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Background and objectives No medication has Food and Drug Administration approval for cannabis use disorder (CUD), and most medication development focuses on the withdrawal syndrome. We evaluated the effects of short-term treatment using the α-2A-adrenergic receptor agonist, guanfacine, on withdrawal symptoms in volunteers with CUD and a history of early onset of cannabis use. Methods Non-treatment-seeking healthy volunteers (n = 7) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for CUD participated in a two-phase, within-subjects study. Volunteers received placebo or guanfacine (3 mg/day) for the first 8-day inpatient study and the alternative medication for the second 8-day inpatient study. On day 1 of both treatment periods, participants received 30 mg of synthetic Δ9 -tetrahydrocannabinol for standardization of abstinence onset. On days 2 to 7, participants received study medication. Cannabis withdrawal symptoms, sleep, craving, and physiology were assessed on all inpatient days. Results Compared with placebo, guanfacine did not show significant effects on withdrawal, craving, or sleep, although there were trends for guanfacine to increase positive mood symptoms and decrease craving-associated compulsivity. Discussion and conclusions Compared with former studies, we could not prove significant improvement in sleep or decrease of negative symptoms, but we found trends for increased positive mood symptoms. Our data did not show significant effects of guanfacine on withdrawal symptoms or craving. Due to early and longer cannabis use, our subjects indicate a great severity of illness increasing the likelihood of treatment resistance. Scientific significance On the basis of trends demonstrated here and other lines of evidence, further investigation is warranted regarding the utility of guanfacine as a potential treatment for CUD. (Am J Addict 2019;00:1-10).

BACKGROUND Serotonin and norepinephrine reuptake inhibitors are effective first-line agents for the treatment of posttraumatic stress disorder (PTSD), but treatment is associated with a range of side effects that limit treatment adherence. Prazosin, an α1-noradrenergic antagonist with a half-life of roughly 2-3 hours, has shown promise in the treatment of sleep disturbance and nightmares. Doxazosin extended release (XL) is also an α1-noradrenergic antagonist but with a half-life of approximately 15-19 hours. METHODS We conducted a double-blind, placebo-controlled, within-subjects trial to characterize the impact of doxazosin XL on PTSD symptoms. Participants (N = 8) were diagnosed using DSM-IV criteria. They completed the study twice, once during treatment with doxazosin XL and once during treatment with matched placebo, with a 2-week washout separating the 2 episodes. Doxazosin XL was titrated from 4 mg/d to 16 mg/d over 12 days. After 4 days of treatment at 16 mg/d or the equivalent number of placebo capsules, PTSD symptoms were assessed using the Clinician-Administered PTSD Scale (CAPS17) and the PTSD Checklist-Military version (PCL-M). Repeated measures analysis of variance were used to evaluate effects of treatment, time, and treatment × time. This study was run from November 20, 2013, to June 31, 2014. RESULTS Doxazosin XL treatment was associated with a nonsignificant treatment × time reduction in ratings on the CAPS hyperarousal subscale (P < .10) (but not on the CAPS Total score) and with significant treatment × time reductions in PCL-M ratings (P = .002). CONCLUSIONS Doxazosin XL may be an effective alternative to prazosin for the treatment of some PTSD symptoms. TRIAL REGISTRATION ClinicalTrials.gov Identifier:NCT02308202.

The cannabinoid-1 receptor (CB1R) agonist Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, adversely effects working memory performance in humans. The α2A-adrenoceptor (AR) agonist guanfacine improves working memory performance in humans. The authors aimed to determine the effects of short-term (6 days) treatment with guanfacine on adverse cognitive effects produced by THC. Employing a double-blind, placebo-controlled crossover design, the cognitive, subjective, and cardiovascular effects produced by oral THC (20 mg) administration were determined twice in the same cannabis users: once after treatment with placebo and once after treatment with guanfacine (3 mg/day). Compared with performance at baseline, THC negatively affected accuracy on spatial working memory trials while participants were maintained on placebo (p=0.012) but not guanfacine (p=0.497); compared with placebo, accuracy was significantly (p=0.003, Cohen's d=-0.640) improved while individuals were treated with guanfacine. Similarly, compared with baseline, THC increased omission errors on an attentional task while participants were maintained on placebo (p=0.017) but not on guanfacine (p=0.709); compared with placebo, there were significantly (p=0.034, Cohen's d=0.838) fewer omissions while individuals were maintained on guanfacine. Although THC increased visual analog scores of subjective effects and heart rate, these increases were similar during treatment with placebo and guanfacine. THC did not significantly affect performance of a recognition memory task or blood pressure while individuals were maintained on either treatment. Although preliminary, these results suggest that guanfacine warrants further testing as a potential treatment for cannabis-induced cognitive deficits.

