Our multiple-disciplinary approach, combining the PCR data with literary-historical analysis and AMS-based 14C dating of the textile samples, has enabled us to unearth this little known aspect of textile history e i.e. ancient hemp in the Land of Israel.Progress in the treatment of schizophrenia has been hindered by an inadequate understanding of the pathogenesis of this disease and of the mechanisms by which drugs that block D 2 -family dopamine receptors mitigate its symptoms. Although dopamine neurotransmission is thought to be abnormal in schizophrenia, D 2 -blocking drugs are only partially effective in preventing its diverse manifestations. Thus alterations in other brain signaling pathways have been postulated, and hypotheses on the causation of schizophrenia extended to include interactions among multiple neurotransmitter systems in addition to dopamine . However, despite the urgent need for improved antipsychotic therapies, the nature of these transmitter interactions is still largely unknown. Several lines of evidence suggest that schizophrenia may be associated with anomalies in the function of cannabinoid receptors and their attendant system of endogenous activators. Cannabinoid receptors are the pharmacological target of marijuana and hashish, cannabis-derived drugs that contain Ä 9 -tetrahydrocannabinol . Prevalence of cannabis consumption is significantly higher among schizophrenics than normal individuals, and prolonged abuse of large quantities of pots for cannabis plants may trigger relapse of psychotic symptoms in schizophrenic patients. These phenomena, though unexplained at the molecular level, are consistent with the neuroanatomical distribution of cannabinoid receptors.
Indeed some of the highest densities of these receptors are found in regions of the human brain that have been implicated in schizophrenia, including prefrontal cortex, basal ganglia, hippocampus and anterior cingulate cortex. Similarities between certain cognitive impairments occurring in psychoses and the pharmacological effects of Ä 9 – THC have also been documented. Additional support for a role of cannabinoid signaling in schizophrenia comes from the existence of functional interactions between dopamine and anandamide , an endogenous cannabinoid compound. Microdialysis experiments have shown that anandamide release in rat dorsal striatum is dramatically stimulated by activation of D 2 -family, but not D 1 -family dopamine receptors. The physiological significance of this effect is still unresolved, but behavioral experiments indicate that anandamide may act as a local modulatory signal to offset dopamine-induced psychomotor activation. Along with anandamide, brain neurons produce two additional lipids that have been involved in cannabinoid signaling: 2- arachidonylglycerol and palmitylethanolamide. Neither compound appears to be released by D 2 -family receptor activation in vivo , however, pointing to a speci®c role for anandamide in this response. To reveal possible abnormalities of endogenous cannabinoid signaling in schizophrenia, we have measured endogenous cannabinoid levels in cerebrospinal fluid of schizophrenic patients and non-schizophrenic controls by using a combination of high-performance liquid chromatography and gas-chromatography/mass spectrometry techniques, which provide the high degree of sensitivity and selectivity needed to accomplish this task.Ten patients with acute schizophreniform psychotic symptoms were included in our study. Nine patients fulled the diagnostic criteria from DSM-IV for schizophrenia and one for schizophreniform psychosis . Patient characteristics are summarized in Table 1. Four patients had a history of intermittent consumption of cannabis resin and/or alcohol, but did not match the diagnostic criteria for acute intoxication, drug dependence or withdrawal syndrome.
Schizophrenic symptoms lasted at least 4 months in all patients. Psychopathological disturbance was additionally quantified using the seven step Brief Psychiatric Rating Scale. BPRS scores reflecting the psychopathological condition at the time of lumbar puncture are provided in Table 1. All CSF samples were collected for diagnostic purposes. Patients were informed that the rest of the samples would be stored and used for further research investigations. The mean age of the patients at the time of examination was 27.7 years . Control subjects were a group of 11 age-matched subjects free of diagnosable psychopathology according to DSMIV criteria. CSF was obtained for neurological differential diagnoses, revealing no significant pathological findings. All patients and subjects gave informed consent according to the Declaration of Helsinki.Lumbar punctures were done around noon, with the subjects in lying position and the needle inserted in the lumbar 4±5 interspace. Anatraumatic Sprotte needle was used to collect 15± 30 ml CSF. Routine CSF investigations were performed according to a recent European consent, including total cell count, total protein, measurement of the concentrations of albumin and IgG in CSF and serum by kinetic nephelometry, and determination of oligoclonal bands by isoelectric focusing and silver staining. An extensive virological and microbiological testing of the CSF was also performed. Samples were stored at ÿ 80 8 C for various lengths of time before analysis.We have found that CSF concentrations of anandamide and PEA, two lipid compounds that have been implicated in different aspects of endogenous cannabinoid signaling, are markedly elevated in individuals with schizophrenia compared with controls. Since anandamide is released in rat brain by activation of D 2 -family dopamine receptors, our findings may reflect a homeostatic adaptation of the endogenous cannabinoid system to neurotransmitter imbalances that involve dopamine. Such imbalances have been postulated to occur in schizophrenia. Alternatively, increased anandamide concentrations in CSF may reflect a primary hypercannabinergic’ state, which may occur in schizophrenia or in a subgroup of schizophrenic syndromes.
