The legalization of cannabinoid products and standardizing cannabis-drug development in the United States: a brief report
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This brief report covers recent advances in cannabis and cannabinoid regulation and drug approval. The popularity of cannabis and cannabinoid products continues to rise, and these products are available for the majority of the population in the United States to purchase as easily as alcohol. Although many states have approved programs and research licenses, these activities and products all remain federally illegal. The solution may be for the United States to offer multiple pathways for product approval that adapt to the diversity of the products and the needs of the consumer. Multiple pathways for market approval would protect public health, whether the public is using cannabis and cannabinoids as a medicine, a wellness product, or as a recreational substance.
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Este breve informe cubre los avances recientes en la regulación del cannabis y los cannabinoides y en la aprobación de medicamentos. La popularidad del cannabis y de los productos cannabinoides continúa aumentando. Estos productos están disponibles para la mayoría de la población en los Estados Unidos y se pueden comprar tan fácilmente como el alcohol. Aunque muchos estados han aprobado programas y licencias de investigación, estas actividades y productos siguen siendo ilegales a nivel federal. La solución para Estados Unidos sería ofrecer múltiples vías para la aprobación de productos que se adaptarían a la diversidad de los productos y las necesidades del consumidor. Estas múltiples vías para la aprobación del mercado protegerían la salud pública, ya sea que el público esté utilizando cannabis y cannabinoides como medicamento, producto de bienestar o o sustancia recreativa.

Ce rapport couvre les progrès récents dans la réglementation du cannabis et des cannabinoïdes et l'approbation des médicaments. La popularité du cannabis et des dérivés cannabinoïdes continue d'augmenter, et ces produits sont disponibles pour la majorité de la population aux États-Unis, où ils s'achètent aussi facilement que l'alcool. Bien que de nombreux états aient approuvé des programmes et les licences de recherche, ces activités et produits demeurent tous illégaux au niveau fédéral. La solution pourrait être pour les États-Unis d'offrir plusieurs voies d'approbation qui s'adaptent à la diversité des produits et aux besoins du consommateur. Plusieurs voies d'approbation du marché protégeraient la santé publique, que le cannabis et les cannabinoïdes soient consommés en tant que médicament, produit de bien-être ou substance récréative.

Adolescent treatment admissions for marijuana following recreational legalization in Colorado and Washington.

INTRODUCTION: There is concern that recreational marijuana legalization (RML) may lead to increased cannabis use disorder (CUD) among youth due to increased marijuana use. This study investigates whether adolescent substance use disorder treatment admissions for marijuana use increased in Colorado and Washington following RML. METHODS: Annual data on 2008-2017 treatment admissions for marijuana use from the SAMHSA TEDS-A dataset for adolescents age 12-17 were used to model state treatment admissions trends. Difference-in-differences models were used to investigate whether treatment admissions increased following RML in Colorado/Washington compared to non-RML states, after adjusting for socioeconomic characteristics and treatment availability. RESULTS: Over all states in the analysis, the rate of adolescent treatment admissions for marijuana use declined significantly over the study period (ß=-3.375, 95 % CI=-4.842, -1.907), with the mean rate falling nearly in half. The decline in admissions rate was greater in Colorado and Washington compared to non-RML states following RML, though this difference was not significant (ß=-7.671, 95 % CI=-38.798, 23.456). CONCLUSION: Adolescent treatment admissions for marijuana use did not increase in Colorado and Washington following RML. This may be because youth marijuana use did not increase, CUD did not increase (even if use did increase), or treatment seeking behaviors changed due to shifts in attitudes and perceptions of risk towards marijuana use.

Drug Legalization and Decriminalization Beliefs Among Substance-using and Nonusing Individuals.

