single active marijuana cigarettes (closed symbols) relative to placebo marijuana cigarettes (open circles), produced under these controlled laboratory conditions. Based on this figure, it can be seen that subjective and cardiovascular effects peak within 7-10 minutes after marijuana smoking, and are Δ 9 -THC concentration dependent (eg, 3.9%>1.8%>placebo).
Visuospatial Working Memory
Consistent with these results, it has also been found that smoked marijuana decreased performance accuracy and increased response time on a simpler delayed matching-to-sample task in infrequent marijuana smokers (2-10 days/month), despite performance accuracy being reinforced with monetary earnings. Thus, it appears that single administrations of marijuana or Δ 9 -THC acutely impaired visuospatial working memory performance in relatively infrequent marijuana smokers. Further, since this impairment occurred whether or not participants were being reinforced for accuracy with monetary payment, performance motivation did not appear to play a role.
Verbal Working Memory
The results indicated that, relative to placebo, marijuana (1.8 or 3.6% Δ 9 -THC) had no effect on accuracy or response time on digit recall, or on serial addition/subtraction, a task that requires a significant contribution from working memory. Consistent with these results, another study 53 found that single marijuana cigarettes (3.6% Δ 9 -THC) had no impact on the accuracy of backwards digit recall in a comparable group of 14 marijuana users. However, in a smaller study 54 of similar marijuana smokers (n=3), smoking two consecutive marijuana cigarettes (2.6% Δ 9 -THC) did impair accuracy of digit recall and accuracy and response time on serial addition/subtraction, despite task performance being reinforced with monetary earnings.Go To Passage
Secondary Working Memory Measures
Therefore, the marijuana employed in these studies appears to be relevant and meaningful. In conclusion, if one considers both accuracy and response time as meaningful components of working memory function, it appears that Δ 9 -THC acutely decreases working memory function in marijuana smokers. As such, this review is consistent with the conclusions of Ranganathan and D’Souza.
Acute Δ 9 -Thc Effects And Schizophrenia
The conclusion that Δ 9 -THC acutely impairs working memory in psychiatrically healthy participants may suggest that marijuana smoking is a mechanism by which individuals already vulnerable to schizophrenia may further impair this critical function, albeit acutely. However, the working memory deficits acutely induced by Δ 9 -THC in psychiatrically healthy marijuana smokers appear to be fairly mild 49 relative to those reported in nonintoxicated schizophrenia patients. Additionally, schizophrenia is a disorder with multiple classes of symptoms, some of which appear to be related to working memory deficits, 19,68,69 but some of which may not be.
Acute Δ 9 -Thc Effects In Individuals At Risk For Schizophrenia?
Since the clinical impact of Δ 9 -THC is of the most concern in relatively young individuals who smoke marijuana regularly and are at risk for schizophrenia, acute studies of Δ 9 -THC in individuals already diagnosed with schizophrenia may have limited relevance to the broader question of marijuana’s relationship to the development of schizophrenia. Testing smoked marijuana’s acute effects in marijuana smokers who are at risk to develop schizophrenia would address this concern. Given that first-degree relatives of schizophrenia patients share some latent liability for schizophrenia, they constitute one potential group for examination.
Conclusion
This article argues for the centrality of working memory function in schizophrenia, examines the association between marijuana smoking and schizophrenia, and reviews studies of the acute effects of Δ 9 -THC on working memory in psychiatrically healthy participants. The authors generally found that in psychiatrically healthy marijuana smokers, Δ 9 -THC acutely decreased working memory performance, including speed and/or accuracy, regardless of route of Δ 9 -THC administration (smoked or IV), with more prominent effects on visuospatial working memory. Thus, Δ 9 -THC acutely impairs a critical cognitive function that is associated with the development of schizophrenia.
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Validation of a two-dimensional gas chromatography mass spectrometry method for the simultaneous quantification of cannabidiol, Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC in plasma
Summary of this paper
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Introduction
Cannabis sativa contains over sixty cannabinoids, including cannabidiol (CBD) and Δ 9tetrahydrocannabinol (THC). Although THC is the principal euphoric chemical in cannabis, its therapeutic properties include analgesia, muscle relaxation, anti-emesis, and appetite stimulation. CBD, a non-psychoactive cannabinoid, is an analgesic, anti-convulsant, anxiolytic, anti-oxidant, anti-psychotic, and muscle relaxant [1].
Calibrators, Quality Control Samples And Internal Standards
Individual stock solutions (1 mg/mL) were diluted in methanol and combined to prepare an intermediate calibration standard (10 μg/mL) containing CBD, THC, 11-OH-THC and THCCOOH. Methanolic working calibrator solutions at 10, 100 and 1000 ng/mL were prepared by dilution of the 10 μg/mL intermediate cannabinoid standard. Daily calibration curves were prepared by fortifying 1.0 mL blank plasma with appropriate amounts of working calibrator solution.