Although anandamide and PEA are produced in brain through a common biochemical mechanism, PEA does not bind to CB1 cannabinoid receptors and it is not released in vivo by neural activity or D 2 -receptor occupation. Pharmacological ence indicates, however, that PEA may reduce excitotoxicity in cerebellumvide and activate CB2-like receptors in peripheral tissues. Our findings, showing elevated PEA levels in schizophrenia, emphasize the need to investigate further the biochemical and pharmacological properties of this putative signaling molecule. There are several limitations and possible confounders in our study. First, like other phospholipid metabolites, anandamide and other acylethanolamides accumulate post mortem in the central nervous system . Although this phenomenon may confuse quantitative analyses in autopsy tissues, it is unlikely to account for the differences observed in CSF of schizophrenic and control subjects. In agreement with this conclusion, we found that the levels of 2-AG and oleylethanolamide, which are also increased following ischemia, are not changed in schizophrenia. Second, after release from neurons, anandamide is rapidly inactivated by highaf®nity uptake and enzymatic hydrolysis.PEA may also be a substrate for hydrolase enzymes. Thus differences in acylethanolamide levels in CSF may reflect changes in either release or inactivation of these compounds. Third, the neuronal origin of the acylethanolamides found in CSF remains conjectural. It is important to point out, however, that the predominant cannabinoid compound released by vascular cells is 2-AG, which was undetectable in CSF. Finally, although the apparent lack of correlation between antipsychotic drug exposure and acylethanolamide levels suggests that medication does not account for our observations, further studies will be needed to establish this point on a ®rmer basis.U.S. officials cultivated the malevolence assumption. The legal status of cannabis was initially transformed from a prescribed medicine into a proscribed vice by the moral entrepreneurship of the Bureau of Narcotics during the Great Depression . A 1934 Bureau report to the League of Nations, for example, asserted that “fifty percent of the violent crimes committed in districts occupied by Mexicans, Turks, Filipinos, Greeks, Spaniards, Latin Americans and Negroes may be traced to the abuse of marijuana” . Beyond stoking racial and ethnic prejudice that demonized cannabis users, the Bureau also generated fear around the effects of cannabis flood table itself.It gives men the lust to kill, unreasonably, without motive – for the sheer sake of murder itself” . In 1936, just prior to passage of the Marijuana Tax Act of 1937 that criminalized cannabis in federal law, the Bureau-sponsored film, Reefer Madness, depicted American youth smoking a few puffs of cannabis and quickly engaging in wild sex, assault, and even homicide.
When cannabis use spread among White middle-class youth in the 1960s, however, the alleged malevolence shape-shifted: Then drug control officials claimed cannabis caused not violence but an “amotivational syndrome” that sapped energy and ambition, leaving a generation of stoners.The Bureau helped lead the drive for global cannabis criminalization, which reached fruition in a 1961 UN drug control treaty . The Netherlands is a signatory to this treaty, so how did the Dutch manage—in splendid isolation until recently—to avoid the malevolence assumption and demonization and to effectively decriminalize cannabis ? Three bits of background will provide some context for Dutch decriminalization.First, the Netherlands has long been known for its culture of tolerance , which has deep roots . With nearly half their land mass below sea level, the Dutch have always faced the primal threat of inundation. But as the enemy sea could not be defeated, they learned to accommodate it with dykes, pumps, and sluices that channel it in less harmful directions. The Netherlands also has a long history of bloody religious wars, being on the front lines of Europe’s Reformation battles. Slowly the Dutch developed a pluralist state structure in which Protestants, Catholics, and later others agreed to tolerate each other under the same civic roof to the benefit of all . The pragmatic advantages of pluralism and tolerance were further highlighted by centuries of Dutch success in international trade . Add to this history the painful experience of Nazi occupation during World War II and you can see why tolerance remains woven into the cultural DNA of the Netherlands. Their pioneering move to a harm reduction drug policy was a natural extension of Dutch gedogen. Second, the officials who developed modern Dutch drug policy had an intuitive understanding of labeling theory and the risks of punitive prohibition. Their first moves toward cannabis decriminalization were based on reports from two expert national commissions in the late 1960s . Neither expressed moral approval of drug use, but both paid close attention to evidence showing that although experimentation was common, addiction was rare and controlled use was the norm. The culture of tolerance allowed both commissions to distinguish between acceptable and unacceptable risks, which led them to propose separating the market for cannabis from the market for riskier drugs. And both emphasized the importance of avoiding punishments likely to stigmatize and marginalize users, thereby intensifying their deviance and making it harder to return to socially accepted lifestyles. These consequences were the type labeling theorists hypothesized—what Lemert called “secondary deviance” and Becker described as developing deviant identities and careers. Both commissions concluded that cannabis use should be removed from the province of criminal law.Third, there is flexibility in the Dutch legal culture, starting with a preference for informal over formal social controls whenever feasible . The Dutch legal system distinguishes between law and policy and operates under “the expediency principle” , which is also part of European Union law; the words in Dutch denote something that is suitable and well timed. This principle allows prosecutors wide latitude to decide whether enforcing a law makes sense as practical policy “in the public interest” . As a matter of statutory law, cannabis remains criminalized, but the Dutch Prosecutors General have decided that enforcing that law is not expedient or practical and so have made it national policy to not enforce it. In short, Dutch policy makers had a more open juridical path to decriminalization than policy makers elsewhere.Returning to the article at hand, Jacques et al.’s beginning premise is that “prohibition undercuts the state’s regulatory capacity by producing zones of virtual statelessness” where law and legal means of dispute resolution are not available, which in turn increases the likelihood of victimization and extralegal retaliation. The Dutch Opium Act of 1976 that allowed cannabis sales and “separation of markets” was designed to reduce some of these illicit market risks and had the added virtue of constricting the geography of any potential “gateway” from cannabis to harder stuff. Jacques et al. hypothesized that illegal drug sellers would be more often victimized, and in response be least likely to mobilize law and most likely to retaliate; that legal sellers of alcohol in caf´es would be least victimized, most likely to mobilize law, and least likely to retaliate; and that the semi-licit cannabis sellers in coffee shops would fall in between.