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    Consult your doctor before using. Remember Me Log in. Description Additional information Description. If using orally, place under tongue for about 90 seconds then, swallow for best results Want to open your mind? Ten hand-touch sites on both wards were screened weekly using standardised methods and patients were monitored for meticillin-resistant S. Patient and environmental meticillin-resistant S. Results Enhanced cleaning was associated with a Increasing hospital-acquired infections have generated much attention over the last decade.

    We introduced an additional cleaner into two matched wards from Monday to Friday, with each ward receiving enhanced cleaning for six months in a cross-over design.

    Enhanced cleaning was associated with a To investigate the effects of an aerobic training in subjects with Parkinson's disease PD as compared to a medical Chinese exercise Qigong. PD out-patients referred to a Neurorehabilitation facility for the management of motor disability. A spirometry test and maximum cardiopulmonary exercise test CPET were also performed to determine the pulmonary function, the metabolic and cardio-respiratory requests at rest and under exercise.

    All measures were taken immediately before and at the completion of each treatment phase. The statistical analysis focusing on the evolution of motor disability and quality of life revealed a significant interaction effect between group and time for the 6MWT time x group effect: Post hoc analysis showed a significant increase in 6MWT and a larger decrease in Borg score after aerobic training within each subgroup, whereas no significant changes were observed during Qigong.

    The analysis of cardiorespiratory parameters showed significant interaction effects between group and time for the Double Productpeak time x group effect: Intraileal casein infusion increases plasma concentrations of amino acids in humans: A randomized cross over trial.

    Activation of the ileal brake by casein induces satiety signals and reduces energy intake. However, adverse effects of intraileal casein administration have not been studied before. These adverse effects may include impaired amino acid digestion, absorption and immune activation.

    To investigate the effects of intraileal infusion of native casein on plasma amino acid appearance, immune activation and gastrointestinal GI symptoms. Thirty minutes after intake of a standardized breakfast, participants received an ileal infusion, containing either control C consisting of saline, a low-dose Blood samples were collected for analysis of amino acids AAs , C-reactive protein CRP , pro-inflammatory cytokines and oxylipins at regular intervals.

    Furthermore, GI symptom questionnaires were collected before, during and after ileal infusion. A 6-camera synchronised array GoPro Omni, [California, United States] was suspended inverted and recorded an elective laparoscopic cholecystectomy in Group B were reversed. Each video was probed at designated time points for engagement levels and task-unrelated images or thoughts. Alternating question banks were administered following each video experience.

    Feedback was obtained via a short survey at study completion. Preclinical undergraduate students from a medical university in Ireland. Forty students participated with a mean age of Randomized cross-over trial of polyethylene glycol electrolyte solution and water for colostomy irrigation.

    Water for colostomy irrigation is largely absorbed by the colon, which may result in less efficient expulsion of stool. This study compared the outcome of colonic cleansing with water and polyethylene glycol solution. In a cross-over study, 41 colostomy irrigators were randomly assigned to water or polyethylene glycol solution irrigation first and then the other regimen, each for one week. Patients recorded fluid inflow time, total washout time, cramps, leakage episodes, number of stoma pouches used, and satisfaction scores Visual Analog Scale, The median and interquartile range for each variable was calculated, and the two treatments were compared Wilcoxon's test.

    Eight patients failed to complete the study. Thirty-three patients 20 females; mean age, 55 range, years provided irrigation sessions: The median and interquartile range for water vs.

    The exponential growth of image-based diagnostic and minimally invasive interventions requires a detailed three-dimensional anatomical knowledge and increases the demand towards the undergraduate anatomical curriculum.

    This randomized controlled trial investigates whether musculoskeletal ultrasound MSUS or arthroscopic methods can increase the anatomical knowledge uptake. Second-year medical students were randomly allocated to three groups.

    In addition to the compulsory dissection course, the ultrasound group MSUS was taught by eight, didactically and professionally trained, experienced student-teachers and the arthroscopy group ASK was taught by eight experienced physicians. The control group CON acquired the anatomical knowledge only via the dissection course. The theoretical anatomic learning outcomes were tested using a multiple-choice questionnaire MCQ , and after cross-over an objective structured clinical examination OSCE.

    Differences in student's perceptions were evaluated using Likert scale-based items. The benefit of the ASK module was limited to the shoulder area p Arthroscopy or ultrasound in undergraduate anatomy education: Background The exponential growth of image-based diagnostic and minimally invasive interventions requires a detailed three-dimensional anatomical knowledge and increases the demand towards the undergraduate anatomical curriculum.

    Methods Second-year medical students were randomly allocated to three groups. The benefit of the ASK module was limited to the shoulder area p Effect of almond consumption on vascular function in patients with coronary artery disease: Almonds reduce cardiovascular disease risk via cholesterol reduction, anti-inflammation, glucoregulation, and antioxidation.

    The objective of this randomized, controlled, cross-over trial was to determine whether the addition of 85 g almonds daily to a National Cholesterol Education Progr Cross -flow shearing effects on the trajectory of highly buoyant bent- over plumes.

    The dynamics of highly buoyant plumes in cross -flow is ubiquitous throughout both industrial and environmental phenomena. The rise of smoke from a chimney, wastewater discharge into river currents, and dispersion of wildfire plumes are only a few instances.

    There have been many previous studies investigating the behavior of jets and highly buoyant plumes in cross -flow. So far, however, very little attention has been paid to the role of shearing effects in the boundary layer on the plume trajectory, particularly on the rise height.

    Numerical simulations and dimensional analysis are conducted to characterize the near- and far-field behavior of a highly buoyant plume in a boundary layer cross -flow.

    The results show that shear in the cross -flow leads to large differences in the rise height of the plume in relation to a uniform cross -flow, especially at far-field. Any opinions, findings, and conclusions or recommendations expressed in the material are of the authors and do not necessarily reflect the views of NSF.

    Wind-forced modulations in crossing sea states over infinite depth water. The present work is motivated by the work of Leblanc ["Amplification of nonlinear surface waves by wind," Phys. Fluids 19, ] which showed that Stokes waves grow super exponentially under fair wind as a result of modulational instability. Here, we have studied the effect of wind in a situation of crossing sea states characterized by two obliquely propagating wave systems in deep water.

    It is found that the wind-forced uniform wave solution in crossing seas grows explosively with a super-exponential growth rate even under a steady horizontal wind flow. This is an important piece of information in the context of the formation of freak waves. However, because the surface motion is estimated in the line-of-sight LOS direction, it is not possible to differentiate between vertical and horizontal surface motions from a single stack.

    Cross -track data, i. We implemented a cross -track fusion of PS-InSAR point cloud data, making it possible to separate the vertical and horizontal components of the surface motion.

    Multibeam bathymetric data reveals seafloor fabrics, i. The seafloor depths combined with shipboard gravity data indicate the structure of oceanic lithosphere, thermal state, and mantle dynamics and become more accurate data set to estimate fine-scale crustal structures and subsurface mass distribution.