During the period of tobacco smoke research from the early 1950s to the mid-1960s it was repeatedly asserted that a) tobacco and many tobacco components were involved in the pyrogenesis of polycyclic aromatic hydrocarbons (PAHs), several of which were reported to initiate tumors on the skin of laboratory animals and b) tobacco additives (flavorants, casing materials, humectants) were highly likely to be similarly involved in PAH pyrogenesis. Extensive knowledge on PAHs was deemed highly necessary because of their claimed importance in the smoking-health issue. The numerous assertions about the generation of PAHs in cigarette mainstream smoke (MSS) triggered extensive and intensive research both within and outside the Tobacco Industry to define the nature of the PAHs, their per cigarette MSS delivery amounts, their precursors, etc. It was not until 1960 that VAN DUUREN et al. (1) reported three specific aza-arenes in cigarette MSS that were asserted to be involved in smokers’ respiratory tract cancer. As noted in a recent Letter to the Editors (2), the presence of these three aza-arenes in tobacco smoke has never been confirmed. Between 1960 and 1965, other MSS components (phenols as promoters, polonium-210, N-nitrosamines, ciliastatic compounds) were asserted to be responsible for smoking related diseases. However, no major assertions were made that phenols, polonium-210, or the N-nitrosamines were derived from flavorants, casing materials, or humectants. Some investigators did report that several ciliastats were derived from added sugars and glycerol. The ciliastat proposal was drastically diminished in importance by the findings in the 1960s that only a relatively small proportion of the ciliastats reached the smoker's cilia. During that time, pertinent skills and competencies in research on tobacco smoke composition, particularly the PAH fraction, have been developed. Such skills permitted the isolation in crystalline form of 14 PAHs and the quantitation of these and many other PAHs. They were also used to put in perspective the pyrogenesis of PAHs from a) specific tobacco components, b) additives, and c) processed tobaccos (reconstituted tobacco sheet [RTS], expanded tobacco). R.J. Reynolds Tobacco Company (RJRT) pioneered the use of RTS (1953) and expanded tobaccos (1969) in cigarette blends and generated much previously unpublished data on the effect of such processed tobaccos on MSS composition.

Hurricane Katrina was a devastating event to New Orleans. There was a mandatory evacuation of the city during which victims in affected areas were not allowed to return for months. Many residents were unable to return to their previous residence due to the destruction of their home or change in ownership. In its aftermath, a phenomenon of displaced residents becoming psychotic and returning to their pre-Katrina homes that they no longer owned became apartment. While the clinical ramifications of these behaviors remain unclear, in the wake of Hurricane Sandy monitoring of psychotic patients for similar behaviors may be warranted. We present two such cases of this phenomenon, colloquially called “Post-Katrina Syndrome” by psychiatrists in the New Orleans area.

Authored by two longtime researchers in tobacco science, The Chemical Components of Tobacco and Tobacco Smoke, Second Edition chronicles the progress made from late 2008 through 2011 by scientists in the field of tobacco science. The book examines the isolation and characterization of each component. It explores developments in pertinent analytical

