From Seed to Harvest: Mastering the Art of Cannabis Farming

Posted on December 7, 2023 by hemp2022

Human use of these devices for ingestion of cannabis extracts or cannabidiol is becoming so popular that terming these devices e-cigarettes or ENDS is becoming a misnomer; Electronic Drug Delivery Systems is more accurate. The primary goal of this study was to establish methods for delivering physiologically and behaviorally significant amounts of heroin to rats via vapor inhalation. To this end we adapted an e-cigarette based vaporization system we have previously shown is effective for the delivery of nicotine , THC , cannabidiol , methamphetamine , 3,4-methylenedioxypyrovalerone and oxycodone to rats. Other work has demonstrated antinociceptive effects of inhaled oxycodone in male rats and a preliminary work demonstrates antinociceptive efficacy of inhaled heroin and methadone in male and female rats, and reinforcing effects of inhaled heroin in female rats. Nearly identical systems have been shown to deliver nicotine , THC from cannabis extracts and the potent synthetic opioids sufentanil and fentanyl , to laboratory rodents. To validate the delivery of heroin by vapor inhalation, we used a warm water tail-withdrawal assay for assessing effects on nociception, and a radiotelemetry system capable of reporting body temperature and activity responses. The telemetry measures were selected based on prior evidence that parenteral injection of opioids causes hyperthermia and increased locomotor activity in both rats and mice. For example, intravenous morphine increased the rectal temperature of anesthetized rats , as did intrathecal morphine in freely moving male Wistar rats measured with telemetry . Both morphine and oxycodone produce hyperthermia when injected subcutaneously in rats . Solis and colleagues showed that intravenous fentanyl initially decreased body temperature of rats in the first hour after administration, did not, but each drug induced hyperthermia in the interval approximately 60–120 minutes after injection .

Heroin has also been shown to increase the locomotor activity of rats when injected subcutaneously or intraperitoneally in doses of ~0.25–1.0 mg/kg, although in some early studies a contrast of this described effect with vehicle injection was not made clear . Nevertheless,vertical growing racks system in other studies it was shown that heroin injection ~0.25–0.5 mg/kg, s.c., significantly increases the locomotor activity of rats in comparison with a vehicle injection. A secondary goal of this study was to determine the parameters necessary for dose control / manipulation within an effective range. As we’ve shown in prior studies , this can be effected with changes in drug concentration in the vapor vehicle and the duration of exposure, thus these parameters were under investigation. The final goal was to determine if there are any substantive sex differences in the response to heroin inhalation, see Craft for review, consistent with current suggestions for the inclusion of both male and female subjects in research where possible . While male and female rats acquire intravenous oxycodone self-administration at similar rates with 1-h access sessions , our recent study with 8-h access found that female rats self-administered more oxycodone in acquisition, but did not reach higher breakpoints in a PR dose-substitution . A prior study reported no sex difference in the anti-nociceptive effect of heroin or oxycodone injected subcutaneously in Sprague-Dawley rats , thus no sex difference was predicted for this study. The rats were implanted with sterile radiotelemetry transmitters in the abdominal cavity as previously described on Post-Natal Day 31. For studies, animals were evaluated in clean standard plastic homecages in a dark testing room, separate from the vivarium, during the dark cycle. Radiotelemetry transmissions were collected via telemetry receiver plates placed under the cages as described in prior investigations . Test sessions for exposure studies started with a 15-minute interval to ensure data collection, then a 15-minute interval for baseline temperature and activity values. The rats were then moved to a separate room for the vapor exposure sessions and then returned to the recording chambers for up to 300 minutes after the start of vapor exposure.

These experiments were conducted over the adult age interval of PND. The subjects had participated in similar telemetry recording experiments following vapor and injected exposure to doses of nicotine and THC from PND 50 to PND 190 with active dosing conducted no more frequently than two times per week, in studies not previously reported. The telemeterized body temperature and activity rate were collected on a 5-minute schedule in telemetry studies but are expressed as the average of six sequential measurements for primary analysis. The time courses for data collection are expressed relative to the initiation of vapor exposure and times in the figures refer to the end of the interval . Any missing temperature values were interpolated from the values before and after the lost time point. Activity rate values were not interpolated because 5-minute to 5-minute values can change dramatically, thus there is no justification for interpolating. Data for the first time-point after the start was inadvertently missing for two female rats in the 30-minute PG condition. The values for the second time point were used in place of the missing values. These ended up being very similar to the respective values recorded for this time point for the 15-minute PG condition. The telemetry data were generally analyzed with two-way Analysis of Variance including repeated measures factors for the Vapor condition and the Time after vapor initiation. A mixed-effects model was used instead of ANOVA wherever there were missing data points. The nociception data were analyzed by three-way ANOVA including repeated-measures factors for Duration of exposure and Vapor condition and a between-groups factor of Sex. Any significant main effects were followed with posthoc analysis using Tukey or Sidak procedures. All analysis used Prism 8 for Windows . This study confirms that this method of inhalation of heroin, based on vapor created by an Electronic Drug Delivery System device, produces significant effects in vivo in both male and female rats. The effects are dose-dependent, as they vary with both inhalation duration and with drug concentration in the e-cigarette vehicle .

We have previously shown that heroin vapor exposure produces moderate anti-nociceptive effects in male and female Wistar rats and that is extended to Sprague-Dawley rats, and to a wider range of inhalation conditions, in the present study. As we’ve previously shown, differences between common laboratory rat strains can result in quantitative or even qualitative differences in response to vapor inhalation of drugs, effects which may vary depending on the outcome measure . The present results obtained near-maximal antinociceptive effects in more animals in the 100 mg/mL condition, compared with that prior study, however there were equipment differences between the two studies which may have resulted in more effective drug delivery. For example that prior study reported no antinociceptive effect of oxycodone vapor inhalation using first generation Protank 3 canisters, whereas a study using the second-generation Herakles Sub Ohm canisters, more similar to the present second-generation SMOK canisters,vertical marijuana grow did report anti-nociception subsequent to 100 mg/mL oxycodone vapor inhalation . Although vapor cloud density and chamber fill can be roughly equated by eye, it may be the case that different devices generate different droplet sizes or drug concentrations per droplet that produce complex interactions of a given drug with a given device to effect in vivo drug delivery. In that prior study a 1 mg/kg, s.c., heroin injection produced antinociception comparable to the effects of 30 minutes of 50–100 mg/mL exposure in this study. The data also show that the threshold for statistically reliable effects is 15-minutes of exposure to the 50 mg/mL condition. These exposure parameters led to significant antinociception and produced significant effects on body temperature in the female rats. This study therefore establishes 50–100 mg/mL as an effective concentration range, and 1 mg/mL as an ineffective concentration, for 15–30 minutes of non-contingent inhalation exposure to heroin in rats. This is a nontrivial advance from the prior demonstrations that rats and mice, respectively, will self-administer the potent opioids sufentanil and fentanyl . First, the doses needed to produce robust changes in nociception, thermoregulation and locomotor behavior are often far in excess of the doses that rodents will self-administer. Second, we found previously that cocaine and some amphetamine or cathinone class psychomotor stimulants which exhibit both low potency and lower solubility in PG may not readily be delivered in active doses with this approach . Thus, it was critical to show that a less potent opioid such as heroin can be delivered with this method. There were biphasic dose-dependent effects of inhaled heroin on body temperature which was expressed as lower exposure conditions producing reliable increases in temperature, and higher doses / exposures initially reducing body temperature, at least in the female rats. A prior study found similar biphasic effects after intravenous fentanyl, which initially decreased body temperature of male Long-Evans rats in the first hour after administration, but induced hyperthermia thereafter . This may reflect potency, or brain penetration speed, as potential differences between the two opioids that permitted this initial hypothermia to be observed.

It could similarly be the case in the present study that the inhaled route of administration speeds the brain entry of heroin versus the more common s.c. or i.p. or even i.v. routes of administration. The observation that injected heroin did not have immediate effects on female rats’ body temperature , and induced less complete suppression of activity compared with inhaled heroin , supports this interpretation. If so, this may be a key area in which the development of this inhalation model allows the investigation of effects of heroin which are unique to this route of administration. It may also be the case that effects of inhalation are more similar to the effects of the intravenous route, in this case the method offers several practical advantages over implanting and maintaining intravenous catheters in rodents. Such advantages include overall cost, surgical expertise and avoiding subject loss due to occluded catheters or health complications related to the catheter. The apparent sex difference is most likely a difference in effective dose when heroin is inhaled, since pilot work with a group of male Sprague-Dawley rats illustrated a consistent hypothermia associated with a high exposure condition and hyperthermia with a lower exposure condition . Also, female rats in this study were affected in terms of body temperature and anti-nociception after 15-minute inhalation of Heroin 50 mg/mL, whereas male rats were only affected on the anti-nociception assay and only to an extent that failed to reach statistical significance. Overall, these patterns are more consistent with a dosing difference across sex rather than a sex difference per se; additional work with more expanded dosing conditions might further explicate this interpretation. Interestingly, when mg/kg equivalent doses were injected the males’ body temperature was consistently elevated whereas the females’ temperature was not. A previous study found no difference in the ED50 for heroin in a warm water tail-withdrawal test between male and female Sprague-Dawley rats and where sex differences were found the males were more sensitive. Nevertheless, female mice develop greater hypothermia than do males after a mg/kg equivalent injection of morphine . The initial suppression of activity, followed by a rebound of increased activity, is similar to that reported for injected morphine but differs somewhat from prior results for injected heroin, which appeared to show a monotonic effect of time where activity is highest at the first time-points observed after dosing and then declined steadily with time. The pattern of initial suppression followed by a rebound was observed in the 1.0 mg/kg, s.c. injection study, as well as in the 30-minute inhalation experiments, suggesting the difference is not due to route of administration. One possible difference is that some of those studies were conducted with rats in the light part of the cycle , however others reporting similar monotonic time courses were on a reverse cycle and were tested in the dark . A more consistent difference is that many studies of the effects of injected heroin used a non-housing, specialized photo cell cage with mesh or rod floors, unlike the plastic floored normal housing cages with a thin layer of bedding used here. It may be the case that the more familiar, housing-type environment facilitated expression of a more naturalistic response. There are a few necessary caveats; given the selected repeated measures experimental design it is always possible that a degree of plasticity, either sensitization or tolerance, may have developed. The counterbalanced testing order, however, minimizes the concern that this would have a systematic effect on any specific dosing conditions. Likewise, the animals had participated in prior studies involving exposure to THC, which might potentially produce cross tolerance, and because of that the animals were in the middle adult age range. It is entirely possible that responses in younger adults might differ.

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The Science Behind the Strain: A Deep Dive into Cannabis Cultivation

Posted on December 6, 2023 by hemp2022

Notably missing from the HIV literature is an examination of differential associations by sex or race/ethnicity and APOE’s association with cognition and brain integrity. In a meta analysis of aging research studies, APOE e4 women were found to be at greater risk of AD compared to APOE e4 men but only between the ages of 65 and 75 . Additionally, there are known differential effects of APOE status on AD risk by race. The effect of APOE status on AD risk is significantly attenuated in African Americans/Black people compared to non-Hispanic white people . Therefore, future examination of the relationship between sex, race/ethnicity, APOE status, and other genetic markers of AD risk within PWH is certainly warranted. In summary, considering the HIV literature, the middle-aging literature, and the finding that episodic memory was associated with prefrontal structures rather than medial temporal lobe structures, episodic memory in middle-aged PWH is more likely related to frontally mediated etiologies. This could indicate that memory in middle-aged PWH is associated with HIV disease. Notably, this association was seen in PWH on ART without a detectable viral load, showing that this association is seen even in PWH who are virally suppressed. However, it is of course difficult to differentiate between the effect of HIV itself versus the effect of comorbid conditions, many of which may be increased in PWH due to the downstream effects of HIV and ART, or a combination of the two. The medial temporal lobe was not associated with episodic memory, which overall may indicate that at this age range, preclinical AD is not likely a contributor to memory functioning. However, the middle-aging literature does not provide a good estimate of when, on average, to expect to start detecting differences, even small,vertical grow factory in memory and medial temporal structures in those that are on an AD trajectory; therefore, it is possible that this group is too young to even start detecting any preclinical AD effect.

This is further complicated because the middle-aging literature is demographically different from the CHARTER sample, thus highlighting the need for more diverse aging studies. Additionally, this study did not specifically examine differences in the associations between memory and brain structures by AD risk ; thus, future research should examine memory associations by AD risk, particularly given that APOE status was associated with delayed recall. Relatedly, these findings show that on average this group is not showing associations with memory and the medial temporal lobe and early signs of preclinical AD, but this does not mean that no participants are on an AD trajectory. In fact, given base rates, some of this group will eventually develop AD. First, the multi-level models examining the cross-level interactions between time and medial temporal structures with dichotomous recognition as the outcome did not converge. This analysis would have examined if baseline medial temporal lobe structures are associated with greater likelihood of impaired recognition over time. Given that the models did not converge, this indicates the models were over parameterized and that the model was not supported by the data. This was possibly affected by the modest sample size, with a particularly small group of participants with impaired recognition at baseline. Examining the variability in recognition over time within this study is still meaningful. For example, of the 12 participants that were impaired at baseline, only two remained impaired. Moreover, in those that were not impaired at baseline but were impaired at some point in time, most reverted back to unimpaired at subsequent visits. Only four participants remained impaired in recognition over time, although with limited follow-up. There is not data on why these participants do not have additional follow-up , and thus it is hard to make any definitive conclusion as to if consistently impaired recognition is a risk factor for negative outcomes. However, it would certainly be warranted to examine if consistent recognition impairment is associated with negative outcomes in a larger group of middle-aged and older PWH. For example, this small group of participants that were consistently impaired in recognition memory could represent those that are progressively declining and are on more of an AD trajectory. Moreover, a better understanding of how those that are consistently impaired differ from those that revert to unimpaired recognition would be beneficial.

