Experience during adolescence shapes brain development: From synapses and networks to normal and pathological behavior.

Adolescence is a period of dramatic neural reorganization creating a period of vulnerability and the possibility for the development of psychopathology. The maturation of various neural circuits during adolescence depends, to a large degree, on one's experiences both physical and psychosocial. This occurs through a process of plasticity which is the structural and functional adaptation of the nervous system in response to environmental demands, physiological changes and experiences. During adolescence, this adaptation proceeds upon a backdrop of structural and functional alterations imparted by genetic and epigenetic factors and experiences both prior to birth and during the postnatal period. Plasticity entails an altering of connections between neurons through long-term potentiation (LTP) (which alters synaptic efficiency), synaptogenesis, axonal sprouting, dendritic remodeling, neurogenesis and recruitment (Skaper et al., 2017). Although most empirical evidence for plasticity derives from studies of the sensory systems, recent studies have suggested that during adolescence, social, emotional, and cognitive experiences alter the structure and function of the networks subserving these domains of behavior. Each of these neural networks exhibits heightened vulnerability to experience-dependent plasticity during the sensitive periods which occur in different circuits and different brain regions at specific periods of development. This report will summarize some examples of adaptation which occur during adolescence and some evidence that the adolescent brain responds differently to stimuli compared to adults and children. This symposium, "Experience during adolescence shapes brain development: from synapses and networks to normal and pathological behavior" occurred during the Developmental Neurotoxicology Society/Teratology Society Annual Meeting in Clearwater Florida, June 2018. The sections will describe the maturation of the brain during adolescence as studied using imaging technologies, illustrate how plasticity shapes the structure of the brain using examples of pathological conditions such as Tourette's' syndrome and attention deficit hyperactivity disorder, and a review of the key molecular systems involved in this plasticity and how some commonly abused substances alter brain development. The role of stimulants used in the treatment of attention deficit hyperactivity disorder (ADHD) in the plasticity of the reward circuit is then described. Lastly, clinical data promoting an understanding of peer-influences on risky behavior in adolescents provides evidence for the complexity of the roles that peers play in decision making, a phenomenon different from that in the adult. Imaging studies have revealed that activation of the social network by the presence of peers at times of decision making is unique in the adolescent. Since normal brain development relies on experiences which alter the functional and structural connections between cells within circuits and networks to ultimately alter behavior, readers can be made aware of the myriad of ways normal developmental processes can be hijacked. The vulnerability of developing adolescent brain places the adolescent at risk for the development of a life time of abnormal behaviors and mental disorders.

Changes in cannabis potency and first-time admissions to drug treatment: a 16-year study in the Netherlands.

BACKGROUND: The number of people entering specialist drug treatment for cannabis problems has increased considerably in recent years. The reasons for this are unclear, but rising cannabis potency could be a contributing factor. METHODS: Cannabis potency data were obtained from an ongoing monitoring programme in the Netherlands. We analysed concentrations of δ-9-tetrahydrocannabinol (THC) from the most popular variety of domestic herbal cannabis sold in each retail outlet (2000-2015). Mixed effects linear regression models examined time-dependent associations between THC and first-time cannabis admissions to specialist drug treatment. Candidate time lags were 0-10 years, based on normative European drug treatment data. RESULTS: THC increased from a mean (95% CI) of 8.62 (7.97-9.27) to 20.38 (19.09-21.67) from 2000 to 2004 and then decreased to 15.31 (14.24-16.38) in 2015. First-time cannabis admissions (per 100 000 inhabitants) rose from 7.08 to 26.36 from 2000 to 2010, and then decreased to 19.82 in 2015. THC was positively associated with treatment entry at lags of 0-9 years, with the strongest association at 5 years, b = 0.370 (0.317-0.424), p < 0.0001. After adjusting for age, sex and non-cannabis drug treatment admissions, these positive associations were attenuated but remained statistically significant at lags of 5-7 years and were again strongest at 5 years, b = 0.082 (0.052-0.111), p < 0.0001. CONCLUSIONS: In this 16-year observational study, we found positive time-dependent associations between changes in cannabis potency and first-time cannabis admissions to drug treatment. These associations are biologically plausible, but their strength after adjustment suggests that other factors are also important.