The draft initial list of harmful or potentially harmful tobacco and/or smoke components prepared by the Constituent Subcommittee of the Tobacco Products Scientific Advisory Committee (TPSAC) differs significantly from the similar lists prepared by Hoffmann and colleagues who had over four decades of experience and knowledge in tobacco and/or tobacco smoke components and their chemical and biological properties. The draft list comprises 106 components, 60 of which were included in the recent Hoffmann et al. lists but does not include nine of the Hoffmann-listed components. All of the 106 components appear in a list by Rodgman and Green of 162 tobacco and/or tobacco smoke components, each of which was defined as biologically adverse at one time or another over the previous years by one or more investigators. As with the Hoffmann et al. lists, the list by the TPSAC Constituent Subcommittee contains numerous anomalies. · Three harmful components (dibenz[a, j]acridine, dibenz[a, h]acridine, 7H-dibenzo[c, g]carbazole) first reported in tobacco smoke in the 1960s that were not confirmed over the next forty years by many talented investigators in Japan, Germany, and the USA, including several at the U.S. Department of Agriculture (USDA). · Two harmful components (arsenic, N-nitrosodiethanolamine) the levels of which have decreased significantly because their precursors have not been used in tobacco agronomy for over three decades. · The many water-soluble components that reach the lung at a much reduced level to exert their ciliastasis. · A component (chrysene) that the International Agency for Research on Cancer (IARC) has removed from its tumorigenicity listing, a decision accepted by Hoffmann et al. who removed chrysene from their more recent tobacco/tobacco smoke listings of adverse components. TPSAC gives no indication of the following: · The relationship between the per cigarette delivery of some of the harmful components and their level of permissibility by Occupational Safety & Health Administration (OSHA). · The components on its list that significantly offset the adverse biological activity of several others of its listed components. · Many components in tobacco and/or tobacco smoke not listed by TPSAC have been reported to significantly reduce the adverse biological effect of several components on the TPSAC list plus several others.

Tobacco and tobacco smoke are both complex mixtures. We previously reported 8430 unique chemical components identified in these complex mixtures but two years later our updated number was 8889. Addition of unlisted isomers raised these numbers to 8622 and 9081, respectively. Our previous number of 4994 identified tobacco components is now 5229; our previous number of 5315 identified tobacco smoke components is now 5685. An operational definition of a complex mixture is as follows: A complex mixture is a characterizable substance containing many chemical components (perhaps thousands) in inexact proportions. Detailed knowledge of the amount and type of each component within the substance is uncertain even with today's analytical technology. Although it has been estimated that as many as 100000 components are present in these complex mixtures, their analyses indicate that the vast majority of the mass of each of these complex mixtures accounts for the 8430 compounds reported previously. Over 98.7% of the mass of tobacco has been accounted for in terms of identified components in tobacco. Greater than 99% of the mass of whole smoke has been accounted for based on identified chemical components. Certainly, many more tobacco and tobacco smoke components are present in these complex mixtures but the total mass of these components obviously is quite small. One of the significant challenges we face as a scientific community is addressing the problems of determining the risk potential of complex mixtures. Many issues are associated with toxicological testing of the complex mixture of tobacco smoke. Conducting valid experiments and interpreting the results of those experiments can be quite difficult. Not only is the test agent a complex mixture but also the tests are performed on species that have complicated life-processes. Interpretations of test results are often paradoxical. Significant progress has been made in the toxicological evaluations of complex mixtures in the last 80 years. The challenges we face in terms of testing the biological properties of tobacco smoke are substantial. The statement by DIPPLE et al. in their summary of the research on polycyclic aromatic hydrocarbons from the 1930s through 1980 is equally true today for the cigarette smoke situation: …many important questions remain unanswered …many questions persist despite the considerable progress that has been made.

Because of the significant advancements in fractionation, analytical, and characterization technologies since the early 1960s, hundreds of components of complex mixtures have been accurately characterized without the necessity of actually isolating the individual component. This has been particularly true in the case of the complex mixtures tobacco and tobacco smoke. Herein, an historical account of a mid-1950 situation concerning polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke is presented. While the number of PAHs identified in tobacco smoke has escalated from the initial PAH, azulene, identified in 1947 to almost 100 PAHs identified by late 1963 to more than 500 PAHs identified by the late 1970s, the number of PAHs isolated individually and characterized by several of the so-called classical chemical means (melting point, mixture melting point, derivative preparation and properties) in the mid-1950s and since is relatively few, 14 in all. They were among 44 PAHs identified in cigarette mainstream smoke and included the following PAHs ranging from bicyclic to pentacyclic: Acenaphthylene, 1,2-dihydroacenaphthylene, anthracene, benz[a]anthracene, benzo[a]pyrene, chrysene, dibenz[a, h]anthracene, fluoranthene, 9H-fluorene, naphthalene, 1-methylnaphthalene, 2-methylnaphthalene, phenanthrene, and pyrene. One of them, benzo[a]pyrene, was similarly characterized in another study in 1959 by Hoffmann.