There are multiple reasons that may explain why recognition impairment status was variable over time. First, HIV-associated neurocognitive impairments are known to fluctuate over time. For example, in the CHARTER study, 17% of the sample improved over time . Therefore, this could simply reflect the heterogeneous and fluctuating course of HAND over time. Second, recognition is sometimes used as an embedded performance validity measure. While all participants were administered a standalone performance validity test at the beginning of the neuropsychological evaluation to verify credible test performance, effort can fluctuate throughout testing. That said, none of the participants at baseline were below the proposed cut-off of ≤5 for HVLT-R recognition , making this explanation less likely. Lastly, this variability over time may be in part due to the psychometric properties of the HVLT-R and the BVMT-R. Recognition for both the BVMT-R and the HVLT-R are skewed with known ceiling effects, meaning that there is limited variability in this variable . Therefore, a one- or two-point difference can result in large differences in the normative score. Moreover, there are known modest interform differences on the HVLT-R recognition . Additionally, while the HVLT-R and BVMT-R test-retest reliability of recognition show adequate test-retest stability coefficients, the test-retest reliability of recognition is less reliable than other test measures such as total learning or delayed recall . Next, longitudinal delayed recall was examined. Most notably, there was little decline in delayed recall over time; the delayed recall T-score decreased by 0.041 per year. Additionally, there was little variability in this slope given that the standard deviation of the slope was 0.678. None of the cross-level interactions between medial temporal lobe structures and years since baseline were significant indicating that medial temporal lobe structures at baseline were not associated with a change in delayed recall. However, given that there was little variability in delayed recall over time, this was not surprising.

As discussed in the introduction, worse baseline medial temporal lobe structures, particularly the hippocampus and entorhinal cortex, have been associated with an increased risk of future AD, MCI, and decline in cognition in older adults without HIV . This relationship is less understood in middle age. One study by Gorbach et al. found that hippocampal atrophy was associated with a decline in episodic memory in adults over the age of 65 but not in middle-aged adults between the ages of 55 to 60. As highlighted above, it is possible that the cohort from the current study is too young to expect to see associations between medial temporal lobe structures and longitudinal memory. Importantly, the current study only examined cross-sectional structural MRI; therefore, we cannot assume that smaller or thinner medial temporal lobe structures are indicative of atrophy. Additionally, this study does not have an HIV-negative comparison group and did not use normatively-adjusted morphometric values , so it is unclear if participants in this cohort deviate from average, although accelerated brain atrophy has been demonstrated in PWH previously . Therefore, research examining changes in the medial temporal lobe and how that change relates to episodic memory, particularly recognition memory,vertical grow indoor in persons with and without HIV over the age of 65 is needed. This research may help to better understand if medial temporal lobe structures are associated with the risk of an AD trajectory and if these associations differ by HIV-serostatus. While there may be some individuals in this group that are experiencing objective decline, on average, in this group of middle-aged PWH we did not observe a decline in delayed recall T-scores over time. These T-scores are age-corrected, so the raw scores on the tests may be declining but they are not declining at a rate greater than what would be expected for age. Additionally, these T-scores also account for practice effects, which if unaccounted for can mask decline, although the best method of practice-effect correction is still debated . Similar results showing stable cognition over time were found in a study by Saloner et al. in a larger sample of CHARTER participants aged 50 and over. This study employed growth mixture modeling, and none of the three latent classes demonstrated a decline in global T-score over time. However, other studies of PWH over the age of 50 have observed a greater than expected effect of aging on episodic memory and a recent systematic review found accelerated neurocognitive aging in 75% of longitudinal studies in PWH . Some researchers have questioned if accelerated aging could be due to a neurodegenerative cause such as AD given the high prevalence of risk factors for AD in PWH such as chronic inflammation, increased cardiometabolic comorbidities, and lower brain reserve . While emerging studies have demonstrated some possible ways to disentangle HAND and aMCI , it remains unclear if PWH are at increased risk of AD or if a neurodegenerative etiology could, at least in part, account for someof the observed accelerated aging.

For example, Milanini et al. showed a low frequency of amyloid positivity, measured via PET imaging, among virally suppressed PWH over the age of 60, and the rates of amyloid positivity were similar to published rates among an age-matched seronegative sample. However, a recent study among Medicare enrollees did find a higher prevalence of AD and related disorders among PWH . In summary, this aim showed that recognition was variable over time. While amnestic decline could not specifically be tested given that recognition models did not converge, these analyses indicated that within this group, medial temporal lobe integrity was not associated with a decline in delayed recall over time. Additionally, delayed recall only marginally declined over time , thus adding to the mixed literature examining episodic memory in middle-aged and older PWH. Overall, this study did not detect clear signs of preclinical AD in this group, as delayed recall did not change over time and baseline measures of medial temporal lobe integrity were not associated with memory over time as seen in HIV-negative older adults. However, it is not clear if these associations would be expected in a middle-aged cohort of PWH due to a lack of literature on this topic in middle-aged adults. Therefore, it would be beneficial to re-examine this analysis in an older cohort of PWH.The last aim of this study was to examine if the medial temporal lobe mediates a relationship between peripheral inflammation and memory. It was hypothesized that medial temporal lobe structures would mediate a relationship between peripheral inflammation and episodic memory. Five peripheral biomarkers of inflammation were examined , and these biomarkers were chosen given that they have been associated with cognition in AD and HIV. In this mediation model, the association between peripheral biomarkers of inflammation and medial temporal lobe structures was also explored and the relationship between medial temporal lobe structures and memory was also reported, although this second relationship was already explored in aim 1. First, the mediation models examining recognition indicated poor model fit. Therefore, the relationship between the five plasma biomarkers of inflammation and recognition was examined instead. Greater levels of plasma CRP were associated with lower odds of having impaired recognition. None of the other plasma biomarkers of inflammation were associated with recognition impairment. These findings are generally not in line with the HAND , middle-aging , or older adult literature . Aging and HIV studies have found that a greater concentration of these plasma biomarkers of inflammation are associated with greater risk of HAND, worse memory, and an increased risk of future development of MCI or AD. However, many of these studies only find weak associations, and these studies do not examine recognition memory. The current study had a very small sample of PWH with impaired recognition; thus, it is possible that the CRP finding is spurious, and this finding should not be over-interpreted. Therefore, analyses should be reexamined in a larger, more generalizable sample. Next, a single-mediator model was used to examine if medial temporal lobe structures mediate the relationship between plasma biomarkers of inflammation and delayed recall.

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Vertical Harvest: Revolutionizing Cannabis Farming for Increased Efficiency

Posted on December 5, 2023 by hemp2022

This drop is significant as it does not appear in BEA_beta, showing that sites with the same DoC can have drastically different contributions to capacitance. The source of this low-CCpC region becomes clear when examining representative configurations of the most highly confined anions of BEA and BEA_beta in Figure 5.8. In BEA, the anion islocated in a cylindrical, nanotube-like structure, with a coordination shell of electrode atoms encircling the anion on all sides, while the anion in BEA_beta is only confined on two out of four sides by the electrode. The cylindrical pore of BEA is too small to fit another anion or even solvent molecule, but too large to snugly fit BF4 – , causing it to be stuck in the middle of the pore where it is not close enough to induce a strong compensating charge on any of the atoms within its coordination shell. As a result, the coordination shell atoms in BEA have a total charge of −0.026 e, while the coordination shell in BEA_beta has a total charge of 0.223 e. This effect has also been observed in the literature; for example, Kondrat et al. showed a local minimum in capacitance when the pore-to-ion-diameter ratio L/d was around 1.5, and increased capacitance when L/d was near 1 and 2.The charge storage efficiency also depends on the ion size in relation to the pore size: In the electrolyte studied here the cation is larger than the anion and its charge is distributed on three sites. As such, when a cation is at the center of the nanotube-like pore, the partial charges of its coarse-grained sites are able to approach more closely to the electrode surface, making the equivalent pore in the cathode more efficient at storing charge. This explains why there is no drop in h CCpCi DoC in the BEA cathode . These observations highlight one important role of pore geometry in determining charge storage efficiency, by influencing local ion density and electrolyte coordination environment. We show in Figure 5.11 the structures of the materials with highest and lowest Csim − Cf it,vertical garden grow system indicating the average charge of each crystallographically unique electrode carbon atom during the equilibrated constant potential run, along with the probability density isosurfaces of counterion locations within the electrodes.

Isosurfaces for adsorption sites with more than 0.1 e total charge compensation are shown in purple, while sites with less than 0.1 e charge compensation are shown in green. This allows us to visually associate geometry with average contribution to capacitance for an individual pore. We observe that the adsorption site iso surfaces which have more than 0.1 e coordination shell charge compensation are close to the surface of the frameworks, while the isosurfaces associated with less than 0.1 e charge compensation tend to be in the middle of the pores. Inspecting the average atomic charges, we observe that BEC and h91 have more individual carbon atoms with high charge, corresponding to high CCpC. As seen in Figure 5.9, BEC and h91 are also the two materials with the highest enhancement in capacitance compared to materials of similar A/h dsepi . In contrast, h18, h49, and ISV, which have A/h dsepi similar or greater than that of BEC, but lower capacitance, have fewer highly charged atoms. Figure 5.11f provides further quantitative evidence of the correlation between the probability of highly-charged atoms and Csim −Cf it: structures with a higher probability density of average atomic charge greater than 0.1 e tend to have a higher Csim − Cf it. In order to rationalize the differences in charge storage between these materials, we focus on the local radius of curvature of the materials, as this roughly determines the distribution of ion-electrode distances at a particular adsorption site. In BEC, which has square-shaped windows with right-angle “corners,” we see electrode atoms with large average partial charges at two locations for each adsorption isosurface, corresponding the positions at which an adsorbed ion can be in close proximity with two “walls” of the framework simultaneously. In h91, cynlindrical pores adjoining with rounded beams create small-radius of curvature sites where ions can again approach the electrode surface closely at multiple sites, leading to more electrode atoms with large partial charges. In contrast, adsorption sites which are near large radius of curvature sites, such as in h18, h49, and ISV, , tend to be associated with materials with lower capacitances relative to their respective A/h dsepi . In adsorption sites with a large radius of curvature, an ion is not able to induce as many favorable Coulombic interactions with the electrode surface, leading to lower charge compensation for ions within those materials.

ISV merits particular mention, as it does contain some adsorption sites with low radius of curvature and high charge compensation , but because it also has high radius of curvature/low charge compensation sites , ISV still has a relatively low capacitance considering its high A/h dsepi . Overall, our results demonstrate that pore geometries which are capacitance-enhancing tend to faciliate the close approach of counterions to multiple carbons within the electrode via low radius of curvature adsorption sites, so that the compensating charge from the electrodes can be localized and large in magnitude to most efficiently screen counter charges and allow for higher counterion loading in the pores. Conversely, capacitance-diminishing properties include pores with high radius of curvature and cylindrical and ill-fitting pores, as these types of sites have inefficient charge storage and therefore decrease the overall capacitance of the material.For a preliminary assessment of the ability of the different models, method and protocols to describe the adsorption of THC in microporous materials and MOFs, we investigated the well-studied Mg-MOF-74. This MOF was chosen because of its large channel diameter, which can host the bulky THC molecule, and because of the presence of strongly charged Mg open metal sites, which have a partial charge of 1.59 e as computed with the DDEC protocol.190 This allows us to asses the contribution of Coulombic interactions in the adsorption of THC, a weakly charged molecule within frameworks having strongly charged binding sites. The THC-head model was used for a preliminary simulations. Since the alkyl tail is charge-neutral, the THC-head portion of the molecule is also neutral and therefore it can be used to assess the contribution of Coulombic interactions. We ran NVT Monte Carlo simulations at 309 K, the human body temperature, and at infinite dilution, i.e., with one THC-head particle per simulation box, for a total of 2 · 106 Monte Carlo steps . To equilibrate the system before the production, 10 000 cycles were added, i.e., one tenth of the total number of steps. Each move was chosen from translation, rotation, and random insertion with equal probability. From the output of these calculations we observed that, while the acceptance ratios of translation and rotation moves are close to the 50%, the regrow acceptance ratio is only 4.8%. This means that it is particularly difficult for the THC molecule to find a new position in the pore volume that is not overlapping with the framework.