    The cruise was as a part of SORA Abe, Cruise report for geological and geophysical studies in the southern Pacific, and was an unprecedented opportunity to collect data in the regions of the Pacific Ocean where it has been sparsely surveyed using state-of-the-art echo-sounding technology.

    Our multibeam bathymetric and shipboard gravity survey track crossed over the Pacific, the Antarctic, and the Nazca plates, and covered lithospheric ages varying from zero to Ma.

    Strikes of lineated abyssal hills give critical evidences for future studies of the plate reconstruction and tectonic evolution of the old Pacific Plate because magnetic lineations are unconstrained on the seafloor in the Cretaceous magnetic quiet Ma zone. Consecutive trends of lineated abyssal hills and fracture zones indicate stable tectonic stress field originated from the Pacific Antarctic Ridge PAR and the Chile Ridge spreading systems.

    The seafloor fabric morphology revealed a clear boundary between the PAR and the Chile Ridge domains. The observed bathymetric boundary is probably a part of a trace of the Pacific-Antarctic-Farallon Nazca plate's triple junction. The result will be constraint for future studies of the plate reconstruction and tectonic evolution of the PAR. Micromechanical analysis of composites with fibers distributed randomly over the transverse cross -section.

    A new method to generate the random distribution of fibers in the transverse cross -section of fiber reinforced composites with high fiber volume fraction is presented in this paper.

    Based on the microscopy observation of the transverse cross -sections of unidirectional composite laminates, hexagon arrangement is set as the initial arrangement status, and the initial velocity of each fiber is arbitrary at an arbitrary direction, the micro-scale representative volume element RVE is established by simulating perfectly elastic collision.

    Combined with the proposed periodic boundary conditions which are suitable for multi-axial loading, the effective elastic properties of composite materials can be predicted. The predicted properties show reasonable agreement with experimental results. By comparing the stress field of RVE with fibers distributed randomly and RVE with fibers distributed periodically, the predicted elastic modulus of RVE with fibers distributed randomly is greater than RVE with fibers distributed periodically.

    These boosters are initiated separately by electrical impulse s. Coupling the output of each detonator with an explosive cross-over would reduce the function time between boosters independent of electrical impulse while providing additional redundancy to the system.

    The objectives of this program were to: Homodimeric cross-over structure of the human granulocyte colony-stimulating factor GCSF receptor signaling complex. GCSF-R complex formed a 2: The Ig-like domain cross-over structure necessary for GCSF-R activation is consistent with previously reported thermodynamic and mutational analyses.

    Fermi systems in the cross-over regime between weakly coupled Bardeen—Cooper—Schrieffer BCS and strongly coupled Bose—Einstein-condensate BEC limits are among the most fascinating objects to study the behavior of an assembly of strongly interacting particles. The physics of this cross-over has been of considerable interest both in the fields of condensed matter and ultracold atoms. One of the most challenging issues in this regime is the effect of large spin imbalance on a Fermi system under magnetic fields.

    Although several exotic physical properties have been predicted theoretically, the experimental realization of such an unusual superconducting state has not been achieved so far. The observation of this field-induced phase provides insights into previously poorly understood aspects of the highly spin-polarized Fermi liquid in the BCS-BEC cross-over regime.

    Both ultrahigh vacuum-based and ambient pressure x-ray photoelectron spectroscopy show that iodo- and chlorobenzene IB and CB undergo the cross -coupling reaction towards diphenylacetylene. In particular, the experiments provide the orientation of the intact adsorbates with respect to the surfaces at liquid nitrogen temperature.

    The difference is tentatively attributed to a difference in surface orientation of the different halobenzenes.

    Children's Sleep and Cognitive Performance: Participants were second- and third-grade years old at Time 1 boys and girls. As organized coastal convective storms develop over land and move over the coastal ocean, their storm-scale structures, intensity, and associated weather threats evolve.

    This study aims to quantify the impact of sea surface temperature on the fundamental mechanisms controlling the evolution of coastal quasi-linear convective systems QLCSs as they move offshore.

    Results from this work will contribute to the improved predictability of these coastal, potentially severe warm season storms. The current work systematically studies the interaction between QLCSs and marine atmospheric boundary layers MABLs associated with the coastal ocean in an idealized numerical framework. Sea surface temperature values are selected to represent values observed within the Mid-Atlantic Bight coastal waters, including 5oC min SST - January , 14oC early summer , and 23oC late summer.

    The numerical MABL is allowed to develop through surface heat fluxes. Preliminary simulations indicate that SST influences storm structure, with the stratiform precipitation shield becoming progressively wider as SST increases.

    The physical mechanisms contributing to these and other differences will be discussed. Cross-over studies underestimate energy compensation: The example of sucrose-versus sucralose-containing drinks. We argue that this design may underestimate the effect of the manipulation due to carry- over effects.

    The parallel-groups study included a baseline day in which only the test meal was consumed. Energy intake in that meal was used to control for individual differences in energy intake in the analysis of the effects of sucrose versus sucralose on energy intake on the test day. Together, these results confirm that consumption of sucrose in a drink reduces subsequent energy intake, but by less than the energy content of the drink, whilst drink sweetness does not increase food energy intake. Crucially, though, the studies demonstrate that study design affects estimated energy compensation.

    Published by Elsevier Ltd.. A cross -sectional inquiry into correlates and mechanisms over the life course. In this paper, we examine the relative contribution of four domains of predictors that have been linked to adult criminal involvement: Cross -sectional data were collected through face-to-face interviews with community-recruited adults. Data analysis involved negative binomial regression. Being male, family size, juvenile delinquency, aggression, living with someone involved in illegal activity and recent violent victimization were independently associated with non-violent criminal involvement.

    Aggression, association with deviant peers, and recent violent victimization were independently associated with violent criminal involvement. Juvenile delinquency and aggression mediated the affect of multiple family-of-origin characteristics on non-violent criminal involvement and aggression mediated the effect of childhood physical abuse on violent criminal involvement. The results emphasize the importance of investigating both antecedents and proximal risk factors predictive of different types of criminal involvement, which, in turn, will assist in developing risk-focused prevention and intervention programs.

    Resolution dependence of cross -tropopause ozone transport over east Asia. Detailed analysis of mesoscale transport of ozone across the tropopause over east Asia during the spring of is conducted using regional simulations with the University of Wisconsin Nonhydrostatic Modeling System UWNMS , in situ flight data, and a new two-scale approach to diagnosing this ozone flux. From late February to early April, synoptic activity regularly deformed the tropopause, leading to observations of ozone-rich concentration exceeding 80 ppbv stratospheric intrusions and filaments at tropospheric altitudes.