OBJECTIVES: There has been advocacy for legalization of abusable substances, but systematic data on societal beliefs regarding such legalization are limited. People who use substances may have unique beliefs about legalization, and this study assessed whether they would be in favor of drug legalization/decriminalization. It was hypothesized that those who use particular drugs (especially marijuana) would support its legalization/decriminalization, but that this would not be the case across all classes (especially opioids and stimulants). METHODS: A nationwide sample of 506 adults were surveyed online to assess demographic characteristics, substance misuse, and beliefs regarding drug legalization/decriminalization. Legalization/decriminalization beliefs for specific drugs were assessed on an 11-point scale (0, strongly disagree; 10, strongly agree). RESULTS: For persons with opioid misuse (15.4%), when asked about their agreement with: "heroin should be legalized," the mean score was 4.6 (SEE = 0.4; neutral). For persons with stimulant misuse (12.1%), when asked about their agreement with: "cocaine should be legalized," the score was 4.2 (0.5). However, for persons with marijuana misuse (34.0%), when asked about their agreement with: "medical marijuana should be legalized" the score was 8.2 (0.3; indicating agreement), and for "recreational marijuana" the score was also 8.2 (0.3). CONCLUSIONS: These results suggest that persons who used marijuana strongly support the legalization of both recreational and medical marijuana, whereas persons who primarily have opioid or stimulant misuse have less strongly held beliefs about legalization of substances within those respective categories. By including those who misuse drugs, these data assist in framing discussions of drug legalization and have the potential to inform drug policy considerations.

Association between cannabis laws and opioid prescriptions among privately insured adults in the US.

We examine the association between opioid prescription patterns in privately insured adults and changes in state cannabis laws among five age groups (18-25, 26-35 36-45, 46-55 and 56-64 years). Using the 2016 Clinformatics Data Mart, a nationwide commercial health insurance database, we performed a cross-sectional analysis of two types of opioid prescribing (>30-day and >90-day prescriptions) among all adults aged 18-64 based on the stringency of cannabis laws. We found a significant interaction between age and cannabis law on opioid prescriptions. Age-stratified multilevel multivariable analyses showed lower opioid prescription rates in the four younger age groups only in states with medical cannabis laws, when considering both >30 day and >90 day opioid use [>30 day adjusted odds ratio (aOR) = 0.56, in 18-25, aOR = 0.67 in 26-35, aOR = 0.67 in 36-45, and aOR = 0.76 in 46-54 years; >90 day aOR = 0.56, in 18-25, aOR = 0.68 in 26-35, aOR = 0.69 in 36-45, and aOR = 0.77 in 46-54 years, P < 0.0001 for all]. This association was not significant in the oldest age group of 55-64 years. There was no significant association between opioid prescriptions and other categories of cannabis laws (recreational use and decriminalization) in any of the age groups studied.

Impact of Medical Marijuana Legalization on Opioid Use, Chronic Opioid Use, and High-risk Opioid Use.

OBJECTIVE: To determine the association of medical marijuana legalization with prescription opioid utilization. METHODS: A 10% sample of a nationally representative database of commercially insured population was used to gather information on opioid use, chronic opioid use, and high-risk opioid use for the years 2006-2014. Adults with pharmacy and medical benefits for the entire calendar year were included in the population for that year. Multilevel logistic regression analysis, controlling for patient, person-year, and state-level factors, were used to determine the impact of medical marijuana legalization on the three opioid use measures. Sub-group analysis among cancer-free adults and cancer-free adults with at least one chronic non-cancer pain condition in the particular year were conducted. Alternate regression models were used to test the robustness of our results including a fixed effects model, an alternate definition for start date for medical marijuana legalization, a person-level analysis, and a falsification test. RESULTS: The final sample included a total of 4,840,562 persons translating into 15,705,562 person years. Medical marijuana legalization was found to be associated with a lower odds of any opioid use: OR = 0.95 (0.94-0.96), chronic opioid use: OR = 0.93 (0.91-0.95), and high-risk opioid use: OR = 0.96 (0.94-0.98). The findings were similar in both the sub-group analyses and all the sensitivity analyses. The falsification tests showed no association between medical marijuana legalization and prescriptions for antihyperlipidemics (OR = 1.00; CI 0.99-1.01) or antihypertensives (OR = 1.00; CI 0.99-1.01). CONCLUSIONS: In states where marijuana is available through medical channels, a modestly lower rate of opioid and high-risk opioid prescribing was observed. Policy makers could consider medical marijuana legalization as a tool that may modestly reduce chronic and high-risk opioid use. However, further research assessing risk versus benefits of medical marijuana legalization and head to head comparisons of marijuana versus opioids for pain management is required.