Nonetheless, we determined that this move is reasonably explored in our 2 · 106 steps of simulation. The average adsorption energy of THC in Mg-MOF-74 from the NVT simulation is kJ mol−1 , where the contribution from the Coulombic interaction is less than 0.5%, while most of the adsorption energy comes from dispersion interactions. Indeed, a new calculation with the charges turned off resulted in an adsorption energy of kJ mol−1 , and very similar acceptance ratios for the MC moves. It was therefore reasonable to neglect in the protocol Coulombic interactions even when strongly charged open metals site are present, as in the test case. This assumption has the twofold benefit of speeding up the MC simulations and avoiding the need to compute partial charges for the frameworks. We next compared the rigid THC-head rigid model with the flexible THC-full model that includes four coarse-grained sites to represent the alkyl tail. For this models we added the “reinsertion in place” step, where the algorithm attempts to regrow the alkyl tail from while keeping the aromatic head of the THC molecule fixed,vertical greenhouse growing occurring with the same probability as the other MC steps. The NVT calculation, with Coulomb interactions turned off, gave a resulting adsorption energy of kJ mol−1 , i.e., ca. 26 kJ mol−1 more favourable than using the THC-head model. This difference is due to the additional dispersion interactions of the four beads of the tail with the framework. However, we can not assume a priori that the same difference would be found for all the frameworks. Indeed, even in MOFs with similar chemistries, where we might assume that the dispersion interactions are similar, there is the possibility that in some frameworks, the THC-head model is confined in a small pore in such a way that there would be no room to grow the tail. The advantage, however, of using the rigid THC-head particle is a speedup of ca. 2X times for the non-charged model. Moreover, one has to consider that the reinsertion moves are accepted more rarely using the full model: the acceptance ratios lower to 1.8% for reinsertion and 2.2% for reinsertion in place. Finally, we compared the results from NVT simulations with Widom insertions: both methods are supposed to converge to the same adsorption energy, albeit faster in the first case, but the Widom insertion allows us to compute the Henry coefficient as well. This value quantifies the adsorption free energy at infinite dilution, including the entropy of adsorption which is expected to be largely influenced by the topology of the framework. As before, we tested the THC-head and THC-full particles in the charged MOF-74, for 2 and 20 million Widom insertions. Results are summarized in Table B.1. The electrode charging exhibits multiple timescales which are not captured by the single exponential charging of an ideal RC circuit. Modeling the system with additional RC elements, as in a transmission line model, would better capture charging dynamics, especially since we observe that the electrodes charge progressively, starting from the electrode-bulk interface and moving inward . This spatially progressive charging is a key characteristic of the transmission line model, and is more marked in the materials with smaller pores since slower ion diffusion creates a bigger difference between charging times for the outer and inner regions of the electrode. We observe that in many of the structures, particularly in the outer slice, the total ion occupancy exhibits a maximum value during charging which is higher than the equilibrated value, suggesting that the electrolyte molecules may encounter kinetic trapping as counter-ions enter the pores .

The increase of counter-ions in the pores allows for faster-than exponential charging upon initial application of a potential difference, but then the local density increase makes it more difficult for co-ions to diffuse out of the electrode, slowing further charging. This phenomenon is similar to the “overfilling” observed by Kondrat et al., in which the total number of ions inside the pore during the course of charging reaches values higher than the steady-state value.If the initial charging period after the constant potential is characterized by kinetic trapping, then we should see that the charging profile in this initial period differs between independent charging cycles of the same EDLC. When fit to an exponential, independent runs may have different τ as this is determined by dynamic processes during charging, but they should have similar Qinf . In order to test this we generated independent configurations of the 19 ZTCs from zero-charge runs, and repeated constant-potential simulations to compare the charging curves of the independent runs. These results, shown in Figure C.10, demonstrate that there is indeed more reproducibility in the maximum charge than in the charging rate between independent runs. While all but four of the maximum charges are within 10% of each other in independent runs, two-thirds of the materials have time constants that are more than 10% different from each other. Cancer is the leading cause of overall dog deaths with up to 27% of dog deaths attributed to this disease.This risk is highest for large breed dogs and those over 10 years of age.Cancer and its treatments cause disruptions in nutritional status, such as loss of appetite and cachexia in many species.In humans undergoing or surviving beyond treatment, evidence for the effectiveness of dietary strategies is inconsistent, which might reflect the complexity of the relationships among various nutritional factors, cancer biology, and both general and cancer-specific outcomes.

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Homegrown Bliss: Mastering the Art of Cannabis Cultivation

Posted on December 4, 2023 by hemp2022

With cigarette users as the referent category, the analysis suggests that exclusive e-cigarette users are less likely to have their respiratory symptoms worsen, along with consistent findings , than they are more likely to have their symptoms improve. In sum, with respect to short-term changes in functionally-important respiratory symptoms, the results suggest risk for exclusive e-cigarette users are intermediate–increased harm compared to never tobacco users, but reduced harm compared to cigarette users. Cigar smokers had consistently lower risk for functionally-important respiratory symptoms compared to exclusive cigarette smokers, as was previously reported for some of the single respiratory symptom items in another PATH Study report.Cigar smoking has been associated with higher mortality from respiratory disease and lung cancer,increased risk for diagnosis of lung cancer and COPD,decreased lung function and airflow obstruction,and respiratory symptoms. In all studies including cigarette smokers, risks associated with cigars were lower than for cigarettes; former cigarette smokers switching to cigars had higher risk vs. those who had smoked only cigars.Respiratory symptom risk among hookah smokers has not been studied extensively but was intermediate between never smokers and cigarette smokers in one study.Lower symptom risk with exclusive cigar use may be explained by reduced smoke inhalation.In contrast to cigarettes, cigar tobacco is fermented, and many cigars are smoked with lower frequency. Cigar smokers also tend to inhale less deeply because of smoke alkalinity which also enhances oral nicotine absorption. Only 15% of exclusive cigar smokers report actively inhaling the smoke, compared to two-thirds for users of both cigars and cigarettes .Marijuana was associated with functionally-important respiratory symptoms, consistent with 8 of 10 previous studies.The findings are backed by research involving dual users of marijuana and cigarettes showing higher puff volumes, deeper inhalation,movable vertical grow rack system and greater tar retention from marijuana vs. cigarettes,animal research documenting pulmonary cell changes with chronic marijuana smoking, and prospective research showing changes in lung function among marijuana smokers.

Marijuana use was also a confounder of the e-cigarette—respiratory symptoms association. One study showing an association between e-cigarette use and cough among young never cigarette smokers, failed to adjust for marijuana use in the multi-variable model . Another study of adult PATH Study W4 data found vaping with marijuana to be associated with wheezing , consistent with our findings.Two other studies of youth, one using PATH Study data, have shown that the e-cigarette—respiratory outcome is confounded by marijuana use and marijuana vaping.Clinicians need to be aware of the association between marijuana use and respiratory symptoms as use increases.The study strengths include a nationally representative sample, a validated respiratory outcome related to functional impairment, and adjustment for multiple confounding influences. Limitations include small numbers in some product groups, increasing the probability of a chance finding. Because switching from cigarette smoking to exclusive e-cigarette use is an uncommon event, randomized e-cigarette switching trials may be required to better assess how e-cigarette substitution affects wheezing symptoms among adult cigarette smokers. Risk of marijuana smoking on respiratory symptoms may be underestimated because marijuana use may have included non-combustible products. Relying on self-report of COPD may have resulted in some who were unaware of their diagnosis being retained in the study. The findings relate only to short-term changes in wheezing and nighttime cough, not other bothersome symptoms , longer-term symptom effects, relation to respiratory disease onset, or vaping-related acute lung injury—medical issues that underline concern about any inhaled product use. The analysis included many comparisons and nevertheless employed a p-value of 0.05; the associations reported should be confirmed in other samples. Finally, future analyses with the latest available data from the PATH Study may provide a more refined look at the questions addressed in the present study. In summary, this study of a nationally representative sample of US adults without severe respiratory disease found an association between cigarette smoking and functionally-important respiratory symptoms – and substantially less evidence of associations between respiratory symptoms and exclusive non-cigarette tobacco product use. Microporous materials, which are defined by a pore size of less than 2 nm, are used in both research and industrial applications in chemical separations, catalysis, and energy storage.

They comprise a diverse group of materials, including zeolites, metal-organic frameworks, covalent organic frameworks, and porous carbons. These classes of materials are distinct in their synthesis methods and compositions, but are united by their small pore sizes, which are on the scale of many chemically and industrially important molecules, as well as their potential for large accessible surface areas. Zeolites are naturally occuring aluminosilicate materials that were discovered in 1756.Today, they are produced on an industrial scale, and are ubiquitous in catalysis and other industrial applications due to their chemical and thermal stability.234 distinct zeolite framework types have been classified as of 2019,and the potential for chemical modifications such as ion exchange further increases the design space of such materials. Metal-organic frameworks are a newer class of materials, first synthesized a few decades ago, and comprise a three-dimensional network of metal centers connected to organic linkers by coordination bonds. They are synthesized using reticular chemistry, in which molecular building blocks are assembled to form extended crystalline structures. Like other microporous materials, MOFs also have very high surface areas, with record Brunauer-Emmett-Teller surface areas of about 7000 m g−2 reported to date and hypothetical maximum surface areas predicted to be up to two times larger.The design and synthesis of new MOFs has been a flourishing research area in the past few decades, and the development of more chemically stable MOFs has led to their increasingly widespread use in organic catalysis, gas separations, imaging, sensing, and proton, electron, and ion conduction.Zeolites and MOFs are both crystalline materials, which is a desirable characteristic as it means that composition and pore geometry are well-defined on a large scale. Other microporous materials which have short-range order but can be disordered on longer scales include covalent organic frameworks ,which are also synthesized using reticular chemistry but are composed of organic nodes and linkers and are therefore fully covalently bonded, as well as zeolite-templated carbons .

Reticular synthesis is modular in nature, yielding a virtually limitless design space for MOFs as different combinations of nodes and linkers can be used, which assemble in different topological nets. Ca. 70 000 MOFs have been synthesized to date, as reported on the Cambridge Crystallographic Structure Database ,and thousands of new structures are reported each year. To add to this abundance of experimental structures, there exist libraries of hypothetical MOFs which bring the total number of experimentally synthesized and hypothetical structures into the hundreds of thousands. In order to make this design space tractable, computational chemistry, and in particular molecular simulations, can be used to predict the properties of structures even before synthesis and identify promising structures for a particular application.In this way, computation and experiment can work in tandem, with simulations “discovering” hypothetical materials in silico to inform and inspire experimental synthesis, and experimental results demonstrating new structures and unexpected properties to direct computational study. Achieving correspondence between experimental and theoretical results is not always straightforward, but has led to breakthroughs in material design and elucidation of mechanisms toward better understanding of material properties. Microporous materials have great potential in technologies to decrease the energy needed for existing industrial processes, to mitigate the effects of increased anthropogenic emissions to the atmosphere through carbon capture and sequestration , and to provide more sustainable energy storage solutions. For example, the amine-appended MOF N,N’-dimethylethylenediamine-Mg2 , was shown to exhibit a step-shaped CO2 adsorption isotherm, which indicates potential for high deliverable capacity in a temperature- or pressure-swing adsorption process,movable vertical growing solutions with lower energy requirements than the currently used amine scrubbing technologies for CCS.This step-shaped adsorption isotherm was shown to be due to a phase-change adsorption mechanism involving the amine functional groups.Another study synthesized a library of COFs in silico and screened them for methane storage applications, finding that one of the materials had better predicted methane deliverable capacity than any other reported structures.Similarly, a screening study of the materials in the Nanoporous Materials Genome identified promising materials for hydrogen storage.Microporous materials are also used extensively in electrochemical energy storage applications as the electrode material for batteries and super capacitors.The field is dominated by carbon-based materials due to their affordability and conductivity,though recently asuper capacitor with electrodes made from a neat MOF was demonstrated.Though the equations that describe force fields are simple, when combined they represent a powerful tool that allows for simulation of large systems with relatively high accuracy. Several features of force fields lend themselves to computational efficiency: the first is that non-bonded interactions are pairwise, meaning that the non-bonded potential of a configuration of atoms can be computed by summing interactions between pairs of atoms. In addition, while the electronic density of atoms is spread over a nonzero volume, in classical force fields the electron density is usually treated as a point charge. These features lead to several computational algorithms that allow for short range cutoffs coupled with long-range corrections . As mentioned throughout this overview of force fields, there are myriad ways to increase the complexity of classical force fields, for example by describing bonding implicitly using “reactive” force field methods that calculate bond order on the fly, or by using functional forms that involve more parameters to fit to a class of systems. With the increase of computational power in the last few decades, it is also possible to compute the potential energy of increasingly large configurations of atoms using electronic structure methods. However, due to the computational efficiency of classical simulations, it is likely that they will always enable simulations of larger and more complex systems compared to quantum mechanical methods, and thus classical force fields will remain relevant for a long time.