    Since model resolution is generally not sufficient to capture detailed small-scale mixing processes, an upper bound on the flux is proposed by assuming that there exists a dynamical division by spatial scale, above which the wind conservatively advects large-scale structures, while below it the wind leads to irreversible transport through nonconservative random strain. A formulation for this diagnosis is given and applied to ozone flux across the dynamical tropopause.

    Local and domain-averaged flux values using this method agree with other numerical and observational studies in similar synoptic environments. Sensitivity to numerical resolution, prescribed divisional spatial scale, and potential vorticity PV level is investigated. Divergent residual flow in regions of high ozone, and PV gradients tended to maximize flux magnitudes. We estimated the domain-integrated flow of ozone out of the lowermost stratosphere to be about 0.

    Spectral analysis of the wind field lends support for utilization of this dynamical division in this methodology. Objective To determine whether anti-reflux medications reduce bradycardia episodes attributed to clinically suspected gastroesophageal reflux GER. Study design We conducted a masked trial comparing metoclopramide, 0. Each infant served as his own control.

    Results The mean SD birth weight was g and gestational age was 29 3 weeks. Eighteen infants were enrolled at 35 22 days of age. The mean difference drug minus placebo was 0. There was a decrease in bradycardia episodes over time P over time, unrelated to treatment, unmasked therapeutic trials of medications are likely to lead to misleading conclusions.

    Video-game based therapy performed by children with cerebral palsy: Previous studies reported controversial results about the efficacy of video-game based therapy VGT in improving neurorehabilitation outcomes in children with cerebral palsy CP. Primary aim was to investigate the effectiveness of VGT with respect to conventional therapy CT in improving upper limb motor outcomes in a group of children with CP.

    Secondary aim was to quantify if VGT leads children to perform a higher number of movements. A cross-over randomized controlled trial RCT for investigating the primary aim and a cross -sectional study for investigating the secondary aim of this study. According to the secondary aim of this study a secondary cross -sectional study has been performed. Eight children with CP 6. VGT resulted effective in improving the motor functions of upper limb extremities in children with CP, conceivably for the increased quantity of limb movements, but failed in improving the manual abilities for performing activities of daily living which benefited more from CT.

    VGT performed using the X-Box with. The effect of chronic progressive-dose sodium bicarbonate ingestion on Cross Fit-like performance: A double-blind, randomized cross-over trial. Background Sodium bicarbonate SB has been proposed as an ergogenic aid, as it improves high-intensity and resistance exercise performance.

    However, no studies have yet investigated SB application in Cross Fit. This study examined the effects of chronic, progressive-dose SB ingestion on Cross Fit-like performance and aerobic capacity.

    Methods In a randomized, double-blind, cross-over trial, 21 Cross Fit-trained participants were randomly allocated to 2 groups and underwent 2 trials separated by a day washout period. In order to examine biochemical responses, blood samples were obtained prior to and 3 min after completing each exercise test. Results No gastrointestinal GI side effects were reported during the entire protocol. Sodium bicarbonate SB has been proposed as an ergogenic aid, as it improves high-intensity and resistance exercise performance.

    In a randomized, double-blind, cross-over trial, 21 Cross Fit-trained participants were randomly allocated to 2 groups and underwent 2 trials separated by a day washout period. No gastrointestinal GI side effects were reported during the entire protocol.

    They are found to be 1. Cross layer optimization for cloud-based radio over optical fiber networks. To adapt the 5G communication, the cloud radio access network is a paradigm introduced by operators which aggregates all base stations computational resources into a cloud BBU pool. The interaction between RRH and BBU or resource schedule among BBUs in cloud have become more frequent and complex with the development of system scale and user requirement.

    It can promote the networking demand among RRHs and BBUs, and force to form elastic optical fiber switching and networking. In such network, multiple stratum resources of radio, optical and BBU processing unit have interweaved with each other. In this paper, we propose a novel multiple stratum optimization MSO architecture for cloud-based radio over optical fiber networks C-RoFN with software defined networking. Additionally, a global evaluation strategy GES is introduced in the proposed architecture.

    MSO can enhance the responsiveness to end-to-end user demands and globally optimize radio frequency, optical spectrum and BBU processing resources effectively to maximize radio coverage. The feasibility and efficiency of the proposed architecture with GES strategy are experimentally verified on OpenFlow-enabled testbed in terms of resource occupation and path provisioning latency. Further evidence that aberrant segregation and crossing over in Sordaria brevicollis may be discrete, though associated, events.

    Crosses were made between buff spore colour mutants in Sordaria brevicollis in the presence of flanking markers. Recombinant asci with one or more wild-type spores were isolated and the spores germinated and scored for buff and flanking marker genotype.

    The buff genotype was determined by back- crossing to each parent and looking for recombinants. It was found that the majority of the recombinant asci had aberrant segregation at one or other mutant site but not both. It was inferred that in the recombinants hybrid DNA rarely extended to both sites. When the aberrant segregation was associated with crossing-over , the crossovers were situated at either end of the gene rather than between the allelic sites where the hybrid DNA was believed to terminate.

    Thus, some of the crossovers were separated from the site of the aberrant segregation by a site apparently not involved in hybrid DNA and none was in the position predicted by the Meselson-Radding model, that is, where the hybrid DNA terminates. Low latency adaptive streaming of HD H. Streaming video in consumer homes over wireless IEEE HD video streaming, even with sophisticated H. Cross -layer design strategies have been proposed to address the issues of video streaming over These designs increase streaming robustness by imposing some degree of monitoring and control over Important contributions are made, but none of the existing approaches directly take the In this paper we take a different approach and propose a cross -layer design allowing direct, expedient control over the wireless packet queue, while obtaining timely feedback on transmission status for each packet in a media flow.

    This method can be fully implemented on a media sender with no explicit support or changes required to the media client. We assume that due to congestion or deteriorating signal-to-noise levels, the available throughput may drop substantially for extended periods of time, and thus propose video source adaptation methods that allow matching the bit-rate to available throughput.

    Combining Gender, Work, and Family Identities: Moreover, young women opposed traditional role divisions in the family domain by decreasing their family aspirations in face of norms of lower family involvement or higher career involvement of men. Conversely, in line with traditional gender roles, young men showed lower family aspirations in the face of strong male career norms; and showed increases in their career aspirations when perceiving women to take up more family roles.

    Altering these norms may provide leverage for change to allow both men and women to combine their multiple identities in an enriching way. The current study investigates how descriptive and prescriptive gender norms that communicate work and family identities to be in compatible with gender identities limit or enhance young men and women's family and career aspirations.

    Spill- over effects of norms across life domains and cross-over effects of norms across gender-groups indicated that young women, more than young men, aimed to 'have it all': Young men's family aspirations were, however, more influenced by new norms prescribing men to invest more in their family, suggesting opportunities for change.

    Together, these findings show that through social norms, young adults' gender identity affects aspirations for how to manage the co-presence of their work and family identities. Cross stratum resources protection in fog-computing-based radio over fiber networks for 5G services. In order to meet the requirement of internet of things IoT and 5G, the cloud radio access network is a paradigm which converges all base stations computational resources into a cloud baseband unit BBU pool, while the distributed radio frequency signals are collected by remote radio head RRH.