Marijuana Use in the Era of Changing Cannabis Laws: What Are the Risks? Who is Most at Risk?

We review recent findings on medical aspects of marijuana use in order to identify those who are at greatest risk of marijuana-related medical problems. We analyze the impact of medical marijuana laws on health, in particular the disproportionate effects on adolescents and children. Chronic marijuana use predominantly affects certain areas of the brain that overlap the default mode network, linked hubs in the brain that play a supervisory role in critical thought processes such as attention, memory, and social interactions. Disruption of the default mode network areas has been documented in schizophrenia and Alzheimer's disease, illnesses with symptoms and brain changes that parallel findings in marijuana abusers. These findings counter the claim that marijuana is a harmless drug and are a cause for alarm in persons with cannabis dependence.

Medical use of cannabis: Italian and European legislation.

This review illustrates some brief considerations of the medical use of cannabis recently issued in Italy. History and uses of cannabis throughout centuries and different countries are illustrated together with a description of botany and active phytocannabinoids. Then, medical use of cannabis anti-pain treatment for patients resistant to conventional therapies is described in case of chronic neuropathic pain, spasticity, for anticinetosic and antiemetic effect in nausea and vomiting caused by chemotherapy, for appetite stimulating effect in cachexia, anorexia, loss of appetite in cancer patients or patients with AIDS and in anorexia nervosa, hypotensive effect in glaucoma resistant to conventional therapies and for reduction of involuntary body and facial movements in Gilles de la Tourette syndrome. Italian most recent legislation on medical cannabis is detailed with some law proposals, also showing the inconsistent legislation within European Union. Some final considerations of future studies are also reported.

Propuestas de regulación del uso terapéutico de los productos derivados del cannabis / Proposals for the regulation of the therapeutic use of products derived from cannabis

En las últimas décadas en España se ha producido un movimiento de la sociedad civil reivindicando la regulación del consumo, cultivo y distribución del cannabis. Al mismo tiempo, se ha reclamado reiteradamente, tanto por pacientes, asociaciones de pacientes y distintos profesionales, la regulación del uso terapéutico del cannabis y de los productos derivados, que en nuestro país carece de una regulación específica. El presente estudio tiene como finalidad ofrecer con carácter general las propuestas que en la legislación española existen acerca del uso terapéutico del cannabis y productos derivados. La exigua legislación que se aplica a dicho uso deriva de la Convención Única de 1961 de Estupefacientes y su protocolo; en esta legislación se permite que el THC se pueda dispensar en oficinas de farmacia con receta médica y que pueda ser objeto de investigación médica o científica, con la preceptiva autorización. Por lo que parece que en nuestro país se encuentra permitido el uso terapéutico del cannabis, aunque sometido a requisitos muy estrictos. Sin embargo, esta normativa resulta insuficiente para regular todos los aspectos que se pueden derivar del uso terapéutico del cannabis, por cuanto se ha puesto de relieve que hay unas limitaciones importantes en cuanto al uso que se realiza del mismo y en cuanto al acceso, lo que determina que existan vacíos legales que requieren de una regulación más concreta. Esto ha motivado la presentación, tanto en el ámbito autonómico como en el estatal, de diversas propuestas de creación de comisiones y comités que estudien en profundidad dicho uso, y de regulación del uso terapéutico del cannabis, que todavía no se han materializado en una normativa concreta