Two-Dimensional Gas Chromatography Mass Spectrometry
Derivatized extracts (4 μL) were injected in splitless injection mode. Analyte retention times on the primary column were determined by injecting a neat derivatized high concentration cannabinoid standard containing CBD, THC, 11-OH-THC and THCCOOH with column effluent directed to a flame ionization detector (FID). Heart cuts (0.4-0.6 min) containing each analyte peak were made, diverting flow to the secondary column.
Data were analyzed with Agilent Chemstation software version D.01.00. Analytes were identified by comparing retention times (± 0.15 minutes) and qualifier ion ratios (± 20%) to average calibrator values obtained in the same run. Quantification was determined by the ratio of target analyte peak area to corresponding internal standard peak area.
Extraction efficiency for each analyte was assessed in fortified blank plasma (n = 4) at each QC concentration (0.35, 7.5, 20, and 75 ng/mL). Extraction efficiency was calculated by comparing mean target ion peak areas in samples fortified prior to extraction with samples fortified after extraction, but before evaporation.
Although CBD and THC elute from the secondary column less than one minute apart, a single MS acquisition window was created for CBD and THC ions to manage potential retention time shifts. Also, a new oven temperature ramp was developed for extended retention of analytes on the secondary column to minimize retention time drift (Table 1). Complex oven temperature parameters were required for CBD and THC resolution.
Imprecision and bias were determined at 0.35, 7.5, 20 ng/mL for all analytes and additionally at 75 ng/mL for THC, 11-OH-THC and THCCOOH. Inter-and intra-assay imprecision (%CV) were <7.8 and <6.4% for all analytes, respectively ( Table 3). The method was highly reproducible and QC samples quantified within ± 9.2% of target.
This validated analytical method was applied to a plasma specimen from a participant enrolled in a controlled CBD and THC administration protocol. The plasma specimen contained 1.1 ng/mL CBD, 3.4 ng/mL THC, 3.6 ng/mL 11-OH-THC and 49.4 ng/mL THCCOOH. Extracted ion chromatograms are shown in Figure 1.
This complex instrumental method should be applicable to multiple biological matrices, following matrix validation, and should be highly useful for clinical research, forensic toxicology, workplace drug testing, and DUID programs. Extracted ion chromatograms from a) blank extracted plasma, b) blank plasma fortified with analytes at the limits of quantification-0.25 ng/mL cannabidiol (CBD), Δ 9tetrahydrocannabinol (THC), 11-nor-9-carboxy-THC (THCCOOH) and 0.125 ng/mL 11hydroxy-THC (11-OH-THC), and c) extracted participant specimen from Sativex ® administration a . Arrows indicate retention times of analytes.
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Section 1
A sensitive and specific breathalyzer for D9-tetrahydrocannabinol (THC) is being developed to determine recent cannabis intake.
Cannabinoid Markers
Anti-doping: drug testing in sports to deter athletes from ingesting prohibited drugs to achieve an unfair advantage in competition. Cannabinoids: a class of closely related compounds of the cannabis plant including D9tetrahydrocannabinol (THC, the primary psychoactive chemical in cannabis), more than 100 other structurally related chemicals in the plant, and the endocannabinoid neurotransmitters produced by the human body and many other living organisms, as well as synthetic cannabinoids produced by clandestine chemists, all of which interact with cannabinoid receptors. Cannabinoid disposition: the movement of cannabinoids from the blood into tissues, urine, feces, and bile, as well as into alternative matrices such as oral fluid, sweat and hair.
Urine Markers
When studying THCCOOH urinary excretion in frequent cannabis users, our laboratory group observed positive urine tests for weeks after last use, making it difficult to determine if individuals were abstaining or relapsing in drug treatment [35]. Studying cannabinoid distribution in frequent cannabis users is difficult because ethical and safety concerns prohibit administering the expected amount and frequency of cannabis taken by this population. Nevertheless, this has led to several studies where every urine sample can be analyzed for THCCOOH and creatinine during sustained abstinence to determine THCCOOH pharmacokinetics in frequent users [36].
Hair Markers
In addition, contamination of hair with THC but not THCCOOH by side-stream smoke was reported [52]. Recently, one study reported that THC, THCCOOH, and the THC precursor, D9-tetrahydrocannabinolic acid A, could all be present in hair samples from non-consuming individuals owing to transfer of cannabinoids from cannabis consumers via their hands, sebum/sweat, or cannabis smoke (e. g., exhaled) [53]. Given the poor incorporation of THC in hair and the possibility of contamination from environmental smoke, THCCOOH is considered to be the best hair marker for identifying cannabis use.