    A precondition for centralized processing in the BBU pool is an interconnection fronthaul network with high capacity and low delay.

    Cloud radio over fiber network has been proposed in our previous work already. In order to overcome the complexity and latency, in this paper, we first present a novel cross stratum resources protection CSRP architecture in fog-computing-based radio over fiber networks F-RoFN for 5G services. Additionally, a cross stratum protection CSP scheme considering the network survivability is introduced in the proposed architecture.

    The CSRP with CSP scheme can effectively pull the remote processing resource locally to implement the cooperative radio resource management, enhance the responsiveness and resilience to the dynamic end-to-end 5G service demands, and globally optimize optical network, wireless and fog resources. The feasibility and efficiency of the proposed architecture with CSP scheme are verified on our software defined networking testbed in terms of service latency, transmission success rate, resource occupation rate and blocking probability.

    Figure illustrates Stark modulation spectrum of the Q 6 E with the external electric field of The Lamb dips are assigned to the magnetic quantum numbers of the lower and upper states, M'',M' according to the Clebsch-Gordan coefficients.

    We found that the relative intensity of the cross-over resonance to the associated Lamb dips depends on the P, Q, and R branches. We ascribe the dependence to the collisional relaxation processes. Inherited differences in crossing over and gene conversion frequencies between wild strains of Sordaria fimicola from "Evolution Canyon". Recombination generates new combinations of existing genetic variation and therefore may be important in adaptation and evolution. We investigated whether there was natural genetic variation for recombination frequencies and whether any such variation was environment related and possibly adaptive.

    Crossing over and gene conversion frequencies often differed significantly in a consistent direction between wild strains of the fungus Sordaria fimicola isolated from a harsher or a milder microscale environment in "Evolution Canyon," Israel. First- and second-generation descendants from selfing the original strains from the harsher, more variable, south-facing slope had higher frequencies of crossing over in locus-centromere intervals and of gene conversion than those from the lusher north-facing slopes.

    There were some significant differences between strains within slopes, but these were less marked than between slopes. Such inherited variation could provide a basis for natural selection for optimum recombination frequencies in each environment.

    There were no significant differences in meiotic hybrid DNA correction frequencies between strains from the different slopes. The conversion analysis was made using only conversions to wild type, because estimations of conversion to mutant were affected by a high frequency of spontaneous mutation. There was no polarized segregation of chromosomes at meiosis I or of chromatids at meiosis II. Extra virgin olive oil phenols and markers of oxidation in Greek smokers: To examine the effect of a low phenol olive oil and high phenol olive oil on markers of oxidation and plasma susceptibility to oxidation in normolipaemic smokers.

    Randomized single-blind cross-over trial with two intervention periods. Twenty-five healthy males and females completed the study. Each intervention was of three weeks duration and intervention periods were separated by a two week washout. Seventy grams of extra virgin olive oil was supplied to each subject per day in the intervention periods.

    The olive oils supplied differed in their phenol content by Two fasting venous blood samples were taken at the end of each intervention period. The markers of antioxidant capacity measured in fasting plasma samples total plasma resistance to oxidation, concentrations of protein carbonyl as a marker of protein oxidation, malondialdehyde and lipid hydroperoxides as markers of lipid oxidation and the ferric reducing ability of plasma did not differ significantly between the low and high phenol olive oil diets.

    No effect of olive oil phenols on markers of oxidation in smokers was detected. It may be that the natural concentrations of phenols in olive oil are too low to produce an effect in the post-absorptive phase.

    Possible reasons for period effects and interactions between diet and administration period need attention to aid further cross-over trials of this kind. Unilever Research Vlaardingen, The Netherlands. A Randomized Cross-over Design. However, the traditional PBAC paper diary might be subject to recall bias and compliance issues, especially in adolescents.

    We developed a mobile application app version of the PBAC score and evaluated patient satisfaction and compliance with app reporting vs paper reporting. Participants agreed to track bleeding in 2 consecutive menstrual cycles and were randomized to use the PBAC paper diary or mobile app format first.

    At the end of each cycle, a satisfaction survey and system usability scale app only was used to assess the acceptability of the format used. Participants' PBAC scores did not vary significantly between the paper diary median, 95 and mobile app median, All paper diaries met definition for high compliance.

    There was no significant period or carryover effect. This study showed that a PBAC app compared with the paper diary was the preferred method of recording menstrual bleeding in adolescents and showed feasibility as a research data collection tool. Published by Elsevier Inc. The occurrence of double strand DNA breaks is not the sole condition for meiotic crossing over in Drosophila melanogaster. However, when the inversions occurred together the frequencies of single crossovers no longer increased, but the frequency of double crossovers, as well as the coefficient of coincidence did increase.

    To ensure that the instrument was operating properly, a QC solution was injected after every nine test samples, and the QC chromatogram was examined for integrity. A mixture of terpenes, cannabinoids, hydrocarbons, and the internal standard was selected for QC to provide a reference of known peaks throughout the entire time of the run.

    Each test sample chromatogram was evaluated for acceptability before data analy- sis. If the chromatogram exhibited an unusual baseline or low sensitivity, the injection was repeated. The area under each peak was measured using ITDS software in the manual mode rather than the automatic mode so that the operator could evaluate each of the peaks plus the internal standard peak for proper peak shape and to ensure correct identity assignments as well.

    Quantitative values of each peak were automati- cally calculated by determining the ratio of the area of the peak to that of the internal standard within the same chromatogram and comparing that ratio to that of a standard- ized calibration file. To analyze the data using the power of Pirouette, first the database of all mari- juana exhibits from the four countries and two states was used to construct a model of the six classes of fingerprints.

    The data within the model were examined to ascertain similarities and differences of the location classes. Having appropriate models for comparison, the remainder of the proposed data analysis experiments were conducted, constructing additional models as neces- sary. All results were based on the a K-nearest-neighbor classification method Similarities Within the Model Within the comparison of the broad classes of domestic vs foreign, all foreign exhibits were correctly classified.

    Only one domestic exhibit, a Hawaiian specimen, was misclassified. When the domestic exhibits were compared with the four foreign countries, the single exhibit discrepant in the domestic vs foreign test was again misclassified, being indicated to be from Jamaica. The number of misclassifications increased when the exhibits representing indi- vidual states were tested within a six-region model. The majority of misclassified Hawaiian specimens again looked Jamaican. All Californian exhibits were correctly identified.

    Identification of Unknowns Satisfied that the phase II fingerprint data were valid when samples included in the model were tested, the system was challenged with specimens not included in the model.

    This evaluation was repeated five times, each time removing different exhibits and testing those against each new model. The results are summarized in Table 2, which shows correct classifi- cations vs total unknowns for each of the five rounds of evaluation and the totals of the individual rounds. Although the results certainly ascertained the viability of the fingerprint system, we were still concerned about the source of the errors.