In recent decades in Spain there has been a movement of civil society demanding the regulation of consumption, cultivation and distribution of cannabis. At the same time, regulation of the therapeutic use of cannabis and derived products has been repeatedly demanded by patients, patient associations and different professionals, which in our country lacks specific regulation. The present study has as a general purpose to offer the proposals that in Spanish legislation exist on the therapeutic use of cannabis and derived products. The meager legislation that applies to such use derives from the 1961 Single Convention on Narcotic Drugs and its protocol; This legislation allows THC to be dispensed in pharmacies with a medical prescription and that can be the subject of medical or scientific research, with the required authorization. It seems that in our country is allowed the therapeutic use of cannabis, although subject to very strict requirements. However, this legislation is insufficient to regulate all aspects that can be derived from the therapeutic use of cannabis, since it has been emphasized that there are important limitations in the use that is made of it and in terms of access, Which determines that there are legal loopholes that require more concrete regulation. This has motivated the presentation, both in the autonomous and in the state, of various proposals for the creation of commissions and committees that study in depth such use, and regulation of the therapeutic use of cannabis, which have not yet materialized in legislation concrete

Support for marijuana legalization in the US state of Washington has continued to increase through 2016.

BACKGROUND: Support for the legalization of recreational marijuana continues to increase across the United States and globally. In 2016, recreational marijuana was legalized in the most populous US state of California, as well as three other states. The primary aim of this study was to examine trends in support for recreational marijuana legalization in Washington, a state which has had legal recreational marijuana for almost four years, using data collected over the four years post-legalization. A secondary aim was to examine trends in support for the cultivation of marijuana for personal use. METHODS: Data come from geographically representative general population samples of adult (aged 18 and over) Washington residents collected over five timepoints (every six months) between January 2014 and April 2016 (N=4101). Random Digit Dial was used for recruitment. Statistical analyses involved bivariate comparisons of proportions across timepoints and subgroups (defined by age, gender, and marijuana user status), and multivariable logistic regression controlling for timepoint (time) to formally test for trend while controlling for demographic and substance use covariates. All analyses adjusted for probability of selection. RESULTS: Support for legalization in Washington has significantly increased: support was 64.0% (95% CI: 61.2%-67.8%) at timepoint 1 and 77.9% (95% CI: 73.2%-81.9%) at timepoint 5. With each six months' passing, support increased 19% on average. We found no statistically significant change in support for home-growing. CONCLUSIONS: Support for marijuana legalization has continued to significantly increase in a state that has experienced the policy change for almost four years.

US Adult Illicit Cannabis Use, Cannabis Use Disorder, and Medical Marijuana Laws: 1991-1992 to 2012-2013.

Importance: Over the last 25 years, illicit cannabis use and cannabis use disorders have increased among US adults, and 28 states have passed medical marijuana laws (MML). Little is known about MML and adult illicit cannabis use or cannabis use disorders considered over time. Objective: To present national data on state MML and degree of change in the prevalence of cannabis use and disorders. Design, Participants, and Setting: Differences in the degree of change between those living in MML states and other states were examined using 3 cross-sectional US adult surveys: the National Longitudinal Alcohol Epidemiologic Survey (NLAES; 1991-1992), the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; 2001-2002), and the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III; 2012-2013). Early-MML states passed MML between NLAES and NESARC ("earlier period"). Late-MML states passed MML between NESARC and NESARC-III ("later period"). Main Outcomes and Measures: Past-year illicit cannabis use and DSM-IV cannabis use disorder. Results: Overall, from 1991-1992 to 2012-2013, illicit cannabis use increased significantly more in states that passed MML than in other states (1.4-percentage point more; SE, 0.5; P = .004), as did cannabis use disorders (0.7-percentage point more; SE, 0.3; P = .03). In the earlier period, illicit cannabis use and disorders decreased similarly in non-MML states and in California (where prevalence was much higher to start with). In contrast, in remaining early-MML states, the prevalence of use and disorders increased. Remaining early-MML and non-MML states differed significantly for use (by 2.5 percentage points; SE, 0.9; P = .004) and disorder (1.1 percentage points; SE, 0.5; P = .02). In the later period, illicit use increased by the following percentage points: never-MML states, 3.5 (SE, 0.5); California, 5.3 (SE, 1.0); Colorado, 7.0 (SE, 1.6); other early-MML states, 2.6 (SE, 0.9); and late-MML states, 5.1 (SE, 0.8). Compared with never-MML states, increases in use were significantly greater in late-MML states (1.6-percentage point more; SE, 0.6; P = .01), California (1.8-percentage point more; SE, 0.9; P = .04), and Colorado (3.5-percentage point more; SE, 1.5; P = .03). Increases in cannabis use disorder, which was less prevalent, were smaller but followed similar patterns descriptively, with change greater than never-MML states in California (1.0-percentage point more; SE, 0.5; P = .06) and Colorado (1.6-percentage point more; SE, 0.8; P = .04). Conclusions and Relevance: Medical marijuana laws appear to have contributed to increased prevalence of illicit cannabis use and cannabis use disorders. State-specific policy changes may also have played a role. While medical marijuana may help some, cannabis-related health consequences associated with changes in state marijuana laws should receive consideration by health care professionals and the public.