The 10.0% enhancement in linear conversion of Ni-MOF-74 relative to FAU is in good agreement with the 11.1% enhancement observed experimentally by Mlinar et al., suggesting that our model and theoretical framework capture quantitatively the influence of the adsorbent material on product distribution. Interestingly, the absolute predicted linear conversions are 13.0% lower than their respective experimental values. This means the experimental materials are consistently more selective towards linear isomers than their simulated counterparts. This could be due to diffusive barriers not accounted for by our simulations, which would favor the less-bulky linear isomers. We also want to emphasize that these calculations rely on equilibrium thermodynamics, and thus presume that Brønsted-Evans-Polanyi conditions are met. From this comparison with the experimental results of Mlinar et al., we can conclude that the contribution of the pores to the free energy of formation is indeed a useful indicator of how the product distribution varies with the catalyst material. It is therefore interesting to explore how this distribution can be further changed by using a different zeolite MOF structure. Expanding the database of structures allows us to better understand how molecular descriptors correlate with product distribution, and further elucidate design principles of materials for propene dimerization.Cannabis has in recent years seen increasing decriminalization for both recreational and medical use under some local and state jurisdictions. Since 2012, 10 U.S. states have legalized recreational use of cannabis and 33 states medical use of the drug, coinciding with a shift in societal attitudes regarding cannabis use.Immoderate cannabis use has been shown to have public health and safety implications, for example a moderate increase in risk of injury or fatality while driving under intoxication.As a result, increasing use of cannabis requires improved methods, similar to alcohol, for portable detection of cannabis intoxication in order to promote more consistent cannabis regulation and safer cannabis use. The pharmacological effects of cannabis result from a variety of chemical compounds, including several hundred types of cannabinoid which can be found in the plant. The principal psychoactive component of cannabis is ∆9 -tetrahydrocannabinol , which affects motor and cognitive function and has been linked to increased risk of motor vehicle crashes.For roadside testing applications, breath-based testing of THC has the greatest potential as it is less invasive than testing of urine or blood. Breath detection has other advantages as well. The window of detection of THC in breath coincides with the period of peak impairment.THC and its metabolites can also be detected in blood and urine, but as cannabinoid compounds persist for several times longer in these bodily fluids they are not a reliable indicator of intoxication.Though the full window of driving impairment may extend longer than 2 h, the short detection window in breath may be able to be extended using methods that have increased sensitivity.

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The second research question involved longitudinal analyses of youth tobacco use initiation

Posted on December 1, 2023 by hemp2022

The wave 2 questionnaire introduced the term “electronic nicotine products,” of which “ecigarettes ” was a subset. In this analysis, we considered the most inclusive electronic nicotine product wording at each wave as e-cigarette use. The first research question was used to assess parent or guardian knowledge or suspicion of their child’s tobacco use. Each wave, parents or guardians were asked, “Asfar as you know, has [child’s first name] ever smoked a cigarette or used other tobacco products, such as e-cigarettes, cigars, a pipe, a hookah, smokeless tobacco, dissolvable tobacco, bidis, or kreteks?” Parents were categorized as knowing or suspecting tobacco use if endorsing “you know that she/he has” or “you strongly suspect she/he has.” The responses “you don’t think she/he has” and “you are confident that she/ he has not” were categorized as not aware or suspicious. “Don’t know” responses were uncommon and were coded as not aware or suspicious. Parents or guardians and youth were independently asked to consider “rules about using tobacco inside your home” as applied to “everyone who might be in your home, including children, adults, visitors, guests, or workers.” Separate items referred to “tobacco products that are burned, such as cigarettes, cigars, pipes, or hookah” and “tobacco products that are not burned, like smokeless tobacco, dissolvable tobacco, and e-cigarettes.” Endorsing that product use “is not allowed anywhere or at any time inside my home” was classified as strict household rules, whereas endorsing “in some places or at some times,” “anywhere and at any time,” or “don’t know” was considered more permissive. Additionally, youth were asked, “In the past 12 months, have your parents or guardians talked with you, even once,vertical grow racking system about not using any type of tobacco product?” which we categorized as “yes” versus “no” or “don’t know.” For both research questions, covariables included in multivariable models were parent or guardian educational attainment ; the child’s age , sex, and race and/or ethnicity; whether anyone who now lives with the child uses tobacco ; and whether the child lives somewhere else with another parent .

Models of parental knowledge or suspicion additionally included whether the parent or guardian was the child’s biological mother. Models of tobacco initiation additionally included child ever use of alcohol and cannabis, whether the child has a curfew , and the sensation seeking score.For the pseudo time-series analysis, parental knowledge or suspicion of their child’s tobacco use was modeled as the dependent variable by using logistic regression with wave-specific, cross-sectional, balanced repeated replicate weights, allowing each wave to be nationally representative despite participant overlap. Youth tobacco use category was the main predictor variable, with tobacco use 3 survey wave interaction terms added to assess wave-specific differences in parental knowledge or suspicion according to youth tobacco use status. For longitudinal analyses, youth tobacco initiation at waves 2, 3, and 4 were the dependent variables in separate logistic regression models with longitudinal weights. Wave 1 household tobacco rules and talking about not using tobacco were the main predictor variables. Household rules was specified as a 5-level categorical variable: both parent or guardian and child endorse more permissive rules on both product types, both endorse strict rules on burned tobacco , both endorse strict rules on not burned tobacco , parent and youth discordant on both product types, and both endorse strict rules on both products types. As exploratory analyses, we examined several alternative model specifications. We hypothesized that changes in social environments as youth age could reduce any impact of household rules on tobacco initiation over time. Therefore, we explored interactions of household rules with baseline age. Additionally, we explored whether household rules may differentially impact initiation of different types of tobacco by specifying multinomial logistic regression models for a 4-level dependent variable: no initiation, initiation of combustible tobacco only, initiation of noncombustible tobacco only, initiation of both product types. Finally, given that exposures and covariables are potentially time varying, we specified a repeated measures model using generalized estimating equations for 1-year initiation outcomes, taking any observation of a youth tobacco never user in waves 1, 2, and 3. For all models, missing covariable values were multiply imputed .

Although missingness was uncommon for any one tobacco use variable , missing tobacco responses were also imputed when examining parental knowledge or suspicion because missingness compounded when deriving categories: 7.7% of participant observations were missing $1 tobacco variable. Analyses were conducted by using Stata 16.0 . Results were considered statistically significant at P , .05.Tobacco poly use was the most common behavior among current youth tobacco users in waves 1 to 3; in wave 4, e-cigarette only use was most common . Among poly tobacco users, 77% to 80% reported smoking cigarettes, depending on the survey wave. Social and demographic variables were similar in distribution over time . In all waves, parents or guardians were substantially less likely to report knowledge or suspicion that their children had used tobacco if their children reported use of only e-cigarettes, non-cigarette combustible products, or smokeless tobacco compared with use of cigarettes or multiple tobacco products . In covariable adjusted models, other factors associated with greater parent knowledge or suspicion included lower parent educational attainment; the child being older, being male, identifying as non-Hispanic white, living with a tobacco user, or residing in another home; and the parent respondent being the child’s mother .Among wave 1 youth who reported never using tobacco, most parent child pairs mutually endorsed having strict household rules that prohibited use of any burned tobacco and not-burned tobacco . Half of youth reported that a parent or guardian had talked with them about not using tobacco within the past 12 months. There was high percentage agreement between parent and youth responses regarding household rules , although inter rater reliability was constrained under a high marginal prevalence of strict rules . Household rules and talking about tobacco were uncorrelated . Strict household tobacco rules were associated with less tobacco initiation . Among wave 1 tobacco never users, 15% initiated use of $1 tobacco product by wave 2, 24% by wave 3, and 33% by wave 4. At all time points, children in households with the strictest rules prohibiting tobacco use had 20% to 26% lower odds of tobacco initiation compared with children in the most permissive households .

Households with strict rules only for burned or not burned tobacco were also numerically associated with less initiation compared with the most permissive households, albeit not statistically significantly in these groups of smaller sample size. In contrast, youth who reported that their parent or guardian had talked with them about not using tobacco did not demonstrate lower odds of tobacco initiation; in fact, tobacco initiation was higher at waves 3 and 4 . Other factors positively associated with tobacco initiation in all waves were the child being older, the child living with another tobacco user, the child residing at least part-time in another home, the child having used alcohol or cannabis, and greater sensation seeking . In exploratory analyses, although interaction by child age was not statistically significant overall, numerically, strict household rules were associated with lower odds of tobacco initiation among children who were younger at wave 1 . In multinomial models, strict household rules were associated with lower odds of noncombustible tobacco initiation at all 3 time points but not necessarily with lower odds of combustible tobacco initiation . However, initiation of only combustible tobacco was uncommon , which yielded imprecise estimates. In the repeated measures analysis, strict household rules remained associated with lower odds of tobacco initiation within a year .In this assessment,vertical growing cannabis we identified substantial lapses in parents’ awareness of their children’s tobacco use. Most parents or guardians registered suspicion when their children smoked cigarettes or reported poly tobacco use . Only approximately half as many knew or suspected when their children used only e-cigarettes or non-cigarette combustible products. Of parental strategies to prevent future tobacco use by their children, setting strict household rules that prohibit all forms of tobacco use by anyone within the home was associated with less youth tobacco initiation, whereas talking with children about tobacco was not. The percentage of parents aware or suspecting their children’s cigarette smoking was higher than in previous findings suggesting poor parental awareness of youth smoking. Greater awareness may be due to increasing social concern around youth smoking or survey measurement differences. However, low parental awareness of e-cigarette use belies rising public and media attention surrounding youth vaping.

Constantly changing e-cigarette device designs and terminology pose an increasing challenge for parents to recognize, whereas lack of smoke and odor enhance concealability.Notably, PATH Study data were collected before a 2019 outbreak of vaping-associated lung injury,which could heighten parental awareness going forward. Cigarette smoking youth smoke more frequently than e-cigarette users use e-cigarettes, potentially increasing parental awareness opportunities. Lower awareness for cigars and hookah, which do produce smoke and odors, suggests a wider need for parents to monitor for all tobacco products, including those they may perceive as less common or concerning. Findings related to tobacco-free households align with previous research revealing that home anti-smoking attitudes and rules contribute significantly to youth smoking prevention.The present work suggests that this benefit extends beyond cigarettes to include initiation of any tobacco product use. Creating home tobacco-free environments offers the additional advantage of protecting children from harmful secondhand smoke exposure and may also benefit household adults by aiding smoking cessation.Our results align with longitudinal findings revealing a benefit of household smoking bans, whether or not youth lived with smokers.Our finding that the benefits of strict household rules appear greatest at younger ages suggests a need for additional focused prevention when adolescents transition to young adulthood and potentially enter new social environments. Unexpectedly, strict household tobacco rules were more strongly associated with prevention of noncombustible tobacco use than combustible tobacco use. This result must be interpreted cautiously because many youth initiate use of both product types, and strong concordance between burned and not-burned household tobacco rules makes it difficult to isolate independent effects. Nonetheless, setting household tobacco use rules may be a promising tool against the rise in youth e-cigarette use. Contrary to rules governing tobacco use in the home, youth who reported that that their parent or guardian had talked with them about not using tobacco were at higher odds of initiating tobacco use after 2 or 3 years. An implication of this result is that telling children not to use tobacco does not benefit youth compared with setting norms and examples via tobacco-free rules that apply to everyone. Alternatively, it is possible that parents were more inclined to talk about tobacco with youth already at elevated risk of tobacco use on the basis of personality aspects not captured by study variables.In the current study, we did not measure the quality or frequency of parents’ anti-tobacco communication: likely key elements of effectiveness.Therefore, although strong household rules appears to be a much more promising approach, it should not necessarily be concluded that all parental communication is unhelpful in youth tobacco use prevention. Advantageously, the current study features a large, prospective, nationally representative sample. To our knowledge, this analysis is the first to assess prospective outcomes of home tobacco use policies on youth initiation of cigarette and noncigarette tobacco use and the first national study to assess parental awareness of their children’s use of multiple noncigarette tobacco products. Numeric findings were robust to the length of follow-up and adjusted for an extensive suite of established youth tobacco use risk factors. Among methodologic considerations and limitations, the main outcome measure in this study, initiation of any tobacco use, is a critical milestone, particularly among youth for whom daily smoking may develop over several years.However, long-term established tobacco use deserves attention in future research. Speculatively, youth might report tobacco use differently with in-home questionnaire administration versus in-school questionnaire administration, with unclear impact on the present results. In our 2- and 3-year models, we did not account for the timing of tobacco initiation or time-varying exposures or covariables. However, in an 11-year longitudinal study in Italy, the authors reported that living with smoking family members in adolescence and absence of a household smoking ban in young adulthood were both associated with established smoking among young adults.

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D9 -THC is the only natural cannabinoid presently used in the clinic

Posted on November 30, 2023 by hemp2022

In the age ranges and samples in which we found that ERO was significant for the onset of alcohol use or alcohol dependence, it was the lower values which characterize the risk factor, which is consistent with the results in adolescents and young adults in the studies by Rangaswamy et al. , Kamarajan et al. , and Gilmore et al. . In those investigations high risk groups had lower ERO values than the low risk groups. That no effects of regular alcohol use on ERO values were found is consistent with similar results obtained by Perlman et al. .It is important to note that the objectives of the twin studies considered here and of this study are quite different. The twin studies investigate the presence of a ‘‘disease’’ condition, although exactly which condition varies considerably among studies. The objective of this study, as a survival analysis, is to analyze the factors contributing to an event, the onset of a condition. Once the condition has come to pass, it is not of further interest in survival analysis. The genetic effects which produce the condition are only significant at the onset of the condition, and their effects persist only if the subsequent onset of the condition in other subjects is attributable to them. In the twin studies post-onset presence of the condition is part of the outcome analyzed. That is, in the longitudinal studies using multistage models, the affected subjects are retained throughout the study subsequent to their becoming affected, while in the survival analysis method used in this study, the affected subjects are removed from consideration in the study once they have become affected, and no longer influence the results. Therefore, although the use of a longitudinal multi-stage model in van Beek et al. and Baker et al. enables genetic influences to have age-specific characteristics,vertical growing garden these effects are modeled as persisting through time as a result of an effect at a single age range. If early onset alcohol use is associated with the more genetically determined form of alcoholism then it would be expected that genetic factors leading to early drinking and dependence would be manifest. Our results are consistent with this hypothesis.