    To investigate the causes of the erroneous predictions, we closely examined the data from a different viewpoint. Pre- sented in Table 3 is a matrix chart of the misclassified exhibits showing which loca- tions fit the fingerprint more closely than the model of its actual origin.

    It was evident that exhibits within certain regions tended to be misclassified more often than those from other locations, but those trends would likely be tempered in a database com- posed of more exhibits. Although the distinctive fingerprints of the Hawaiian mari- juana improved the classification rates of those exhibits, those differences also weakened the domestic model.

    Indoor vs Outdoor For year-round production and to avoid routine surveillance, marijuana growers in the United States increasingly prefer to nurture their plants indoors out of sight.

    An added benefit of indoor horticulture is that the grower, rather than Mother Nature, controls the environment and can provide ideal lighting and temperature conditions as well as exact levels of water and nutrients. Not surprisingly, therefore, the fingerprints of plants grown indoors are significantly dissimilar to those of outdoor plants.

    A model consisting of three classes—outdoors in the ground, outdoors in pots commercial potting soil , and indoors commercial potting soil —was constructed from fingerprints of Jamaican plants grown in the UM facilities. All of those speci- mens were then tested against that model. The only misclassifications were within the outdoor group, as those plants with roots in the earth were sometimes confused with those in pots, a trend that indicates that light and temperature may influence the chemical profiles more than soil conditions.

    Daughter Plants Grown in a Different Region A most interesting experiment was the test to see how the fingerprints of plants from foreign seeds cultivated in Mississippi would fare in the system.

    Fingerprints of the resulting plants were tested against the model constructed from all of the phase II exhibits. The high rate of misclassification supported original predictions that, although genetic relationships are reflected in the fingerprints, the environment has a greater effect on the chemical profiles.

    Age and Sex The original experimental design of the fingerprint study required that all speci- mens included in the database be from mature female plants, the type of marijuana commonly trafficked in the illicit market.

    To determine if those criteria were actually necessary was the intention of the exercise based on the age and sex of plants. Experi- mentally grown specimens of 8 and 12 weeks of age were considered immature, whereas those 16, 20, and 25 weeks of age were included in the mature class.

    An equal number of both sexes were included. It appears from these data that the sex of the plant did not contribute as much to the fingerprint as did the age of the plant. The maturity of the plants, although not of great interest to the intelligence community, was definitely a factor in the accuracy of the fingerprint system.

    Our experience analyzing confiscated marijuana for more than 30 years shows that the majority of the samples were from mature plants based on the physical examination of the samples. The only exception is those samples seized at the growing locations before time to harvest. Storage Conditions To determine the effect of storage conditions on chemical fingerprints, sets of data were compiled into four models, each having one constant condition and one variant condition of the two factors: Application of the Marijuana Fingerprint System to Analysis of Hashish Samples The fingerprints of hashish exhibits are expected to differ greatly from those of marijuana because hashish is a product of Cannabis processed to concentrate the cannabinoids, primarily THC.

    Five countries were represented in the 68 hashish exhibits provided for the study, but only three broad regions: Because it was noted that the misclassified Afghan, Indian, and Pakistani exhibits all fell in the other Asian classes, those countries were combined, and a second model was created with South America, Middle East, and Southwest Asia as the classes. The anomalies in the Colombian samples were attributed to the small number of available exhibits.

    Although the Cannabis fingerprint system as designed for marijuana reliably determined the origins of hashish samples, a fingerprint based on the actual peaks found in hashish chromatograms would undoubtedly improve the accuracy. Addition- ally, a study of a marijuana profile compared with the profile of hashish made from that same marijuana could offer insight into the design of a hashish database. Three sesquiterpenes—peak 70, peak 92, and peak 63—were predominantly found in domestic fingerprints.

    Peak 92 was identified as cis- nerolidol, but the others were only tentatively identified because reference standards for those compounds could not be obtained. Peak , identified as butylated hydroxytoluene, was detected only in foreign specimens, particularly Jamaican, but never in domestic ones.

    Peak , a sesquiterpene identified as guaiol, was detected in only a few Californian, Hawaiian, and Mexican specimens. Individual compounds that could possibly be used as markers for indication of origin are summarized in Table 4. The pre- dictions that specimens from mature female plants would yield the most consistent data and that specimens should be protected from elevated temperatures were con- firmed, as was the likelihood that certain chemical compounds, particularly terpenes, contributed the most evidence of geographic origin.

    Having in hand a fully functional Cannabis fingerprint system that could readily be utilized to gather trafficking data, the goals of the study were realized. The system provided a means to distinguish foreign grown marijuana from that grown domesti- cally as well as to distinguish plants grown indoors from those grown outdoors.

    The system could also reliably determine the foreign sources of seizures of both marijuana and hashish. The reliability of the system and its utility is expected to be more in the area of intelligence than for forensic purposes. The techniques developed for the fingerprint system could, however, be applied in certain forensic situations, where the analysis of the multiple constituents of a marijuana sample could rule out the possible sources of origin, but not to definitively determine a specific source.

    Although the system did not correctly classify every single specimen, it did show the possibility that one could confidently reveal trends of both worldwide and domes- tic drug sources.

    For the system to remain useful over time, the database would need to be updated at regular intervals with high-quality authentic samples that reflect cur- rent trends in marijuana production. Following the phase II studies, agencies in the United States and abroad expressed interest in a Cannabis fingerprint system. Since the completion of this work, others have reported on the use of other tech- niques for chromatographic profiling of Cannabis and hashish to a very limited extent 37, Interest in the fingerprint system continues today.

    For example, colleagues at the University of Bern, Switzerland, have recently completed a project to use Pirou- ette software to determine any geographical correlations in Cannabis fingerprints of various origins.

    In a report to the Swiss Federal Office of Public Health in , they concluded that a Cannabis fingerprint system could effectively determine the source of marijuana found within Switzerland We also wish to thank the Drug Enforcement Administra- tion and the National Institute on Drug Abuse, which provided both the impetus and the funding for these studies.

    Cannabindiol and cannabichromene in samples of known geographic origin. De Faubert Maunder, J. Chro- matography , 85— Chemical Fingerprinting of Cannabis 65 Lille 41 4 , 33— Atomic Spectrometry 19 9 , — Acta , — Much knowledge has been gained about the chemistry, pharmacology, metabolism, and pharmacokinetics of pure compounds from Cannabis, as well as the chemical and biological analysis of marijuana smoke con- densate MSC.

    Various analytical parameters of blended marijuana i. The average weight of a marijuana cigarette was 1. The smok- ing machine used was designed to automatically load, light, smoke, and eject approx cigarettes per hour and take a maximum of 10 puffs per cigarette at the rate of From: The mean dry smoke condensate yield was 9.