Is online information on ecstasy tablet content safe?

BACKGROUND AND AIMS: In recent years, the prevalence of ecstasy use has increased in most European countries. Users can acquire information on ecstasy tablet composition through the internet. This study compares online information from two websites, Pillreports and Partyflock, to the validated Dutch Drugs Information and Monitoring System (DIMS) database, and aims to measure its accuracy and potential danger or value. DESIGN, SETTING, PARTICIPANTS: The drug-related information posted on Pillreports.net and Partyflock.nl between 1 January 2014 and 31 December 2015 was investigated for accuracy and several information characteristics such as picture inclusion and dose range inclusion. In total, 471 informatory statements on ecstasy tablet content were analysed relative to the Dutch ecstasy market. MEASUREMENTS: Informatory statements on the content of specific ecstasy tablets were scored as 'too high' or 'too low' if their concentrations deviated > 10 mg from the entries in the DIMS database within a 12-week time-frame, and scored as 'dangerous' if their concentration was > 40 mg too low. Unreported substances were scored as 'dangerous' if listed as an illegal or dangerous substance in the DIMS database and if present in relevant quantities. Also scored were the report characteristics 'picture inclusion', 'spread inclusion' and 'website source', which were tested for their association with report safety/danger. FINDINGS: On average, reports on ecstasy tablets from Pillreports and Partyflock show concentrations which are 10.6 mg too high [95% confidence interval (CI) = 6.7-14.4]. Qualitatively, 39.7% of the reports scored as 'too high' (95% CI = 35.2-44.4), 17.6% scored as 'too low' (95% CI = 14.0-21.2) and 15.5% had 'unreported substances' (95% CI = 12.3-18.9), resulting overall in 15.3% of the reports being scored as 'dangerous' (95% CI = 11.9-18.5). The report characteristic 'spread inclusion' associated inversely with report danger [Exp(b) = 0.511, 95% CI = 0.307-0.850, P = 0.01]. CONCLUSION: Information from the popular Pillreports and Partyflock websites tends to overestimate 3,4-methylenedioxymethamphetamine (MDMA) concentrations in ecstasy tablets. In addition, 15.3% of the reports omit the relevant concentration spread, fail to report additional illegal or dangerous substances contained in the tablets or underestimate MDMA concentration by > 40 mg.

Limitations to the Dutch cannabis toleration policy: Assumptions underlying the reclassification of cannabis above 15% THC.

The Netherlands has seen an increase in Δ9-tetrahydrocannabinol (THC) concentrations from approximately 8% in the 1990s up to 20% in 2004. Increased cannabis potency may lead to higher THC-exposure and cannabis related harm. The Dutch government officially condones the sale of cannabis from so called 'coffee shops', and the Opium Act distinguishes cannabis as a Schedule II drug with 'acceptable risk' from other drugs with 'unacceptable risk' (Schedule I). Even in 1976, however, cannabis potency was taken into account by distinguishing hemp oil as a Schedule I drug. In 2011, an advisory committee recommended tightening up legislation, leading to a 2013 bill proposing the reclassification of high potency cannabis products with a THC content of 15% or more as a Schedule I drug. The purpose of this measure was twofold: to reduce public health risks and to reduce illegal cultivation and export of cannabis by increasing punishment. This paper focuses on the public health aspects and describes the (explicit and implicit) assumptions underlying this '15% THC measure', as well as to what extent these are supported by scientific research. Based on scientific literature and other sources of information, we conclude that the 15% measure can provide in theory a slight health benefit for specific groups of cannabis users (i.e., frequent users preferring strong cannabis, purchasing from coffee shops, using 'steady quantities' and not changing their smoking behaviour), but certainly not for all cannabis users. These gains should be weighed against the investment in enforcement and the risk of unintended (adverse) effects. Given the many assumptions and uncertainty about the nature and extent of the expected buying and smoking behaviour changes, the measure is a political choice and based on thin evidence.

Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15.