The pattern of genetic results obtained here, albeit from a single gene, is weighted towards the strongest effects manifesting themselves in the youngest age range. However, most twin studies find low genetic influences at younger ages and increases in genetic influences with age , although not all twin studies have this conclusion . These results can be understood after examination of the populations from which the twin samples are drawn and the outcomes which are modeled. The samples in the twin studies are drawn from the general population, not from the densely affected families which form the bulk of the sample used here. Thus genetic effects will be more difficult to find in the twin studies, particularly for the rarer, more genetically affected conditions. In a number of studies outcome definitions are broad, and are not subject to as strong genetic effect as more restricted outcomes such as alcohol dependence or externalizing disorders.The discovery of the cannabinoid receptors and endocannabinoid ligands has generated a great deal of interest in identifying opportunities for the development of novel cannabinergic therapeutic drugs. Such an effort was first undertaken three decades ago by a number of pharmaceutical industries, but was rewarded with only modest success. However, the newly acquired knowledge on the physiological roles of the endocannabinoid system has significantly enhanced these prospects. At the June 27, 2004 workshop ‘‘Future Directions in Cannabinoid Therapeutics II: From the Bench to the Clinic’’, sponsored by the University of California Center for Medicinal Cannabis Research, we on the Scientific Planning Committee were asked to identify the areas of research with the most immediate promise for the development of novel therapeutic agents.

The Committee identified four broad areas involving modulation of the endocannabinoid system as particularly promising in this regard: agonists for central CB1 cannabinoid receptors and peripheral CB2 receptors, antagonists of CB1 receptors, inhibitors of endocannabinoid deactivation, and endocannabinoid-like compounds that act through mechanisms distinct from CB1 and CB2 receptors activation. Below, we summarize the data presented at the Workshop and the consensus of its participants on the most exciting opportunities for drug discovery.Two endogenous agonists of cannabinoid receptors have been well characterized and are now widely used in research: anandamide , and 2-arachidonoylglycerol . Both molecules derive chemically from the polyunsaturated fatty acid, arachidonic acid, which is used in nature as the starting material for other important signaling compounds, such as the eicosanoids. Additional endocannabinoid-related compounds present in the body include virodhamine, which may act as an endogenous antagonist of CB1 receptors, and arachidonoylserine, which may engage an as-yet-uncharacterized cannabinoid-like receptor expressed in the vasculature. As is well-known, the Cannabis plant contains more than 60 cannabinoids, which include -D9 -tetrahydrocannabinol , cannabigerol, cannabidiol, cannabinol, cannabichromene and cannabicyclol. Attention has been mostly focused on D9 -THC, because of its multiple biological properties. Nevertheless, less studied compounds such as cannabidiol may also be important, although we do not yet know at which receptors they may act to achieve their effects. In addition to these plant-derived cannabinoids, an extensive set of synthetic cannabinergic agonists has been developed over the last 30 years. Products of these efforts include CP-55940 , created by opening one of the rings of the tricyclic D9 -THC structure and introducing other small changes in its structure; HU-210 , a very potent cannabinoid agonist resembling some D9 -THC metabolites; and WIN55212-2 , which belongs to an altogether different class of chemicals, the aminoalkylindoles.

Additionally, the metabolically stable synthetic analog of anandamideR-methanandamide is routinely used as a pharmacological probe to circumvent the short half life of the natural substance. Two important new additions to this armamentarium under discussion at the workshop include a peripherally acting cannabinoid agonist in preclinical development by Novartis for the treatment of neuropathic and inflammatory pain , andBAY-387271 , a centrally acting cannabinoid agonist in Phase II clinical studies for the treatment of stroke. The interest of the pharmaceutical industry in the application of cannabinoid agonists to the treatment of pain conditions is not recent. Indeed, most of the compounds now in experimental use derive from such an interest. Historically however cannabinoid agonist development has not proved clinically fruitful, largely because of the profound psychotropic side effects of centrally active cannabinoid agonists, hence the attention given to peripherally acting cannabinoids, which exhibit significant analgesic efficacy and low central activity in animal models. Neuroprotection is a relatively new area for cannabinoid agonists, but one that appears to be already well advanced. Preclinical studies have made a convincing case for the efficacy of cannabinoid agents not only in experimental brain ischemia, but also in models of Parkinson’s disease and other forms of degenerative brain disorders. The results of a Phase II clinical trial with BAY-387271 are awaited with great excitement. Also highlighted during the conference were various derivatives of cannabidiol. Particularly interesting in this regard was the compound -7-hydroxy-4#- dimethylheptyl-cannabidiol a hydroxylated, dimethylheptylated cannabidiol,vertical growing greenhouse structurally related to HU-210. Like D9 -THC, 7-OH-DMH-CBD is a potent inhibitor of electrically evoked contractions in the mouse vas deferens. However, 7-OH-DMH-CBD does not significantly bind to either CB1 or CB2 receptors and its inhibitory effects on muscle contractility are not blocked by CB1 or CB2 receptor antagonists, suggesting that the compound may target an as-yet-uncharacterized cannabinoid-like receptor. This hypothesis is reinforced by pharmacological experiments, which suggest that 7-OH-DMH-CBD displays anti-inflammatory and intestinal-relaxing properties, but does not exert overt psychoactive effects in mice. However, the nature of this hypothetical receptor and its relationship to other cannabinoid-like sites in the vasculature and in the brain hippocampus remains to be determined.Another way to reduce central side effects is to target peripheral CB2 receptors, which are expressed in the brain only during inflammatory states and even then are limited to microglia. Selective CB2 receptor agonists include the compounds AM1241 and HU-308 . Compounds of this type offer a great deal of promise in the treatment of pain and inflammation. Studies conducted on multiple animal models of pain have shown that the CB2-selective agonist AM1241 has robust analgesic effects and is very potent in neuropathic pain models.

These effects are maintained in CB1-deficient, but not in CB2-deficient mice.Cannabinoid analogs are currently in development or being tested by Astra, Bayer, Endo, GSK, GW Pharmaceuticals, Indevus, Kadmus Pharmaceuticals, MAK Scientific, and Pharmos. Some of the obvious issues in drug development are efficacy, side effects, and regulatory scheduling. With regard to efficacy, the primary clinical targets are pain, stroke, nausea, appetite, and cough. Potential side effects in addition to the well-known central psychotropic actions include cardiovascular and immune perturbations, as well as fertility problems. Finally, a major question from the perspective of drug industry is one of regulatory scheduling: that is, whether any drug acting either directly or indirectly through the endocannabinoid system will be subject to the restrictive scheduling of D9 -THC, or whether scheduling will be determined by side effects, as is the case with most drugs. A large number of pharmaceutical companies have started active CB1 antagonist programs, mostly as a result of the clinical success of SR141716A , the first CB1 antagonist to be developed. This molecule has successfully completed Phase III studies and is anticipated to become available within a year for the treatment of obesity and tobacco addiction. Rimonabant is an inverse CB1 agonist with a Ki of 11 nM at the CB1 receptors and 1640 nM at CB2. Additional agents currently in development include SLV-326 and LY320135 . However, all of these compounds are inverse agonists. A series of neutral antagonists has been generated, but remains not as well characterized in the literature. Examples of this class are the compounds O-2654 and AM5171 . As noted above, therapeutic areas for cannabinoid antagonists include obesity, drug addiction and perhaps CNS disorders.The mechanism by which cannabinoid antagonists exert their anti-obesity effects is still not fully understood. Data on rimonabant presented at the workshop identified two possibilities. First, there is a loss of appetite. Mutant mice that are deficient in CB1 receptors eat less than wild-type controls. Second, there is an increase in metabolic rate and a loss of fat mass. These effects may be linked, on the one hand, to the ability of rimonabant to affect corticotropin-releasing hormone , as suggested by the fact that CB1 receptors colocalize with CRH receptors in the hypothalamus. This may be significant for explaining the drug’s effects on appetite drive, as it is known that CRH is anorexigenic. On the other hand, mice that lack CB1 receptors display a hyperactivity of the hypothalamicpituitary-adrenal axis, with increases in both ACTH and corticosterone. This phenotype may be important in regard to overall metabolic rate. Another possible mediator of the long-lasting effect on body weight reduction unrelated to altered food intake is the adipocyte, because CB1 receptor activation causes lipogenesis, which is blocked by rimonabant.CB1 cannabinoid receptors are present on the cell surface of neurons within the brain reward circuitry. Furthermore, endocannabinoids may be released from dopamine neurons in the ventral tegmental area , and from medium spiny neurons in the nucleus accumbens of the brain reward circuit. Additionally, endocannabinoids and D9 -THC activate CB1 receptors and by doing so regulate reward strength and drug craving. Though we do not know how this occurs, it is likely that these mechanisms extend to all drugs of abuse, because collectively these drugs show the propensity to increase VTA dopamine neuron activity, which might be coupled to augmented endocannabinoid production from the dopamine neurons themselves. Finally, cannabinoid receptor antagonists block the effects of endocannabinoids in these reward circuits. Preclinical work shows that priming injections of cannabinoid agonists reinstate heroin-seeking behavior after a prolonged period of abstinence in rats trained to self-administer heroin. The cannabinoid antagonist rimonabant fully prevents heroin-induced reinstatement of heroin-seeking behavior. Additionally, rimonabant significantly attenuates cannabinoid-induced reinstatement of heroinseeking behavior. All these findings clearly support the hypothesis of a functional interaction between opioid and cannabinoid systems in the neurobiological mechanisms of relapse and might suggest a potential clinical use of cannabinoid antagonists for preventing relapse to heroin abuse.

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Random urine electrolytes were obtained after the patient was admitted to the PICU

Posted on November 29, 2023 by hemp2022

The classic triad of findings in rhabdomyolysis is muscle pain, weakness, and dark urine. Patients with rhabdomyolysis usually have some combination of highly elevated creatine kinase, myoglobinuria, hyperkalemia, hyperphosphatemia, acute kidney injury, hypocalcemia, and metabolic acidosis with or without an anion gap.In this patient’s case, there was no clear inciting event, and her symptoms were episodic with spontaneous resolution. Additionally, she did not complain of focal pain or weakness as would be expected in compartment syndrome. Although she did have an elevated creatine kinase, the elevation was not significant and the expected laboratory findings of hyperkalemia and hyperphosphatemia were not present. I felt that compartment syndrome and rhabdomyolysis were unlikely. In this young adult patient with episodic weakness and hypokalemia, hypokalemic periodic paralysis was immediately considered as part of the differential diagnosis. This condition is characterized by attacks of weakness with a normal neurologic exam in between, as seen in this patient. Primary hypokalemic periodic paralysis follows an autosomal dominant inheritance pattern, and notably this patient had no known family history of the same. Bulbar and respiratory functions are preserved and between attacks, patients will also present with normal plasma potassium. Triggers include stress, exercise, and carbohydrates. The condition also presents with arrhythmias.There are, however, other conditions that can cause non-familial hypokalemic paralysis, including RTA.All three sub-types of RTA are characterized by an inability to acidify the urine. As a result of this, RTAs present with an increased urine anion gap, but this information was not provided in the case history. In distal or type 1 RTA,pipp grow racks there is impaired hydrogen ion secretion in the distal tubule of the nephron. In proximal or type 2 RTA, there is impaired bicarbonate reabsorption in the proximal tubule of the nephron. In type 4 RTA, there is decreased aldosterone secretion or aldosterone resistance.

As a result of this, type 4 RTA is associated with serum hyperkalemia while the other two types of RTA result in hypokalemia.8 Due to the serum potassium levels, which were not suggestive of aldosterone resistance, I eliminated type 4 RTA from my list of possibilities. The types of hypokalemic RTAs are differentiated by examining the potential of hydrogen of the patient’s urine. In type 2 RTA, urine pH is initially high, then decreases to < 5.5. The urine pH remains above 5.5 in type 1 RTA.This patient had a urine pH of 7.0, suggesting either a type 1 RTA or an early type 2 RTA. Type 1 RTA can be hereditary or be caused by autoimmune diseases such as Sjögren’s syndrome, or as a complication of chemotherapy or toluene use. The causes of type 2 RTA include genetic abnormalities, Fanconi syndrome, monoclonal gammopathy, and carbonic anhydrase inhibitor use.There was no mention of chemotherapy or carbonic anhydrase inhibitors with the patient’s presentation. The patient had no family history of similar issues, and it would stand to reason that a genetic abnormality would have come to light before age 19 years. As such, I feel type 1 RTA is more likely than type 2 RTA. The Agency for Toxic Substances and Disease Registry notes that toluene is a solvent found in paints, nail polish, paint thinners, and adhesives, among other substances. It can have toxic effects if ingested or inhaled.The findings of acute toluene use include a hypokalemic paralysis and a metabolic acidosis. Patients are also often found to have liver injury and rhabdomyolysis, and may present with altered mentation, renal failure, and acidemia.This patient’s presentation is most consistent with type 1 RTA due to toluene use. She denied any illicit drug use but did admit to a history of alcohol ingestion and marijuana use, raising the question of whether there could be toxic alcohols or other coingestions. Unfortunately, there is no diagnostic test for toluene use. However, proximal and distal RTA can be differentiated by calculating the urinary ammonium ion concentration from the measured urine anion gap and osmolar gap. Therefore, my test of choice would be a urine electrolyte panel to calculate the anion gap and osmolar gap.