    Standard research tobacco cigarettes were also pre- pared. Marijuana and tobacco cigarettes were used to generate smoke condensates under constant draft or intermittent puff smoking modes. The evaluation of smoke condensates from these two systems would provide a qualitative and quantitative range within which the various components of the marijuana smoke actually experienced by human smokers might be found.

    The cigarette smoking was conducted at flow rates of mL per minute for all constant draft combustion runs, 40 mL per 2-second puff one puff per minute for puff mode combustion runs with marijuana, and 35 mL per 2-second puff one puff per minute for puff mode combustion runs with tobacco ciga- rettes.

    Six smoke condensates were generated: MSC—low potency by puff and con- stant draft mode; MSC—high potency by puff and by constant draft; and tobacco smoke condensate by puff and by constant draft.

    A liquid—liquid fractionation scheme 5,6 allowed the separation of these components into different classes of compounds i. The analysis of the basic fraction 1. The phenolic fraction 0. The acidic fraction 1. Fractionation scheme for marijuana smoke condensate. The neutral fraction Van Den Bosch et al. The condensate was fractionated into basic 0. The neutral fraction was further purified by column chroma- tography using silica gel and a step-gradient mobile phase consisting of n-hexane, n- hexane-benzene, benzene, ether, and methanol.

    Zamir-ul Haq et al. The hexane fraction was subjected to column chromatography to yield a fraction enriched in the above-mentioned compounds. For the quantitative analysis, separate experiments were done using indi- vidual radiolabeled carbazole, indole, and skatole as internal standards. The opera- tional losses of carbazole, indole, and skatole were quite different from each other, and thus none of the internal standards could be used for the quantitation of the other components.

    The effect of aging of the condensate was studied by analysis of a composite of all samples collected every 8 weeks for 2 years. The data showed a decrease in the levels of carbazole and indole, whereas levels of skatole increased on standing. The previously described solvent partition method Fig. Enrichment of some trace components was accomplished with high-performance liquid chromatography on an aminosilane-bonded Porasil C The method allowed the identification of more than nitrogen-containing compounds.

    The authors pointed to the fact that certain compounds of the hydrogen-donor nature, e. In addition, the comparison of MSC with that of tobacco prepared and characterized by the same methodology revealed that there are both qualitative and quantitative differences between the two condensates.

    Further analysis of the basic fraction of marijuana and tobacco smoke conden- sates was carried out by Novotny et al. The use of short columns allowed the elution of larger nitrogen-containing molecules in a rea- sonable time without sacrificing the peak resolution needed for the subsequent mass spectral investigations. Marijuana and tobacco smoke condensates showed qualitative similarities with a number of alkylated pyridine and quinoline derivatives, aza-in- doles, and aza-carbazoles; however, quantities of these components in both conden- sates were quite different.

    A capillary column 60 m, packed with DB was used. Approximately com- pounds were identified. About half of this total were amines; with about half of these being aromatic amines.

    Pyrazines, pyrimidines, pyrroles, pyridines, and isoxazoles were the predominant compound classes. Some alkylated pyrazoles and pyrazines, as well as an alkylated benzimidazole, were detected in very large amounts. The methylene chloride-soluble material of the smoke condensate generated from cigarettes prepared from female Mexican marijuana was fractionated between saturated aqueous sodium bicarbonate and then with 0.

    Forty-nine com- ponents were identified in the acidic fraction of Mexican MSC. Analysis of the polynuclear aromatic hydrocarbon fraction see Fig. Approximately polynuclear compounds in each smoke material type were quantitated and tentatively identified as to parent ring structures and type of alkyl substituents.

    Further identification of methyl derivatives of polynuclear aromatic hydrocarbons in air particulates, tobacco, and MSCs was accomplished by chromato- graphic separation into fractions of similar ring types and analysis using nuclear mag- netic resonance The positions of substitution in the rings were identified from the methyl chemical shifts.

    For the lower relative molecular mass fractions of anthracene-phenanthrene and fluoranthene-pyrene, the smaller number of methyl derivatives made identification possible from nuclear magnetic resonance alone. The analysis of the neutral constituents polar and nonpolar of the smoke con- densates of Mexican marijuana and standard tobacco obtained according to Fig.

    Because the constituents of the polar neutral frac- tion were mostly nonvolatile, silylation facilitated a partial characterization of this fraction.

    In total, more than neutral smoke components were char- acterized. It is to be pointed out that the comparison of the chromatographic profiles of the nonpolar fractions for marijuana and tobacco indicated some similarities, but also qualitative and quantitative differences in their terpenic compositions. Terpenes of these and similar structures have previ- ously been found in the unburned marijuana samples 19 and are believed to be responsible for the characteristic odor of marijuana and its smoke.

    The only notable differences are the expected presence of nicotine and main cannabinoids in tobacco and marijuana smoke, respectively. The profiles of phenolic substances in tobacco and marijuana were qualitatively and quantitatively similar. A summary of the acidic, phenolic, non- polar neutral, polar neutral and polynuclear aromatic hydrocarbons is presented in Table 1. Behavioral Activity Whole smoke condensate from female Mexican marijuana was solvent-fraction- ated into four fractions using pentane, ether, methylene chloride, and ethanol.

    These fractions were tested in the rat iv via leg or tail veins for spontaneous posture, cata- tonic, locomotion, and coordination as well as evoked responses of arousal, startle, vocalization, and biting.

    Male Swiss-Webster mice were used for all studies, and all administrations were via the tail vein. A subsequent study on the basic fraction of MSC obtained from Mexican marijuana 0. These effects, although sta- tistically significant, were slight and not consistently dose dependent. Present in tobacco smoke? Ethyl- or dimethylpyrazole or 3,10 Yes imidazole 5 isomers Benzoxazole 10 No 3-Acetylpyridine 10 Yes Methylamino- or 10 Yes aminomethylpyridine 15 isomers Pyridine with five or more carbons 10 Yes in side chains including one double bond, or forming one ring 41 isomers Methylfurfurylpyrrolidine?

    Quinoline or isoquinoline with 10 No four or more carbon atoms in saturated side chain s 2 compounds Methylazanaphthalene 7 isomers 13 Yes Methylazaindole 6 isomers 13 Yes C2 Azanaphthalene 9 isomers 13 Yes C3 Azanaphthalene 2 isomers 13 No An allylquinoline? Glutaric acid 15 Dodecanoic acid 15 Phenylisopropionic acid 15 Tetradecanoic acid 15 Palmitoleic acid 15 Palmitolenic acid 15 Oleic acid 15 Lenoleic acid 15 Arachidic acid 15 Eicosanoic acid 15 Eicosadienoic acid 15 Behenic acid 15 Erucic acid 15 Tricosanoic acid 15 2-Ethylhydroxy 15 pentylbenzoic acid Lignoceric acid 15 Tetracosatetraenoic acid 15 Hexacosanoic acid 15 Hexacosadienoic acid 15 Octacosanoic acid 15 2-Methyl butanoic acid 15 3-Methyl butanoic acid 15 4-Pentenoic acid 15 Phenolic Phenol 0.