Recalibration of nonclinical safety pharmacology assessment to anticipate evolving regulatory expectations.

Safety pharmacology (SP) has evolved in terms of architecture and content since the inception of the SP Society (SPS). SP was initially focused on the issue of drug-induced QT prolongation, but has now become a broad spectrum discipline with expanding expectations for evaluation of drug adverse effect liability in all organ systems, not merely the narrow consideration of torsades de pointes (TdP) liability testing. An important part of the evolution of SP has been the elaboration of architecture for interrogation of non-clinical models in terms of model development, model validation and model implementation. While SP has been defined by mandatory cardiovascular, central nervous system (CNS) and respiratory system studies ever since the core battery was elaborated, it also involves evaluation of drug effects on other physiological systems. The current state of SP evolution is the incorporation of emerging new technologies in a wide range of non-clinical drug safety testing models. This will refine the SP process, while potentially expanding the core battery. The continued refinement of automated technologies (e.g., automated patch clamp systems) is enhancing the scope for detection of adverse effect liability (i.e., for more than just IKr blockade), while introducing a potential for speed and accuracy in cardiovascular and CNS SP by providing rapid, high throughput ion channel screening methods for implementation in early drug development. A variety of CNS liability assays, which exploit isolated brain tissue, and in vitro electrophysiological techniques, have provided an additional level of complimentary preclinical safety screens aimed at establishing the seizurogenic potential and risk for memory dysfunction of new chemical entities (NCEs). As with previous editorials that preface the annual themed issue on SP methods published in the Journal of Pharmacological and Toxicological Methods (JPTM), we highlight here the content derived from the most recent (2015) SPS meeting held in Prague, Czech Republic. This issue of JPTM continues the tradition of providing a publication summary of articles primarily presented at the SPS meeting with direct bearing on the discipline of SP. Novel method development and refinement in all areas of the discipline are reflected in the content.

[Interpretation of the concept of 'medicinal product' in relation to herb- and cannabinoid-based products]. / A gyógyszer fogalmának értelmezése gyógynövényeken és cannabinoidokon alapuló termékek esetén.

On 10th of July 2014 the European Court of Justice made in his decisions in relation to the cases D. (C-358/13) and G. (C-181/14) an interpretation, that the concept of 'medicinal product' according to the law of the European Union does not include the materials, which are - as not covering substances, such as those at issue in the main proceedings, which produce effects that merely modify physiological functions but which are not such as to have any beneficial effects, either immediately or in the long term, on human health, are consumed solely to induce a state of intoxication and are, as such, harmful to human health. The Court made his interpretation after the request for preliminary ruling from the Bundesgerichtshof (the High Court of Justice in Germany). The Court had to decide in two criminal procedures, whether for the retail of mixtures including syntetic canabinoids, such as complements of marihuana, due the fact that they are "unsafe medicinal products", a criminal proceeding can be initiated or not. The Ordinary Courts had two persons (D. and G.) for selling the unsafe medicinal products sentenced to one year and nine months imprisonment, and suspension (D.), and sentenced (G.) to four years and six months imprisonment and fined with a charge of two hundred thousand Euro. The retail of herb mixtures containing, inter alia, synthetic cannabinoids, did not fall under the German law on narcotic drugs at the material time, resulting that the German Authorities could not initiate a criminal procedure.