Sweat Markers
In one study, THC was quantified in sweat patches from frequent users during sustained abstinence. In many frequent cannabis users only the patch applied during the week abstinence had initiated was positive for THC, and in other patches that were applied the second, third, and fourth weeks of abstinence patch cannabinoids documented extended excretion of THC. However, no THC was found in test patches following oral ingestion of up to 14.8 mg of THC [54].
Breath Markers
THC was removed selectively from the filter and quantified by LC-MS/MS; breath samples from 18 chronic and 11 occasional cannabis users were examined following smoking of a 6.5% THC cigarette [56]. THC 50 pg/filter was detected up to 4 h after cannabis smoking in frequent cannabis users and for a shorter time in occasional users. Thus, while breath is a good matrix for identifying recent cannabis use, no THCCOOH has been identified in breath [56].
Synthetic Cannabinoid Markers
LC-MS/MS screening for new synthetic cannabinoids in a targeted method is a good approach and an achievable one based on the available instrumentation and personnel resources to identify NPS markers, but this approach is also limited by the time that is necessary to keep analytical methods current with newly marketed synthetic cannabinoid compounds, and by the constant need for new reference standards that may not yet be available [63,64]. Unfortunately, this is almost an impossible task. A different approach utilizes HR-MS and a consistent acquisition program to facilitate the addition of newly introduced NPS [9].
Challenges In Interpreting Cannabinoid Use Findings
Other challenges for interpreting cannabinoid results comprise the windows of cannabinoid detection that vary by the biological matrix tested and the analyte(s) selected for monitoring. In this manuscript we have discussed the importance of recent use markers to identify the timeframe of cannabinoid intake, especially in chronic frequent cannabis users. Blood is considered to be the biological matrix that best reflects ongoing pharmacological effects, but blood cannabinoid concentrations decrease rapidly.
Concluding Remarks
Data on drug delivery through these new methods does not yet exist, making it impossible to know what new markers might be available and how to interpret their concentrations and toxicity. The need for behavioral and biological cannabinoid markers is expanding with cannabis medicalization and legalization. Therapeutic drug monitoring of effective cannabinoid pharmacotherapies will be required in the future when new cannabinoids are proven safe and efficacious.
Outstanding Questions
What are the major factors differentiating cannabinoid pharmacokinetics in frequent and occasional cannabis users?
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Estimating the Time of Last Cannabis Use from Plasma 9-Tetrahydrocannabinol and 11-nor-9-Carboxy- 9-Tetrahydrocannabinol Concentrations
Summary of this paper
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Section 1
First samples were collected at 1 min after smoking and at frequent intervals up to 168 h. From these data, the authors developed 2 models to predict time of last cannabis use within 95% confidence intervals (CIs). The first model computed the elapsed time between smoking cannabis and blood collection based on plasma THC concentration alone, whereas the second model used the plasma THCCOOH/THC concentration ratio. They applied the models to results from all published studies at the time that reported THC and/or THCCOOH concentrations measured by either RIA or gas chromatography-mass spectrometry with either internal or external standardiza-tion.Go To Passage
Materials And Methods Participants And Study Design
At 0900 on the day of testing, participants received a single oral dose of placebo (n ϭ 10) or up to 90 mg of rimonabant. Two hours later, they smoked a cannabis cigarette containing 2.64% THC by weight, estimated to contain ϳ20 mg of THC. The number of puffs and time between puffs were standardized.Go To Passage
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Analytical Method
Model I determined time estimates from plasma THC concentrations and model II from the plasma THCCOOH/THC concentration ratios. The formulas are reproduced below, with t representing the elapsed time in hours between the beginning of cannabis smoking and blood collection, and CI representing the 95% confidence interval for the estimate of t. The subscripts 1 and 2 refer to models I and II, respectively, and brackets indicate the concentrations of THC or THC-COOH in g/L: 123.420 ͮ These equations were developed from cannabinoid concentrations in plasma samples collected for up to 168 h after controlled smoking of a 1.75% and a 3.55% THC cigarette by each of 6 cannabis users residing continuously in a secure clinical research unit (19 ). Drug administration was not initiated until their urine cannabinoid concentrations were Ͻ20 g/L.Go To Passage
Results