    Octacosane 18 Yes Nonacosane 18 Yes An isomer of triacontane 18 Yes Triacontane 18 Yes Myrcened 18 An acyclic diened 18 Decaned 18 A dihydrolimonened 18 A C4-benzene 18 Tridecened 2 isomers 18 Nocotined 18 Solanoned 18 A tetradecened 18 A dihydrosesquiterpened 18 An isomer of pentadecaned 18 A hexadacened 18 Eicosatetraened 2 isomers 18 Androstadienoned 2 isomers 18 An eicosadiened 18 Eicosatriened 2 isomers 18 Dihydrosesquiterpened 2 isomers 18 Pentacosaned 18 Squalened 18 An isomer of squalened 18 An isomer of nonacosaned 18 An isomer of hentriacontaned 18 Hentriacontaned 18 B Polar neutal 2-Methylphenol 2 isomers 18 Dimethylphenol 3 isomers 18 C3-Phenol 2 isomers 18 Methoxymethylphenold 18 Hydroxyfuroic acid 2 isomers 18 Methylbenzenediol 2 isomers 18 A vinylmethoxyphenol 18 e.

    A styrenetriol 18 A methoxynaphthold 18 A methoxydihydroxybenzofuran 18 C Polynuclear aromatic hydrocarbons Methylindole 6. Further possibilities are the benzo derivatives of acepyrylene and acefluoranthene. The authors concluded from these results that although the basic fraction of marijuana whole smoke condensate has pharmacological activity in mice, it offers little evidence for the presence of highly active compounds.

    Mutagenicity A study by Novotny et al. The total weights of polynuclear aromatic fractions containing three rings or more were significantly higher in MSC than in high-tar cigarette smoke condensate. The mutagens in MSCs required liver enzymes to be activated. Further work on the mutagenic activity of extracts and smoke condensates of marijuana, Transkei home- grown tobacco, and commercial cigarette tobaccos was carried out 26 using Salmo- nella typhimurium strains TA 98, TA , TA , TA , and TA , both with and without metabolic activation.

    No mutagenic activity was detected in the methylene chloride extracts of marijuana and tobacco, but all the smoke condensates exhibited mutagenicity with metabolic activation. Transkei tobacco pyrolyzate was most mutagenic, followed by marijuana, pipe, and cigarette tobacco. Mutagenicity was associated with the nitrogen content of the various products.

    Bioassay results 3 showed that the acidic fractions were not significantly mutagenic, the neutral fractions were weakly mutagenic, but the basic fractions were significantly mutagenic. The constant draft base fractions were more mutagenic than puff mode basic fractions for both marijuana and tobacco, and the more polar subfractions numbers 4—7 of the base fraction were more mutagenic than the less polar subfractions.

    Pulmonary Hazards The pulmonary effects associated with smoking marijuana and tobacco were examined in men mean age Fifteen subjects who had smoked both marijuana and tobacco habitually for the previous 5 years were included in this study. These results may account for previous findings that smoking only a few marijuana cigarettes a day without tobacco has the same effect on the prevalence and chronic respiratory symptoms 28 and the extent of tracheo- bronchial epithelial histopathology 29 as smoking more than 20 tobacco cigarettes a day without marijuana.

    These observations justify concern about the potential adverse pulmonary effects resulting from the long-term smoking of only a few marijuana ciga- rettes a day. Of several other cannabinoids tested, only canna- bidiol showed receptor-binding activity at very high concentrations 5. In vivo measure- ment of estrogen activity using uterine growth bioassay immature rats and crude marijuana extract administered subcutaneously in a dose containing 6.

    In conclusion, direct estrogenic activity of Cannabis extract could not be demonstrated in vivo. The above-mentioned materials competitively inhibited the specific binding of dihydrotestosterone to the androgen receptor with a dissociation constant Ki of 2.

    The data indicate that the antiandrogenic effects associated with marijuana use result, at least in part, from inhibition of androgen action at the receptor level. The nitromethane soluble, neutral fraction of cigarette smoke. Kettenes-Van Den Bosch, J. Constituents of marihuana smoke condensate. Marijuana Smoke Condensate 95 Nature London , — Indiana University, Bloomington, IN, dissertation abstract 42 3 , Novel receptors offer the prospect of new therapeutics, and after decades of sparse research cannabinoid pharmacology is once again on the forefront of medical news.

    The use of molecular biology techniques, such as knockout mice, and the development of antagonists and agonists of the cannabinoid receptors are slowly unraveling a network of intricate physiological and neurological effects. Endogenous Ligands A family of lipids has been identified as the endogenous ligands to the cannab- inoid receptors.

    Two arachidonic acid derivatives were first isolated: Recently, a third derivative was isolated, an ether, 2-arachidonyl glyc- eryl ether, also known as noladin ether 5. Except for the notable absence of a nitrogen atom in THC, there is little to remind us of the eicosanoid- or prostaglandin-like structure of the anandamide family. Endocannabinoids are considered either neurotransmitters or neuromodulators: These requirements are met for anandamide and, From: Metabolism of endogenous cannabinoids.

    Anandamide and 2- AG are produced from cleavage of two different phospholipid precursors present in the cell membranes of neurons and immune cells in particular. The synthe- sis of 2-AG is also calcium-dependent 4. Anandamide is then known to be transported into cells by carrier-mediated uptake, which does not depend on sodium or adenosine-5'-triphos- phate ATP , another difference from classical neurotransmitters, but similar to the structurally related prostaglandin E2 This transporter participates in the inactiva- tion of anandamide.

    Both anandamide and 2-AG are known to be rapidly hydrolyzed by the intracellular enzyme fatty acid amide hydrolase FAAH 6,12, Endocannabinoids may function physiologically as retrograde synaptic messen- gers Fig. When a postsynaptic neuron is strongly depolarized, it synthe- sizes and releases endocannabinoids through a nonvesicular mechanism.

    These molecules, in turn, bind the presynaptic neuron at CB1 receptors and inhibit its neu- rotransmitter release. It is a form of negative feedback. The chemical nature of the presynaptic neuron is important. Several studies argue in favor of this physiological role of anandamide and other endogenous cannabinoids 16— Both DSI and DSE depend on rises in calcium and on Gi proteins, which are also necessary for the synthesis and release of endogenous cannabinoids and a feature of their recep- tors.

    And finally, CB 1 stimulation inhibits GABA release from hippocampal interneurons which synapse with the important pyramidal neurons and glutamate from cerebellar basket cells which synapse with Purkinje neurons.

    Cannabinoid Receptors Two cannabinoid receptors, CB1 and CB2, have been cloned from various animal species, including humans 19— There is a shorter-isoform splice variant of CB1, CB1A, with no known function, and recent reports indicate other types of receptors yet to be cloned.