Additionally, I would consult nephrology to assist in management of this patient.The patient developed bigeminy while in the ED but remained hemodynamically stable and did not have a change in her mental status. Her electrolytes were replaced with oral and intravenous potassium, with improvement of her arrythmia and symptoms. She declined central line placement for more rapid replacement. The patient was admitted to the pediatric intensive care unit for further management and evaluation. Nephrology was consulted because these results demonstrated an elevated urine anion gap suggestive of RTA. The patient’s symptoms completely resolved once her electrolytes were repleted. She was found to have positive antinuclear and anti–Sjögren’s-syndrome-related antigen A autoantibodies, leading to the diagnosis of Sjögren’s syndrome, despite a lack of phenotypic features. The patient’s urine anion gap was indeterminate for the etiology of her non-anion gap metabolic acidosis; however, her urine osmolar gap of less than 150 milliosmoles per kilogram suggested type 1 or type 4 RTA as the etiology. This coupled with laboratory findings suggestive of autoimmune disease led to the diagnosis of type 1 RTA. Her RTA was treated with potassium supplementation and alkali therapy to achieve a normal serum bicarbonate concentration. Unfortunately, the patient has not been compliant with her home therapy and has required multiple hospitalizations since her original presentation. Her presentation and urine anion gap strongly suggest toluene toxicity, but the patient repeatedly denied insufflating glue and there is no diagnostic test for toluene.Hyperchloremic, hypokalemic metabolic acidosis is a condition all emergency providers should be prepared to diagnose and manage. In this case, the patient presented with a cardiac arrhythmia due to severe hypokalemia. The underlying etiology of the hypokalemia should be sought while simultaneously treating the condition. The initial ED evaluation includes obtaining a basic metabolic panel and a urinalysis. Once it is determined that the patient does not have a serum anion gap, the clinician should consider three broad categories of non-anion gap acidosis and their etiologies: increased acid production; loss of bicarbonate; and decreased renal excretion of acid .

Type 1 or distal RTA is a primary problem of urine acidification due to impaired hydrogen ion secretion in the distal convoluted tubules. The underlying etiology in adults is usually autoimmune diseases such as Sjögren’s syndrome or rheumatoid arthritis.In pediatrics, the cause is usually a hereditary gene mutation for either the basolateral chloridebicarbonate exchanger or the apical hydrogenadenosine triphosphatase gene. Lastly, a distal RTA can be iatrogenic due to ifosfamide, a chemotherapeutic analog of cyclophosphamide.Type 2 or proximal RTA is a primary problem of impaired bicarbonate reabsorption leading to increased bicarbonate loss.In adults, the underlying etiology is most commonly proximal tubular toxicity from increased exertion of monoclonal immunoglobulin light chains as seen in multiple myeloma.Type 2 RTAs are seen in Fanconi syndrome , and in patients prescribed carbonic anhydrase inhibitors .In pediatric patients, type 2 RTAs are usually idiopathic, but they can be due to a complication from chemotherapy, cystinosis , or inherited mutations in the KCNJ15 and SLC4A4 genes.The term “type 3 RTA” is rarely used as it is now considered a combination of types 1 and 2. Type 4 RTA is beyond the scope of this discussion. The test of choice when evaluating for a RTA is urine electrolytes so that the clinician can calculate how much ammonium is being excreted.18 Ammonium excretion will be decreased in a true RTA and normal/increased if the acidosis is due to toluene use or chronic diarrhea. Unfortunately, ammonium excretion is rarely measured directly. Urine ammonium excretion can be estimated by using the urine anion gap or urine osmolar gap.20The misuse of opiates is a serious problem worldwide, is increasing in young adults, and has substantial individual and societal consequences. In 2014 in the United States alone, approximately 1.9 million people had an opiate use disorder, including 586,000 heroin users. Neuroimaging in opiate dependence indicates both altered brain structure, particularly in the anterior cingulate cortex , and brain function involving dorsolateral prefrontal cortex and ACC. Magnetic resonance spectroscopy allows the non-invasive quantitation of brain metabolites that provide information on the neurophysiologic integrity of brain tissue. The few 1H MRS studies in opiate dependence to date revealed lower concentration of N-acetylaspartate , a marker of neuronal integrity, in the medial frontal cortex, including the ACC, as well as lower glutamate , a primary excitatory neurotransmitter,motel grow racks or glutamate+glutamine concentration in some but not all studies. The discrepant MRS findings may relate to differences among study participants regarding the prevalence and severity of comorbid substance use , the type, dose and duration of replacement therapy for heroin users , and/or participant age.

The ACC, DLPFC and orbitofrontal cortex are important components of the brain reward/executive oversight system, a neural network critically involved in the development and maintenance of addictive disorders. Structural brain imaging in opiate dependence revealed generally lower gray matter volume or density in frontal regions, including the DLPFC, with thinner frontal cortices related to longer duration of opiate misuse. Functional MR imaging showed that the DLPFC, OFC and ACC are involved in decision making, and in opiate dependent individuals, lower task-based fMRI activity in the ACC related to compromised behavioural control of cognitive interference. Furthermore, smaller frontal gray matter volume in opiate dependence related to higher impulsivity on the Barratt Impulsivity Scale . Correspondingly, opiate dependence is associated with cognitive deficits, primarily in executive functioning and self-regulation . Thus, the neuroimaging literature in opiate dependence suggests altered frontal brain structure as well as compromised neuronal integrity and glutamatergic metabolism. Few if any studies however investigated their relationships to opioid and other substance use behaviour or cognition. Further research into specific regional brain effects and their potential cognitive and behavioural correlates may inform better targeted treatment of individuals with opioid use disorders. We measured in opiate dependent individuals’ metabolite concentrations from the ACC and previously unexplored DLPFC and OFC and related them to quantitative measures of neurocognition, self-regulation, and substance use. Specifically, we compared opiate dependent individuals on buprenorphine maintenance to controls . We also included another control group, a substance-dependent ‘control’ group of 3 week abstinent alcohol dependent individuals , a commonly investigated treatment-seeking group to differentiate opiate dependence from not only control individuals but also individuals with a substance dependence . Our primary hypotheses were that: OD have lower NAA and Glu concentrations than CON in ACC, DLPFC, and OFC, these frontal cortical NAA and Glu deficits are associated with the level of opiate use and cigarette-smoking severity, the frontal NAA and Glu deficits in OD relate to higher impulsivity, poorer executive function, and lower decision making skills, and OD have more pronounced metabolite concentration deficits than ALC. The results of this study will contribute to a better understanding of the neurobiology and neuropsychology in OD, helping to identify novel targets for the treatment of opiate dependence. All participants provided informed consent according to the Declaration of Helsinki and underwent procedures approved by the University of California, San Francisco and San Francisco VA Medical Center 00000068. Twenty-one chronic cigarette smoking OD, stable on buprenorphine maintenance therapy for at least 3 months, met DSM-IV criteria for dependence on opiates; they were allowed to meet DSMIV criteria for current abuse or dependence on cocaine, amphetamines, and/or cannabis, but dependence on alcohol or benzodiazepines was exclusionary. OD was part of a buprenorphine treatment program focusing on smoking cessation and they were studied before smoking cessation. For group comparisons of metabolite concentrations specifically in the ACC, DLPFC, and POC and when correlated with neuropsychological variables, there were data from thirty-five cigarette smoking ALC recruited from local treatment programs of the VA and Kaiser Permanente and 28 cigarette smoking CON recruited from the community. The ALC group met DSM-IV criteria for alcohol dependence and was abstinent from alcohol for 21 ± 11 days at time of study. For group comparisons of metabolite concentrations in the OFC and when correlated with neuropsychological variables , smokers and non-smokers were included in the ALC and CON groups: 21 ALC and 19 CON due to a lack of sufficient data in smokers. All participants were studied with structural MRI, 1H MRS, and neuropsychological testing, all were fluent in English and they were allowed to smoke ad libitum before assessment and during breaks. Table 1 contains demographics, tobacco and alcohol use variables, mood measures, and laboratory variables for the three groups.

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Life expectancy for persons living with HIV is now similar to the general population

Posted on November 28, 2023 by hemp2022

In contrast, both groups showed comparable performance on a DD task that that involved making choices about hypothetical rewards provided in the more distant future. These findings point to key alterations in how people with schizophrenia value different types of rewards.Due to the advent of anti-retroviral therapy in the mid-1990s, HIV is now considered a chronic medical condition rather than a devastating terminal illness. Currently, over 50% of PWH in the United States are over the age of 50, with aging trends projected to continue . As such, researching aging with HIV is critical to better understand the impact of HIV on the aging process and how it may differ from the general population. Aging with HIV is associated with an increased risk of HIV-associated neurocognitive disorders , the current research term to describe neurocognitive impairments associated with HIV disease, with some evidence of accelerated brain aging . Given the potentially compounding effects of HIV and aging on the brain, the rapidly growing population of aging PWH may be at increased risk for Alzheimer’s disease and its precursor, amnestic mild cognitive impairment . As such, there is an urgent public health need to identify clinical tools to accurately identify older PWH on the AD trajectory and understand biological mechanisms that may put PWH at higher risk of aMCI/AD. To clarify, in the HIV literature, “older” PWH usually refers to PWH aged 50 and over; however, in the aging literature, “older” usually refers to people aged 65 and older, and “middle-age” refers to people aged 45 to 64. To rectify this discrepancy in terminology, the aging literature terminology will be used when discussing both the HIV literature and the aging literature.HAND remains prevalent in the ART era . While the pathogenesis of HAND is not entirely clear, HAND is thought to be the result of the neurotoxic cascade initiated by HIV .

The majority of neurocognitive deficits associated with HAND are in the mild range and do not significantly impact everyday functioning ,cannabis grow system and executive functioning, learning, and memory deficits are most common . Importantly, longitudinal studies have shown that HAND is usually non-progressive . AD is a neurodegenerative disease associated with progressive cognitive and functional impairment . AD is the most common cause of dementia, and it affects 10% of persons without HIV over the age of 65 and 17% between the ages of 75-84 . AD is characterized by the accumulation amyloid plaques and tau tangles in the brain, that start in the medial temporal lobe and result in initial atrophy of the medial temporal lobe and later more widespread atrophy . These brain changes start years to decades before clinical symptoms appear . On neuropsychological testing, AD typically presents initially with impairment in memory, which progresses to global impairment and loss of independent functioning . Mild cognitive impairment is defined as the transitional stage between cognitively normal and major neurocognitive impairment in which persons have observable cognitive deficits but these deficits are not yet significantly impacting everyday functioning. MCI can be further divided into amnestic and non-amnestic MCI sub-types, with aMCI being more associated with AD . While participants are often dichotomized as “MCI” or “cognitively unimpaired,” cognitive decline associated with AD is insidious; therefore, even milder deficits in memory in participants classified as cognitively unimpaired are associated with underlying AD pathology such as amyloid accumulation or medial temporal lobe atrophy . Due to the overlap in cognitive presentation , middle-aged and older PWH are at risk of erroneously being classified as HAND, due to HIV diagnosis, when they may instead be on an AD trajectory. Given that aMCI is associated with progressive cognitive and functional impairment, as opposed to HAND, which is more stable, it is imperative that the etiology of the cognitive impairment is correctly identified .

While there is currently no cure for AD, a misdiagnosis of HAND when a person with HIV has aMCI limits the opportunity for early intervention when interventions may be most beneficial . For example, early identification of AD allows more time for life planning and the acquisition of compensation strategies, which may prolong independent functioning, and, by extension, sustain quality of life . Furthermore, accurate diagnosis is important to allay concerns in PWH without indication of an AD trajectory. It is hypothesized that PWH may be at increased risk of AD due to the compounding effects of HIV and aging on the brain , chronic inflammation despite viral suppression, increased prevalence of vascular and metabolic risk factors , and potentially common pathophysiological pathways . While little work has been done in this space, several recent case reports on AD in PWH have highlighted the risk of delayed diagnosis, detailed complications determining the etiology of cognitive impairment, and underscored the clinical need for tools to differentiate HAND and aMCI . Additionally, there is some evidence from the HIV and aging literature to suggest that memory may be particularly affected in older PWH; however, most of these studies do not consider other etiologies that may be contributing to the observed findings. For example, Goodkin et al. found that there was a greater than expected effect of aging on episodic memory in PWH aged 50 and over, and Seider et al. found that verbal memory declines more rapidly with age in PWH as compared to HIV-negative comparison participants. Moreover,in a recent study using latent class analysis to examine a group of PWH aged 50 and over, we found that three classes emerged: a multi-domain impaired group, a learning and memory impaired group, and a cognitively unimpaired group . Due to the medial temporal lobe involvement in aMCI, the cognitive profile is described as “amnestic”, with encoding, storage, and rapid forgetting deficits observed as poor learning, recall, and recognition on memory tests .