Dyke-Davidoff-Masson syndrome is a disorder involving hemiatrophy or hypoplasia of 1 cerebral hemisphere secondary to an insult in the developing brain. Often this will manifest with seizures, hemiparesis, mental retardation, and facial changes. Associated with this pathology are the radiologically evident changes, such as thickening of the calvarium, hyperpneumatization of the sinuses, and dilation of the ipsilateral lateral ventricle among others. The following is a case presentation of an 18-year-old female emigrating from Ghana who presented to the emergency department with complaints of seizures diagnosed as being caused by cerebral malaria at 13 years of age. We hypothesize that the cerebral malaria and related vascular occlusion are the causes of her acquired cerebral changes. Included are computed tomography images.

For nearly four decades, the expansion of tobacco has been recognized as one of eight technologies significant in the design of a ‘less hazardous’ cigarette. The data previously presented at scientific conferences and/or published in several scientific monographs and journals on the effect of the expansion of tobacco on the composition and biological properties of the mainstream smoke from cigarettes containing it are summarized. In addition, previously unpublished data on the same subjects are presented in considerable detail. Included are 1) the effect of tobacco expansion on the yields of total particulate matter (TPM), nicotine, and several hundred components of cigarette mainstream smoke from control tobacco cigarettes vs. expanded tobacco cigarettes; 2) the changes in mainstream smoke yields of total particulate matter, nicotine, and specific smoke components produced by inclusion of various levels of expanded tobacco in a cigarette blend; and 3) the changes in composition of expanded tobacco. In the latter study, the decrease in levels of numerous significant flavorful components of the tobacco produced by expansion provides the need for inclusion of such compounds in flavor formulations. In study 2), the reductions in per cigarette yields of total particulate matter, nicotine, and several components of concern were determined and confirmed the significance of tobacco expansion as a cigarette design technology to produce what was originally defined as a ‘less hazardous’ cigarette but more recently as a ‘potential reduced exposure product’ (PREP).

A la fin des annees 1970, de nouvelles technologies de conception d'une cigarette « moins dangereuse » ont ete considerees comme importantes. Au nombre de huit (8) elles impliquent: le melange de tabac, le bout filtre, des additifs du bout filtres, le tabac reconstitue, des additifs du papier a cigarette, la ventilation d'air par la porosite du papier, le tabac expanse et la dilution d'air par la perforation du bout filtre. En plus de ces huit methodes pour la conception de cigarettes, une autre technologie a ete proposee comportant l'incorporation d'un substitut pour une partie ou la totalite du tabac de la cigarette. Malgre des efforts considerables de recherche et de developpement de substituts de tabac, correspondant dans la plupart des cas a la definition d'une cigarette « moins dangereuse » en ce qui concerne les proprietes chimiques et biologiques de la fumee principale, les cigarettes contenant des substituts de tabac n'ont pas reussit a etre acceptee par les fumeurs. En consequence., les produits contenant des substituts de tabac ont ete disponibles sur le marche que pendant tres peu de temps. Cette etude presente un resume des recherches sur la composition de la fumee principale de cigarettes contenant un substitut complet de tabac, une cigarette comportant divers substituts et melanges de tabac, et d'une cigarette faite de tabac normal.