    Cannabinoid receptors belong to the superfamily of G protein-linked receptors 14,15, These receptors are characterized by 7-transmembrane domains, an extracellular NH2 terminus, and an intracellular COOH terminus. Once bound, G protein-linked receptors activate a G protein. It therefore allows signal transduction from the outside of the cell, where the ligand binds to the receptor, to the inside of the cell, where molecular changes in key target proteins will result in a biological response.

    CB1 receptors are Gi-coupled: The result of cannab- inoid receptor stimulation is therefore a decreased concentration of intracellular cAMP. An enzyme may be turned on or off by phosphoryla- tion, altering metabolic pathways; an ion channel may open or close, changing the membrane potential status of an electrical cell; importantly, transcription factors pro- teins that control gene expression such as cAMP response element-binding protein may be activated and modify the proteins actually expressed by the cell.

    Whereas changes in gene expression might take days to fully take place, opening or closing an ion channel would have immediate effects seconds or less. A rapid effect of CB1 stimulation seems to be mediated through a decreased phosphorylation of A-type potassium channels, resulting in their opening When a potassium channel is opened, the net force electrical and concentration gradient results in an efflux of potassium, and the loss of positive charges from the cell renders the cell less excitable hyperpolarized.

    A number of calcium channels are closed by the same mechanism, particularly neuronal N-type, resulting in a decreased excitability also Most CB1 receptors are found presynaptically and can modulate neurotransmitter release through presynaptic inhi- bition. Other key proteins are regulated through signal transduction from cannabinoid recep- tors.

    In turn, MAPK can activate phospholipase A2 and trigger the arachidonic acid cascade and production of prostaglandins 27 , and can decrease growth factor recep- tor synthesis in certain tissue, a basis for antiproliferative action of cannabinoids PI3K is also biochemically associated with mediation of insulin-like effects with upregulation of glucose transporter 4 insulin-dependent glucose uptake in skeletal muscle and adipose tissue , stimulation of glycogen synthesis, and glycolysis liver cells.

    These latter effects would require the presence of receptors to anandamide on the appropriate target cells. Distribution of receptors and the role of the cells affected can give insight into the pharmacology of agonists and antagonists of these receptors, and correlation between observed effects and expected effects can be theorized. CB1 has been mapped mainly to the central nervous system CNS and peripherally to sensory neurons and the autonomic nervous system.

    CB2 receptors are strictly peripheral and are found particularly on mature B cells and macrophages and on immune-related tissues such as tonsils and spleen. In the CNS, CB1 receptors have been mapped in various animal species and in humans using autoradiography and immunohistochemical mapping tech- niques 29— Whereas CB1 receptors correlate poorly with anandamide distribu- tion, they are found in brain regions rich in the degradative enzyme FAAH.

    Interestingly, FAAH is found postsynaptically and CB1 receptors are found presynaptically, an ana- tomical arrangement that correlates well with the role of endogenous cannabinoids as retrograde synaptic messengers The highest densities are found in the cerebral cortex, particularly the association cortex, in the basal ganglia and cerebellum, and in the limbic forebrain particularly hypothalamus, hippocampus, and anterior cingulate cortex. They are relatively absent from brainstem nuclei.

    Cannabinoids affect cognitive and motor functions. Their subjective effects are well documented by chronic users and include enhancement of senses, errors in time and space judgment, emotional instability, irresistible impulses, illusions, and even hallucinations.

    Objective effects have been measured and studied, and decreased psy- chomotor performance, interference with attention span, and loss of efficiency in short- term memory are classically reported in the literature. Cannabinoids also have a number of peripheral effects, notably vasodilatation, tachycardia, and immunosuppressant prop- erties.

    This chapter explains the neurophysiological and anatomical bases of these disorders and correlate them with what is known of the cannabinoid receptors. Role of brain cortical areas: CB1 receptors are dense in all cortical areas. Classically, three big areas are described. Imagine a driver and the sound of a horn—the temporal association cortex identifies the stimulus. The infor- mation is then relayed to the parietal association cortex, which decides whether to attend to the stimulus or not.

    In turn, the processed information is sent to the frontal association cortex for planning of appropriate behavioral response. Two structures, the corpus callosum and the anterior commissure, allow communication from one side of the brain to the other.

    Much of our understanding of brain regional neurophysiology comes from patho- logical lesions and their observation. Often, a drug, by altering physiological systems, can mimic in part what the pathology describes. For example, lesions of the temporal lobes result in recognition deficits.

    The patient has difficulty recognizing, identifying, or naming familiar objects. Syndromes of temporal lobe lesions are called agnosias, such as prosopagnosia, in which the patient cannot name things.

    Role of basal ganglia and cerebellum in the programmation of movements: CB1 receptors are highly expressed in the basal ganglia and cerebellum. CB1 receptors are particularly dense in all cortical areas 31 , particularly the cingulate cortex see Section 3 , and inhibition of evoked release of a number of neu- rotransmitters would result in cognitive impairment such as perception, attention, and behavioral deficits.

    It is difficult to ascribe specific deficits because of the complexity of the neural wiring in cortical regions. Basal Ganglia and Cerebellum The basal ganglia and the cerebellum interact with the cortex through a series of feedback circuits. The basal ganglia, a group of midbrain nuclei, are involved mainly with the initiation and execution of a movement, whereas the cerebellum tends to modulate ongoing movement Fig. Again, pathology clearly describes the role played by these structures in motor coordination.

    The most relevant disorders are the dyskinesias, or abnormal movements. Cerebellar degeneration is associ- ated with asynergy, the inability to achieve a properly timed and balanced activation of the muscles during movement. Asynergy causes a decomposition of movements, resulting in the move going too far or falling short dysmetria—the error is overcom- pensated.

    The gait becomes uncertain in cerebellar damage, with the feet placed far apart and the steps overshooting ataxia , and it is no longer possible to make move- ments in rapid succession dysdiadochokinesia. There are corresponding disturbances of speech and vision. In cerebellar injuries, the tremors do not appear at rest, but rather occur during movement intention tremors , and the muscle tone tends to be low, with weak muscles that become tired easily. These are the kind of disturbances often seen at the roadside in field sobriety exercises such as one-leg-stand, walk-and-turn, and the finger-to-nose test when a driver is under the influence of drugs such as marijuana.

    CB1 receptors are highly expressed in the basal ganglia and the cerebellum. To understand the possible effect of THC binding to these receptors, some well-estab- lished neuronal connections between these structures are relevant to review prior to correlation with CB1 receptor distribution. The basal ganglia illustrates well the con- cept of disinhibition at the neuronal level.

    Two key pathways are described: The association cortex and substantia nigra send excitatory impulses to the cau- date putamen. The excitation comes from the neurotransmitter released at these syn- apses, glutamate, which is the major excitatory amino acid transmitter in the human brain.

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