Financiación de medicamentos: Los aspectos jurídicos / Financing of drugs: legal aspects

El derecho a la protección de la salud impulsa al poder ejecutivo a establecer una política sanitaria conducente, dentro de los principios de equidad, calidad y participación ciudadana, a la promoción del uso racional del medicamento y a adoptar medidas dirigidas a que la prestación farmacéutica, por el Sistema Nacional de Salud, se realice a precios razonables y con un gasto publico ajustado, dentro de la necesidad de optimizar los recursos disponibles. En la actualidad el Estado de Bienestar alcanzado en nuestro país se hace cada día más gravoso, de aquí que para garantizar la sostenibilidad del Sistema Nacional de Salud el Estado español haya promovido una reforma sanitaria a través de normas, entre otras, el Real Decreto Ley 16/ 2012 del cual analizamos el impacto y consecuencias más destacables en el sector farmacéutico

The right to health protection encourages the Executive to establish a leading health policy according to the principles of equity, quality and citizen participation, to promote a responsible use of drugs and to adopt measures in order to make the provision of pharmaceutical care affordable and with reasonable public health expenditure by the Spanish National Health System as part of the need of optimizing the available resources. Nowadays, the welfare state achieved in our V country is progressively more expensive. Hence, in order to guarantee the sustainability of the Spanish National Health System, the Spanish government has promoted a health reform through standards, among others the Royal Decree-]Law16/ 2012, of April 20, 2012. From this Royal Decree-] Law we analyze the impact and the most noteworthy consequences in the pharmaceutical sector

Thirty years of preclinical safety evaluation of biopharmaceuticals: Did scientific progress lead to appropriate regulatory guidance?

INTRODUCTION: The first biopharmaceuticals were developed 30 years ago. Biopharmaceuticals differ significantly from small molecule therapeutics (SMTs). Because of such differences, it was expected that classical preclinical safety evaluation procedures applied to SMTs would not predict the adverse effects of biopharmaceuticals. Therefore, until sufficient experience was gained, the preclinical safety evaluation of biopharmaceuticals was carried out on a case-by-case basis. 30 years of experience has since expanded the knowledge base in this area, in the hope to design a preclinical safety evaluation procedure suited to biopharmaceuticals. AREAS COVERED: This review describes how the preclinical safety evaluation of biopharmaceuticals has evolved. It shows that, as result of the risk-averse behavior of regulators and industry, classical procedures were taken as starting point although state-of-the-art knowledge on biopharmaceuticals was directed towards creating a new procedure, driven by the specific properties of biopharmaceuticals. EXPERT OPINION: Current preclinical safety evaluation guidance of biopharmaceuticals is criticized because it employs a checkbox approach. The adverse effects induced by biopharmaceuticals are on-target or immune system-induced, therefore, the preclinical safety evaluation should not be standardized, but rather driven by product specific safety concerns.

Assessment of hospice health professionals' knowledge, views, and experience with medical marijuana.

The medicinal and recreational use of cannabis has been controversial, especially in the United States. Marijuana for medicinal use is approved in 14 U.S. states and has recently been considered for legalization in several additional states. Given its demonstrated efficacy in symptom management, marijuana has a potential role in palliative care. This study utilized a 16-item questionnaire to assess the knowledge, experience, and views of hospice professionals regarding the use of marijuana in terminally ill patients. The study results revealed that, like the general public, hospice health care providers are generally in favor of legalization of marijuana and, if legalized, would support its use in symptom management for their terminally ill patients.