The results for predicted elapsed times between the beginning of cannabis smoking and blood collection obtained with model I, model II, and a combination of the models are summarized in Table 2. The conditions for the single cigarette study were similar to those in the study used to produce the models, except that cigarettes contained 2.64% THC instead of either 1.75% or 3.55% THC, and length of inhalation and the time smoke was held in the lungs were not controlled. For model I, Table 2 reflects that, for 392 of 427 samples collected from 38 individuals after they began smoking the first cigarette, the observed time fell within the predicted range of elapsed time.Go To Passage
Discussion
Other studies also have shown that cannabis users tend to titrate their dose of drug to maintain the level of intoxication they Table 3. Predicted elapsed time between cannabis smoking and blood collection with plasma THC between 0.5 and 2.0 g/L and THCCOOH >2.5 g/L. prefer (20 ).Go To Passage
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Introduction
To our knowledge, there have been no studies of deposition of cannabinoids in human hair following controlled administration of cannabis or THC. Most studies rely on self-reports of cannabis use. In cases where individuals have reasons to hide their drug use, self-report can be unreliable [21].Go To Passage
Subjects
They provided written informed consent to take part in controlled oral and smoked drug administration studies evaluating the pharmacokinetics and pharmacodynamics of cannabis. Subjects completed a questionnaire regarding drug use habits and had hair collected before and after drug administration. The National Institute on Drug Abuse Institutional Review Board approved the randomized, double blind, double dummy, placebo-controlled clinical studies and subjects were compensated for participation. Go To Passage
Clinical Research Protocol
The two highest doses were in the last month of administration. The total THC administered was 116 mg. Hair specimens were collected at the end of the 10-week period 7-10 days after the last dose was administered.Go To Passage
Hair Collection Protocol
For the purposes of this investigation and in accordance with routine hair testing practices, the first 3.9 cm of hair closest to the scalp was analyzed to reveal drug use within the last three months. A total of 53 hair specimens were collected. Hair specimens were randomized and blinded prior to analysis at American Medical Laboratories (currently Quest Diagnostics), Las Vegas, NV. Go To Passage
Gcmsms Analysis For Thc And Thccooh In Hair
Calibration samples contained 5 and 0.5 pg/mg THC and THCCOOH, respectively. Controls in certified negative hair matrix were prepared at 0, 3.0 and 7.0 pg THC/mg hair and 0, 0.3 and 0.7 pg THCCOOH/mg hair. A blind quality control sample at a concentration within the linear range was also included with each analytical batch. Go To Passage
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Immunoassay For Cannabinoids In Hair
It was adapted and validated for the analysis of cannabinoids in human hair. The LOD of the assay was 2 pg THC equivalents/mg and a cutoff concentration of 5 pg THC equivalents/mg hair was used to screen all specimens. Intra-and interassay precisions at the cutoff concentration were 1.7 % and 9.3 %, respectively. Go To Passage
Statistical Tests
Several procedures for detecting use of cannabis or THC were evaluated. We determined the fraction of specimens that were positive using each of the following criteria: GCMSMS for THC ≥ LOQ, GCMSMS for THCCOOH ≥ LOQ, immunoassay cannabinoids ≥ 5 pg THC equivalents/mg hair, and both immunoassay and THCCOOH ≥ respective cutoff concentrations. Fisher’s exact test, two-tailed, was used to compare the fractions of positive specimens, i.e. detection rates, for daily and non-daily users, AA and C subjects, and to test for independence of detection rates for subjects before and after smoked cannabis [22]. Go To Passage
Results
For those specimens with detectable cannabinoids, the range of concentrations for THC was 3.4 to > 100 pg/mg of hair and for THCCOOH 0.10 (the LOQ) to 7.3 pg/mg hair (Table 1). THC and THCCOOH concentrations were positively correlated (r = 0.38, p < 0.01, Pearson’s product moment correlation, excluding the subject with > 100 pg THC/mg hair). Median THC and THCCOOH concentrations were higher for daily users and AA subjects, but elevations were not statistically significant (Mann-Whitney Rank Sum Test, all p > 0.2, see Figures 1 and 2). Go To Passage
Discussion
For many drugs the parent compound is in much higher concentration in hair than water-soluble metabolites and this is also true for cannabinoids. Concentrations ranged from 3.4 to > 100 pg THC/mg hair compared to 0.10 to 7.3 pg THCCOOH/mg hair. THC concentrations compared well with those reported by other investigators [7,8,10], while THCCOOH concentrations were similar to those reported by Moore et al. Go To Passage
Conclusions
THC and THCCOOH concentrations were positively correlated (r = 0.38, p < 0.01, Pearson’s product moment correlation). Using an immunoassay cutoff concentration of 5 pg THC equivalents/mg hair, 83% of specimens that screened positive were confirmed by GCMSMS at a cutoff concentration of 0.1 pg THCCOOH/mg hair. Concentrations of (a) Δ 9 -tetrahydrocannbinol (THC) and (b) 11-nor-Δ 9tetrahydrocannbinol-9-carboxylic acid (THCCOOH) in hair of cannabis users. Go To Passage