Among the polycyclic aromatic hydrocarbons (PAHs), a major class of identified cigarette mainstream smoke (MSS) components, are several shown to be tumorigenic in laboratory animals and suspect as possible tumorigens to humans. To date, nearly 540 PAHs have been completely or partially identified in tobacco smoke [Rodgman and Perfetti (1)]. A detailed chronology is presented of studies on four much discussed PAHs identified in tobacco smoke, namely, benz[a]anthracene (B[a]A), its 7,12-dimethyl derivative (DMB[a]A), dibenz[a, h]anthracene (DB[a, h]A), and benzo[a]pyrene (B[a]P). Of the four, DMB[a]A, DB[a, h]A, and B[a]P are considered to be potently tumorigenic on mouse skin painting and subcutaneous injection. Opinions on the tumorigenicity of B[a]A to mouse skin vary. DMB[a]A is frequently used in tumorigenicity studies as an initiator. Examination of the number of tobacco smoke-related citations listed for these four PAHs reveals the enormous effort devoted since the early 1950s to B[a]P vs. the other three. An annotated chronology from 1886 to date describes the tobacco smoke-related research pertinent to these four PAHs, their discovery, isolation and/or identification, quantitation, and contribution to the observed biological activity of MSS or cigarette smoke condensate (CSC). Much of the major literature on these four PAHs in tobacco smoke is presented in order to permit the reader to decide whether the current evidence is sufficient to classify them as a health risk to smokers. There has certainly been a tremendous effort by researchers to learn about these PAHs over the past several decades. Each of these PAHs when tested individually has been shown to possess the following biological properties: 1) Mutagenicity in certain bacterial situations, 2) tumorigenicity in certain animal species, to varying degrees under various administration modes, and 3) a threshold limit below which no tumorigenesis occurs. For more than five decades, it has been known that some of the PAHs, when co-administered in pairs of a potent tumorigen plus a non-tumorigen or weak tumorigen, show inhibitory effects on the tumorigenicity of the most potent, e.g., B[a]A plus DB[a, h]A; B[a]A plus B[a]P; anthracene plus DB[a, h]A. Over the period studied, some regulatory agencies considered these tobacco smoke PAHs to be serious health concerns, others did not. With respect to cigarette MSS, certainly the ‘danger is in the dose’ for any MSS component tested singularly to be tumorigenic. But is the level of any of these MSS PAHs high enough to be of concern to smokers? The information herein presented indicates that over the last five decades the following has occurred: 1) The per cigarette yields of these four PAHs have decreased substantially, 2) compared to CSC or Federal Trade Commission (FTC) ‘tar’, their per cigarette yields have also decreased to a point that they may be below any significance biologically, and 3) the specific tumorigenicity in mouse skin-painting studies of the CSC has decreased. These are the three criteria originally proposed to define the ‘less hazardous’ cigarette. Actually, criterion 1) was first directed only at B[a]P. Previous studies highlighted the concern that some regulatory bodies had in attempting to understand why lung cancer and other forms of cancer seemed more prevalent in smokers. But cigarette smoking alone could not reconcile the evidence. Social, ethnic, environmental, and economic factors are also very important in understanding the entire biological effect. In fact, the level of B[a]P in CSC could only explain about 2% of its specific tumorigenicity observed in skin-painted mice and the combination of the levels of all the known tumorigenic PAHs in CSC could only explain about 3% of its tumorigenicity. Despite an 18-month study in the late 1950s, the search for a ‘supercarcinogen’ in MSS and CSC to explain the observed biological effects was unsuccessful. In addition, the exceptional study on MSS PAHs by United States Department of Agriculture (USDA) personnel in the 1970s indicated no ‘supercarcinogen’ was present. Only recently has the concept of complex mixtures in relation to the understanding of the complexity of carcinogenesis taken hold. Perhaps the reason why MSS is less tumorigenic than expected in humans is because of the presence of other MSS components that inhibit or prevent tumorigenesis. For example, it is well known that MSS contains numerous anticarcinogens present in quantities significantly greater than those of the PAHs of concern. When one reviews the history of these four PAHs in MSS or CSC it is clear that many unanswered questions remain.

Les hydrocarbures polynucleaires aromatiques (PAHs), contenus dans de nombreuses substances auxquelles l'homme est expose, sont classifies comme toxiques. Parmi ces expositions comptent les polluants de l'air de sources multiples, l'alimentation, les boissons ou la fumee du tabac. Depuis le debut des annees 1950, la composition chimique de cette derniere a ete analysee de facon plus approfondie que tout autre produit de consommation. Environ 4800 substances ont ete identifiees dans la fumee du tabac et parmi celles-ci plus de 500 PAHs completement ou partiellement identifiees. Due a la tumorigenicite de nombreux PAHs, beaucoup d'etudes ont ete menees en vue d'examiner la relation entre les structures des PAHs et leurs tumorigenicites specifiques chez les animaux de laboratoire. Jusqu'a present aucune de ces theories n'explique completement toutes les questions. Une approche dans le but de developper une relation plus raisonnable entre la structure et la tumorigenicite des PAHs, est la classification des PAHs completement ou partiellement identifies. Dans ce catalogue, les PAHs sont classifies comme bicycliques, tricycliques, tetracycliques, etc., chaque groupe etant subdivise en PAHs benzenoid et cyclopentanoid-benzenoid. Un autre catalogue comprend les PAHs examines dans des etudes anterieures sur la relation entre la structure et la tumorigenicite, surtout des PAHs benzenoid.