Conversely, HIV particularly impacts fronto-striatal systems , and the frontostriatal involvement associated with HAND accounts for a “sub-cortical” cognitive presentation. Thus, memory deficits in HAND are characterized by relatively normal memory storage and retention but impaired encoding and retrieval resulting in poor learning and delayed recall, but intact recognition . This “subcortical” presentation in HAND has been observed even as PWH age . Therefore, recognition may be more indicative of aMCI than HAND and a useful tool for differential diagnosis . However, because recognition has historically been spared in HAND and only recently have PWH been reaching the ages at which they may develop aMCI/AD, there is little research examining recognition deficits in the context of HIV. Of note, deficits in other domains are unlikely to aid in differential diagnosis without further research. For example, while aMCI is characterized by memory deficits, other deficits, such as executive dysfunction, are also quite common in aMCI and AD . Therefore, the presence of executive functioning deficits, which are common in HAND, could be indicative of HAND, aMCI, or a mixed HAND and aMCI profile. Moreover, biomarkers may aid in differential diagnosis in the future; however, elevated amyloid beta is observed in HIV , so more research is needed in order for biomarkers to be beneficial in differential diagnosis of HAND and aMCI. Our research group at the HIV Neurobehavioral Research Program has begun to examine neuropsychological methods to identify aMCI among PWH using adapted Jak/Bondi MCI criteria. Jak/Bondi MCI criteria is an empirically based MCI criteria that has been shown to have greater associations with AD biomarkers and identify more participants who progress to dementia than traditional MCI diagnostic approaches . Our group utilized the basis of the Jak/Bondi criteria and adapted it to capitalize on the neuropsychological differences between HAND and aMCI . Thus,marijuana grow system aMCI was defined as impairment on at least two memory tests with the adaptation that at least one impaired test be a test of recognition. In a sample of 80 PWH from the National NeuroAIDS Tissue Consortium with neuropathologically characterized Aβ42 and neuropsychological testing within a year of death, 40 participants met the adapted criteria for aMCI. Twenty-nine of the participants with aMCI were also classified with HAND. The aMCI group was 3.5 times more likely to have the presence of Aβ42 plaques. Conversely, when the same sample was split into HAND and no HAND groups, the presence of Aβ42 plaques was not significantly associated with the HAND group. In sum, these findings provide preliminary data to further support that aMCI may go undetected in a large proportion of PWH with HAND, and these PWH may be misclassified or have a mixed HAND and aMCI profile. Secondly, these preliminary analyses also suggest that recognition deficits in older PWH are sensitive to AD pathology .Magnetic resonance imaging has shed light on brain changes associated with aMCI and AD and is increasingly used in clinical assessment of suspected AD . Medial temporal lobe atrophy is a core feature of aMCI/AD and has been shown to correlate with disease progression and predict progression from cognitively normal to aMCI . However, AD is also associated with more widespread cortical and sub-cortical atrophy and white matter abnormalities, particularly as the disease progresses . While neuroimaging has been used extensively to study aging and AD, mostof these neuroimaging studies exclude PWH . Consequently, it is unclear if aging/AD research is generalizable to older PWH. HIV has historically been associated with early changes to fronto-striatal circuits , although recent neuroimaging studies also report cortical atrophy . Similarly, HAND has been associated with fronto-striatal circuits, and, in more recent years, has also been associated with more cortical structures . Neuroimaging studies have examined neuroanatomical correlates of delayed recall as well as the effect of age on the brain within the context of HIV .

Studies comparing PWH with HAND and HIV-negative participants with MCI or AD have shown that hippo campal volumes were able to discern HAND and MCI/AD . Additionally, within the context of HIV, decline in memory has been associated with hippo campal atrophy . However, there are notable limitations to the current literature. For example, most studies have been couched in the context of HAND, are not aimed at examining aMCI within the context of HIV, nor do they consider other etiologies . Additionally, several neuroimaging studies examining the effect of aging in PWH have samples with mean ages in the late 30s or early 40s, which is likely before the initiation of AD pathology . Moreover, memory recognition, which could improve differentiation of HAND and aMCI, was not examined in these studies. Both HIV and aMCI are associated with chronic, low-grade inflammation . As such, inflammation may be one biological mechanism that puts PWH at greater risk of aMCI. Peripheral inflammatory markers can cross the blood-brain barrier, and there is mounting evidence to support the hypothesis that chronic inflammation exacerbates both Ab42 and p-tau pathology and plays a role in the pathogenesis of AD . There is ample evidence linking increased inflammation to brain atrophy, cognition, and cognitive decline in late life , with emerging evidence that this link is present even in midlife . Chronic inflammation is also present in PWH despite viral suppression , and is hypothesized to contribute to and exacerbate HAND . Due to this overlap, inflammation may be one factor that also puts PWH at greater risk of aMCI/AD. While the literature has highlighted the need to investigate this association, little research currently exists . Determining how inflammation impacts brain integrity and cognition in middle-aged PWH could have great implications for our overall understanding of the role of inflammation in AD and for the development of early intervention strategies to lower the risk of AD within PWH. I have begun to examine the relationship between inflammation and change in memory. These preliminary analyses included 57 PWH aged 50 and older with peripheral inflammatory markers and neuropsychological testing at baseline and at 1-year follow-up. Overall, I found that baseline concentrations of inflammatory biomarkers were not associated with baseline memory performance. However, using multi-variable linear regressions, IL-6 and TNF-a were associated with decline in delayed recall, and greater baseline concentrations of CCL2 were associated with decline in recognition . These inflammatory markers were not significantly associated with change in any other cognitive domain. Overall, these findings support the hypothesis that inflammatory markers may be related to cognitive changes associated with abnormal memory decline . As AD drug trials targeting amyloid continue to fail, there is increased focus on repositioning current drugs, such as anti-inflammatory drugs, to reduce the risk of AD .

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All patients fulfilled DSMIV criteria for drug dependence beyond nicotine dependence

Posted on November 24, 2023 by hemp2022

However, assessing dependence severity over the past 12 months could have reflected severity over the past 30 days prior to study participation, while average DPDD or CPD in the past 30 days could have also been comparable to average DPDD or CPD over the past year. Given that the sample was comprised of non-treatment seeking participants, it is plausible to hypothesize that past month alcohol and nicotine consumption closely reflect past year consumption of these substances in the current sample. Nevertheless, as patterns of alcohol or nicotine use may vary over a longer time frame, variables that capture quantity of use or frequency of use over a longer period of time would be preferred in future studies. Lastly, given that the average FTND scores of the current participants reflected low-to-moderate nicotine dependence severity, alcohol users with more severe nicotine dependence may be required to detect effects of nicotine use on brain structure. In conclusion, we examined the relationship between gray matter density and quantity of use/dependence severity for both alcohol and nicotine in 39 heavy drinking smokers using VBM. The multiple regression analysis revealed a significant negative relationship between ADS scores and gray matter density in two brains regions, such that higher ADS scores correlated with lower gray matter density in the hypothalamus and right superior frontal gyrus, after controlling for nicotine dependence severity, age, gender, and ICV. The current results may help clarify the contribution of alcohol and nicotine use to gray matter density in heavy drinking smokers,grow racks with lights which could aid in understanding the neurocognitive consequences of co-morbid substance use in heavy drinking smokers. Substance use disorders and addiction represent a global public health problem of substantial socioeconomic implications. In 2010, 147.5 million cases of alcohol and drug abuse were reported , and SUD prevalence is expected to increase over time.

Genetic factors have been implicated in SUD etiology, with genes involved in the regulation of several neurobiological systems found to be important . However, limitations intrinsic to most genetic epidemiological studies support the search for additional risk genes. Attention-deficit/hyperactivity disorder , the most common neurodevelopmental behavioral disorder, is frequently co-morbid with disruptive behaviors such as oppositional defiant disorder , conduct disorder , and SUD. The close association between ADHD and disruptive behaviors is summarized by longitudinal observations in ADHD cohorts. Children diagnosed with ADHD monitored during the transition into adolescence exhibit higher rates of alcohol, tobacco, and psychoactive drug use than control groups of children without ADHD. It has been estimated that the lifetime risk for SUD is ~50% in subjects with childhood ADHD persisting into adulthood. Reciprocally, the prevalence of ADHD is high in adolescents with SUD and the presence of an ADHD diagnosis affects SUD prognosis, with ADHD being associated with both earlier and more frequent alcohol-related relapses and lower likelihood of cannabis-dependence treatment completion. Strong evidence from family, twin, and genome-wide linkage and association studies suggests that genetic factors play a crucial role in shaping the susceptibility to both ADHD and SUD. During the last 15 years, we have collected families clustering individuals affected with ADHD and disruptive behaviors from disparate regions around the world. Although the prevalence of ADHD co-morbid with disruptive behaviors is variable across populations, we found a higher frequency of CD, ODD, and SUD in ADHD individuals than in unaffected relatives.Fine mapping of the 4q13.2 region identified variants in the adhesion G-protein-coupled receptor L3 gene that predispose to ADHD. Characterization of the association between ADHD and ADGRL3 has provided key information to better predict the severity of ADHD, the long-term outcome, the patterns of brain metabolism, and the response to stimulant medication. To the best of our knowledge, ADGRL3 linkage and association results represent some of the most robustly replicated genetic and pharmacogenetic findings in ADHD genetic research. While ADGRL3 has also shown association with disruptive behaviors in the context of ADHD, a direct link to SUD has not been systematically investigated.

In this manuscript we tested the hypothesis that ADHD risk variants harbored at the ADGRL3 locus interact with clinical, demographic, and environmental variables associated with SUD.This population isolate is unique in that it was used to identify ADHD susceptibility genes by linkage and association strategies. Detailed clinical and demographic information on this sample has been published elsewhere. The sample consists of 1176 people , mean age 28 ± 17 years, ascertained from 18 extended multigenerational and 136 nuclear Paisa families inhabiting the Medellin metropolitan area in the State of Antioquia, Colombia. Initial coded pedigrees were obtained through a fixed sampling scheme from a parent or grandparent of an index proband after having collected written informed consent from all subjects or their parent/guardian, as approved by the University of Antioquia and the NIH Ethics Committees, and in accordance with the Helsinki Declaration. Patients were recruited under NHGRI protocol 00-HG-0058 . Exclusion criteria for ADHD participants were IQ < 80, or any autistic or psychotic disorders. Parents underwent a full psychiatric structured interview regarding their offspring . All adult participants were assessed using the Composite International Diagnostic Interview , as well as the Disruptive Behavior Disorders module from the DICA-IV-P modified for retrospective use. The interview was conducted by a “blind” rater at the Neurosciences Clinic of the University of Antioquia, or during home visits. ADHD status was defined by the best estimate method. Specific information regarding clinical diagnoses and co-morbid disruptive disorders, affective disorders, anxiety, and substance use has been published elsewhere.The ADHD sample consisted of 670 adult ADHD patients, mean age 33 ± 10 years, 69% males , recruited and evaluated at the Psychiatry Department of the Hospital Universitari Vall d’Hebron according to DSM-IV TR criteria. ADHD diagnosis was based on the Spanish version of the Conners Adult ADHD Diagnostic Interview for DSM-IV. Comorbidity was assessed by Structured Clinical Interview for DSM-IV Axis I and Axis II Disorders . ODD during childhood and adolescence was retrospectively evaluated with the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Version .

Thirty-nine percent of ADHD patients fulfilled diagnostic criteria for SUD, 21% for disruptive behavior disorders , 21% for depression , 13% for anxiety , and 8% for phobias . The level of impairment was measured with the Clinical Global Impression included in the CAADID Part II and the Sheehan Disability Inventory. Exclusion criteria for ADHD patients were IQ < 80; pervasive developmental disorders; schizophrenia or other psychotic disorders; presence of mood, anxiety or personality disorders that might explain ADHD symptoms; birth weight ≤ 1.5 kg; and other neurological or systemic disorders that might explain ADHD symptoms. The SUD sample consisted of 494 adults recruited and evaluated at the Addiction and Dual Diagnosis Unit of the Psychiatry Department at the Hospital Universitari Vall d’Hebron with the Structured Clinical Interview for DSMIV Axis I Disorders . None were evaluated for ADHD. The control sample consisted of 483 blood donors in which DSM-IV lifetime ADHD symptomatology was excluded under the following criteria: not having been diagnosed with ADHD and answering negatively to the lifetime presence of the following DSM-IV ADHD symptoms: often has trouble keeping attention on tasks,layout commercial grow room design plans often loses things needed for tasks, often fidgets with hands or feet or squirms in seat, and often gets up from seat when remaining in seat is expected. Individuals affected with SUD were excluded from this sample. None of them had self-administered drugs intravenously. It is important to mention that the exposure criterion was not applied; therefore, this set cannot be classified as “pure” controls. All patients and controls were Spanish of Caucasian descent. This study was approved by the ethics committee of the Hospital Universitari Vall d’Hebron and informed consent was obtained from all subjects in accordance with the Helsinki Declaration.The Multimodal Treatment Study of Children with ADHD was designed to evaluate the relative efficacy of treatments for childhood ADHD, combined sub-type, in a 14-month randomized controlled trial of 579 children assigned to four treatment groups: medication management, behavior modification, their combination, and treatment as usual in community care. After the 14- month treatment-by-protocol phase, the MTA continued as a naturalistic follow-up in which self-selected use of psychoactive medication was monitored. A local normative comparison group of 289 randomly selected classmates group-matched for grade and sex was added when the ADHD participants were between 9–12 years of age. The outcomes in childhood , and adolescence and into adulthood have been reported. Substance use was assessed with a child/adolescent-reported questionnaire adapted for the MTA. The measure included items for lifetime and current use of alcohol, cigarettes, tobacco, cannabis, and other recreational drugs. Also included were items for non-prescribed use or misuse of psychoactive medications, including stimulants. The measure was modeled after similar substance use measures in longitudinal or national survey studies of alcohol and other drug use that also rely on confidential youth self-report as the best source of data. A National Institutes of Health Certificate of Confidentiality further strengthened the assurance of privacy.

Substance use was coded positive if any of the following behaviors, selected after examining distributions, were endorsed as occurring in the participant’s lifetime up to 8 years post-baseline: alcohol consumption more than five times or drunk at least once; cigarette smoking or tobacco chewing more than a few times; cannabis use more than once; or use of inhalants, hallucinogens, cocaine, or any of amphetamines/stimulants, barbiturates/sedatives, and opioids/narcotics without a prescription or misused a prescription . Each of the four types of substances, as well as daily use of tobacco and the number of substance use classes endorsed , were explored in secondary analyses. DSM-IV abuse or dependence was based on a positive parent or child report with the Diagnostic Interview Schedule for Children version 2.3/3.0 at the 6- and 8-year follow-up assessments. The DISC includes both lifetime and past year diagnoses. The Diagnostic Interview Schedule-IV was used at the 8-year follow-up for 18 + year-olds . SUD was defined as the lifetime presence of any abuse or dependence . Additional analyses explored SUD for alcohol, tobacco, and cannabis/other drugs separately. All patients in this study provided informed written consent as approved by the NIH Ethics Committee.A sample of 560 inpatients and outpatients with severe SUD from Central Kentucky psychiatric facilities was collected during a pharmacogenetics investigation. Patient interviews and medical record information DNA was extracted from whole blood or buccal swabs using standard protocols. The Paisa sample was genotyped using the service provided by Illumina . The Spanish, MTA, and Kentucky samples were genotyped for select variants using pre-designed TaqMan® SNP genotyping assays . Allelic discrimination real-time PCR reactions were performed in a 384-well plate format for each individual sample according to the manufacturer’s instructions. Briefly, 20 ng of genomic DNA were mixed with 2.5 μL of 2X TaqMan Universal PCR Master Mix and 0.25 μL of 20X SNP Genotyping Assay in a total volume of 5 μL per reaction. Assays were run in an ABI 7900HT Fast Real-Time PCR System . Allele calling was made by end-point fluorescent signal analysis using the ABI’s SDS2.3 software. In addition, we had previously collected exome genotype data from the MTA sample using the Infinium® HumanExome-12 v1.2 BeadChip kit , which covers putative functional exonic variants selected from over 12,000 individual exome and whole-genome sequences. Processed and raw intensity signals for the array data can be accessed at GEO . SNP markers harbored at the ADGRL3 gene were filtered in from this dataset and added to those genotyped using TaqMan® assays.Association studies of ADGRL3 variants with ADHD, ODD, CD, response to stimulant treatment and severity outcome have been published elsewhere for the Paisa and Spanish populations. We used ARPA to build a predictive framework to forecast the behavioral outcome of children with ADHD, suitable for translational applications. Our goal was to test the hypothesis that ADGRL3 variants predisposing to ADHD also increase the risk of co-morbid disruptive symptoms, including SUD. ARPA is a tree-based method widely used in predictive analyses because it accounts for non-linear and interaction effects, offers fast solutions to reveal hidden complex substructures and provides truly non-biased statistically significant analyses of high-dimension, seemingly unrelated data. In a visionary manuscript, D.C. Rao suggested that recursive-partitioning techniques could be useful for genetic dissection of complex traits.

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The rewarding effects of cocaine are reduced in a very specific way by CB1 receptor antagonists

Posted on November 23, 2023 by hemp2022

In addition to anecdotal evidence that cannabis increases appetite, especially for sweet food, in recreational cannabis smokers , several preclinical studies have shown that CB1 receptor agonists facilitate food reward, in particular, the hedonic response to sweet food that Berridge and Robinson call ‘liking’. For example, THC increases the intake of food and increases the consumption of sweet solutions in rats. In addition, low doses of THC increase hedonic reactions to sucrose and decrease aversive reactions to bitter quinine solutions and THC increases the palatability of sucrose in rats. Also, we recently found that the motivation to respond for food, as measured by break points in responding for food under a progressive-ratio schedule , is increased by administration of THC . Interestingly, enhancement of the motivation to respond for food by THC is dependent on actual food consumption , suggesting that both appetitive and consummatory aspects of food reward may involve the endocannabinoid system. Taken together, these findings provide a rationale for the clinical use of CB1 receptor agonists such as Marinol in anorexic cancer and HIV patients . There are contradictory reports on the effects of CBs on brain stimulation reward. Brain stimulation reward or intracranial self-stimulation is an operant procedure where animals have to press a lever to receive a small electrical current in restricted areas of the brain . Brain stimulation reward is arguably the most robust form of reinforcement and is believed to derive from the ability of electrical currents to activate, probably indirectly, the dopaminergic mesolimbic system . In support of this hypothesis, drugs that activate the dopaminergic system and increase dopamine levels in the nucleus accumbens  also facilitate brain stimulation reward , whereas drugs that block dopamine receptors reduce thresholds for self-stimulation.

Concerning, CB1 receptor agonists, Gardner and colleagues found that THC facilitates brain stimulation reward ,vertical grow rack system whereas other investigators found no effects of the syntheticagonists CP55,940 or AMG-3 and some investigators have found a reduction of brain stimulation reward with CB1 receptor agonists . These discrepancies, which are likely due to procedural differences, remain to be resolved. A caveat of all experiments with directly acting CB1 receptor agonists is that, for several reasons, these drugs do not provide a realistic picture of the physiological role of the endocannabinoids. First, anandamide is a partial agonist , whereas synthetic CB1 receptor agonists are often full agonists and have higher affinities for CB1 receptors . Second, anandamide and 2-AG have very short half-lives , whereas THC and synthetic CB1 receptor agonists have relatively long half-lives. Finally, systemic injections of these compounds result in the activation of all brain areas containing CB1 receptors, whereas physiological activation of endocannabinoid synthesis and release is likely to be region, neuron or even synapse specific . The availability of mice genetically deprived of CB1 receptors in a tissue-specific manner may help address this possibilityAssessment of the roles the endocannabinoid system plays in brain reward processes was greatly facilitated by the discovery of selective CB1 receptor antagonists/inverse agonists such as rimonabant and AM251 . CB1 receptor antagonists decrease the rewarding effects of a wide variety of abused drugs under certain conditions. For example, the rewarding effects of opioids are generally decreased in both intravenous self-administration and conditioned place preference procedures . There have also been reports that rimonabant and AM251 reduce the rewarding effects of methamphetamine , alcohol and nicotine .

CB1 receptor antagonists do not generally alter self-administration of cocaine under low fixed-ratio schedules or conditioned place preference procedures , but AM251 has been found to significantly reduce self-administration of cocaine under progressive-ratio schedules and rimonabant prevents relapse to cocaine-induced and cue-induced cocaine-seeking behaviour . This suggests that the appetitive and conditioned effects of cocaine, but not its direct reinforcing effects, depend on CB1 receptor activation. The effects of rimonabant on opioid reward may be mediated primarily in the NAcc, as blockade of CB1 receptors in this area reduces heroin self-administration . On the other hand, the modulation of ethanol reward by the CB system appears to take place both in the NAcc and in the prefrontal cortex . The brain sites where CBs act to alter the rewarding effects of nicotine and psychostimulants are not known at present. Drugs of abuse share the ability to elevate extracellular levels of dopamine in the shell of the NAcc, as measured by in vivo microdialysis, and this effect is believed to play an important role in their reinforcing effects . CB1 receptor antagonists have been shown to block the elevations of accumbal dopamine levels induced by administration of nicotine or ethanol , but not by administration of heroin , morphine or cocaine . Transient surges of dopamine in the NAcc, as measured by cyclic voltammetry, are also produced by drugs of abuse and are believed to be involved in drug seeking . Interestingly, the transient increases in dopamine produced by administration of nicotine, ethanol and cocaine in the shell of the NAcc of freely moving rats are all blocked by CB1 receptor antagonists . Consistent with a role for endocannabinoids in the rewarding effects of food and in the regulation of appetite and food intake , blocking endocannabinoid tone with CB1 receptor antagonists reduces intake of food and sweet solutions . Also, injection of rimonabant within 24 h of birth completely prevents milk intake and causes almost 100% mortality in mouse pups . The motivational effects of food measured by a progressive-ratio schedule of food reinforcement and the appetitive aspects of food reward are significantly reduced by rimonabant in rats, indicating that some aspects of food intake regulation involve reward and motivational processes.

In addition, AM251 decreases hedonic reactions to sucrose and increases aversive reactions to quinine . Consistent with these preclinical findings, rimonabant has been found to be effective in the clinical treatment of obesity , although the clinical efficacy of this agent appears to be primarily due to its ability to alter peripheral lipid metabolism, rather than to reduce food intake . As in the case of CB1 receptor agonists, the effects of CB1 receptor antagonists on brain stimulation reward are somewhat controversial. Rimonabant has been shown to increase the threshold for brain stimulation reward in some studies or to produce no change in brain stimulation reward thresholds in other studies .Mice genetically engineered to lack CB1 receptors do not show dramatic changes in body weight, food consumption or fertility , suggesting that CB1 receptors modulate rather than mediate basic reward functions or that other systems can compensate for their absence. By using CB1-null mice, the role of CB1 receptors in the rewarding effects of drugs of abuse has been confirmed. For example, in these mutant mice morphine is not self administered , does not induce conditioned place preferences and does not elevate dopamine levels in the NAcc . Also, the rewarding effects of alcohol are reduced in CB1-null mice, as demonstrated by data showing that CB1-null mice do not develop conditioned place preference with this drug and that they do not prefer it over water in a two-bottle free-choice paradigm . However, another study reported that CB1-null mice show slight and short-lasting decreases in preference for ethanol. Development of conditioned place preferences with cocaine is unaltered in CB1-null mice . On the other hand, development of cocaine self-administration behaviour under fixed-ratio schedules of reinforcement in CB1-null mice was reported to be unaltered when mice were restrained , but was reduced in freely moving mice . In addition, cocaine self-administration was significantly reduced under a progressive-ratio schedule of self-administration in CB1-null mice . These contrasting results highlight the fact that, when working with genetically modified mice such as CB1-null mice, not only methodological differences but also differences in the genetic background may result in very different and sometimes contrasting behavioural outputs . It is interesting to note that CB1-null mice show normal elevations in dopamine levels in the NAcc following administration of cocaine ,grow vertical but no elevations following administration of morphine or ethanol , compared with wild-type controls. Finally, CB1-null mice do not develop conditioned place preferences to nicotine , but they self-administer the drug like wild-type controls . It remains to be seen whether increasing the effort needed to obtain nicotine, as with cocaine , could reveal a role of CB1 receptors in some aspects of nicotine reinforcement as suggested by the results with CB1 receptor antagonists . CB1-null mice have also provided evidence for the involvement of the endocannabinoid system in food reward. For example, CB1-null mice eat less than their wild-type control litter mates after food restriction . Moreover, CB1-null mice respond less for sucrose in a two-lever paradigm, have lower break points under progressive-ratio schedules of sucrose delivery and show less preference for sucrose over water in a two-bottle free-choice procedure .

Genetic ablation of CB1 receptors results in small reduction in body weight, reduction in adiposity and resistance to diet-induced obesity . However, as in the case of CB1 receptor antagonists, these effects appeared to be related more to increased metabolic energy consumption than to differences in rewarding effects of food or hypophagia . Interestingly, in the study by Fride et al. , administration of rimonabant in mice pups lacking CB1 receptors still induced a decrease in milk intake and survival rate, suggesting that some of the effects of CBs on food intake may be mediated by still uncharacterized CB receptors. To date, no study has investigated the effects of CB1 receptor deletion on brain stimulation reward. On the other hand, it should be noted that CB1-null mice show increased anhedonia after chronic mild stress , a measure of reduced activity of the reward system and a model of depression , further supporting a role for the endocannabinoid system in brain reward functions.Although measurements of the effects of systemic or intracranial injections of anandamide provide useful information on the functions of the endocannabinoid system, to provide support for a role of neurally released anandamide in brain reward processes it is also important to measure anandamide released in the brain by different abused drugs, by food and by electrical brain stimulation. Release of neurotransmitters such as dopamine or glutamate can be readily measured by micro-dialysis techniques, but only a few studies have employed microdialysis techniques to measure extracellular brain levels of endocannabinoids . Thus, most information on the modification of endocannabinoid levels comes from measurements of tissue levels in different brain areas. Measuring tissue level of anandamide has the limitation that only one time point can be established at a time, limiting information on the pattern of endocannabinoid release. Using tissue levels, it has been demonstrated that chronic administration of several drugs of abuse leads to region specific increases in anandamide levels. For example, when administered chronically, THC decreases levels of anandamide in the striatum , ethanol decreases levels of anandamide in the midbrain but not in the striatum , nicotine decreases levels of anandamide in the striatum but not in the midbrain , and cocaine and morphine do not alter anandamide levels, either in the striatum or midbrain . However, it is difficult to determine from these studies whether measured levels of endocannabinoids reflected the consequences of chronically administered drug or withdrawal. Vigano et al. compared the effects of chronic versus acute administration of morphine on endocannabinoid levels in the brain. They found that acute administration of morphine increased anandamide levels in the striatum, whereas chronic treatment with the drug failed to do so. In addition, they found that chronic treatment with morphine did not alter the ability of a challenge dose of morphine to increase anandamide levels in the striatum; that is, repeated administration of morphine did not induce sensitization or tolerance to this effect . Thus, chronic administration of drug followed by withdrawal, chronic administration of drug followed by an acute drug challenge and acute administration of drug can lead to very different changes in brain anandamide levels. Such profiles of release may indicate that anandamide is released in response to relevant changes in homoeostasis but not when an adaptive response has already occurred.

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