In the mid-1980s, each major US cigarette manufacturer prepared a list of those ingredients added at that time to its cigarette products. The lists were combined into one and submitted to the US Office of Smoking and Health in 1986. It comprised 599 entities. On the basis of extensive literature survey and examination of much unpublished data from the Tobacco Industry members on the chemistry and toxicology of the ingredients, a panel of eminent toxicologists assessed the safety of each listed ingredient with regard to its pyrolysate components and its possible effect when added to cigarette tobacco on the chemical and biological properties of the cigarette mainstream smoke. Subsequently, Doull et al. listed the 599 ingredients and summarized the conclusions of the panel on their effect on the chemical and biological properties of cigarette smoke. In addition to the panel and Doull et al., other investigators have noted that many of the compounds used as ingredients in cigarette tobacco blends are identical with or similar to identified components of tobacco and/or tobacco smoke. The validity of this statement is obvious when the compounds in the Doull et al. list are cataloged as in Table 1. Those tobacco ingredients that are not individual compounds but are naturally-occurring oils, resins, etc. or extracts of naturally-occurring materials not only contain many of the compounds listed by Doull et al. as tobacco additives but also contain many of the same compounds present in tobacco. Detailed examination of the literature on the chemical and biological properties of the recently used tobacco ingredients listed by Doull et al. plus a massive amount of chemical and biological data generated during the past several decades indicates that not only does none of the Doull et al. listed ingredients contribute any significant adverse chemical properties to cigarette mainstream smoke (MSS) but also none affects adversely the biological properties of the MSS. The chemical factors examined included: a) The effect on MSS composition of the ingredients added to cigarette tobacco at the usual use level or several times that. In two major series of studies, one by Carmines et al. and one by Baker et al., the effect of the added ingredient on the concentration in mainstream smoke of specific components defined as toxicants was determined. The Carmines et al. study involved analysis of the smoke components suggested by the US Consumer Product Safety Commission and of concern to the International Agency for Research on Cancer (IARC). The Baker et al. study involved analysis of the so-called ‘Hoffmann analytes’ in cigarette smoke. b) The nature of the pyrolysis products generated during the smoking process or during pyrolysis of an individual ingredient under conditions approximating those in the cigarette pyrolysis zone. In many instances when the added ingredient is a compound, a significant percentage of it is transferred unchanged to the MSS and sidestream smoke (SSS). The small percentage not transferred intact to the smoke is seldom converted to an MSS component possessing significant toxic properties. The extensive biological studies that showed no significant adverse effect of the MSS from ingredient-containing cigarettes included: a) The specific tumorigenicity to laboratory animal skin of the mainstream cigarette smoke condensate (CSC) from ingredient-containing cigarettes vs. the mainstream CSC from ingredient-free cigarettes. b) Exposure of laboratory animals via inhalation to the MSS from ingredient-containing cigarettes vs. the MSS from ingredient-free cigarettes. c) Determination in a variety of tests of the in vitro genotoxicity of the mainstream particulate phase and/or vapor phase. In addition, the results of non-tobacco-related studies are available in which many individual compounds on the Doull et al. list were assayed for mutagenicity in the Ames test with several strains of Salmonella typhimurium. An excellent example is the 1984 study by Ishidate et al. who examined the mutagenicity of many compounds included as additives in Japanese foods. Over 40 of the compounds exhibiting non-mutagenicity also occur on the Doull et al. tobacco ingredient list. Assessment of the total chemical and biological data cited herein provides a noteworthy contradiction to the much repeated assertions - with no data supporting them - that the ingredients added to cigarette tobacco result in significant adverse changes in the chemical and biological properties of the cigarette MSS.