BACKGROUND AND AIMS: Between 2000 and 2005 the average percentage of Δ(9) -tetrahydrocannabinol (THC) in marijuana as sold in Dutch coffeeshops has increased substantially; the potency of domestic products (Nederwiet and Nederhasj) has particularly increased. In contrast with imported marijuana, Nederwiet hardly contained any cannabidiol (CBD), a cannabinoid that is thought to offset some of the adverse effects of THC. In 2005, the THC content in Nederwiet was significantly lower than in 2004. This study investigates the further decrease or increase of cannabinoids in these cannabis products. METHODS: From 2005 to 2015 five different cannabis products were bought anonymously in 50 coffeeshops that were selected randomly each year from all coffeeshops in the Netherlands. A total of 2126 cannabis samples were bought, consisting of 664 Nederwiet samples (most popular), 537 Nederwiet samples (supposed strongest varieties), 183 imported herbal cannabis samples, 140 samples of cannabis resin made of Nederwiet and 602 samples of imported cannabis resin. All samples were analysed chemically for their THC, CBD and cannabinol (CBN) content. RESULTS: Between 2005 and 2015, the mean potencies of the most popular and the strongest Nederwiet and of imported cannabis resin were 16.0±4.0%, 17.0±3,9% and 16.5±6.3%, respectively. Imported herbal cannabis (6.5±3.5%) and cannabis resin made from Nederwiet (30.2±16.4%) contained, respectively, less (ß=-10.0, P<0.001) and more (ß=13.7, P<0.001) THC than imported cannabis resin. Linear regression models were used to study the trends in THC of the different cannabis products over time. A marginal, but significant (P<0.001), overall decline of THC per year of 0.22% was found in all cannabis products. However, no significant difference was found between the five products in the THC linear trajectories across time. Of all the cannabis products, only imported cannabis resin contained a relatively high CBD/THC ratio (median 0.42). CONCLUSION: The average tetrahydrocannabinol (THC) content of the most popular herbal cannabis products in the Netherlands has decreased slightly since 2005. The popular Nederwiet type still has a relatively high THC to cannabidiol ratio.

4-Fluoroamphetamine in the Netherlands: more than a one-night stand.

AIMS: To investigate the temporal pattern of appearance of a new psychoactive substance (4-fluoroamphetamine) on the Dutch drug market, as well as its patterns of use and effects. DESIGN: Data from the Drug Information and Monitoring System (DIMS) was used to investigate the emergence of 4-fluoroamphetamine on the Dutch drug market. An on-line questionnaire was used to study its patterns of use and effects. SETTING: Dutch drug-related websites and social media. PARTICIPANTS: A convenience sample of 249 life-time 4-fluoroamphetamine users was recruited through the internet. MEASUREMENTS: Samples containing 4-fluoroamphetamine were extracted from the DIMS database for further investigation. Patterns of use, settings of use and the subjective effects of 4-fluoroamphetamine, amphetamine and 3,4-methylenedioxymethamphetamine (MDMA) were investigated with the on-line questionnaire. FINDINGS: 4-Fluoroamphetamine was first encountered on the Dutch drug market, sold mainly as amphetamine or ecstasy (MDMA), between 2007 and 2009. These misrepresented drug samples declined when the MDMA and amphetamine markets recovered after a period of shortage, whereas purposefully bought 4-fluoroamphetamine samples showed an increase. Survey results showed that 4-fluoroamphetamine is used predominantly [77.1%, 95% confidence interval (CI) = 72.0-82.3] for its specific effects, rather than its legal status (17.7%, 95% CI = 10.7-22.1). The subjective effects of 4-fluoroamphetamine were compared with those of amphetamine and MDMA. Subjective effect scores of 4-fluoroamphetamine ranged between those of amphetamine and MDMA. CONCLUSIONS: The stimulant 4-fluoroamphetamine is increasingly popular in the Netherlands, which might be due to its subjective effects profile, which lies intermediate between amphetamine and MDMA.

[A patient in a methoxetamine-induced dissociative psychosis]. / Dissociatieve psychose door methoxetamine.

BACKGROUND: The international drug market has dramatically changed with the emergence of various new psychoactive substances that are mostly being sold on the internet. One of those new psychoactive substances is methoxetamine (MXE), a structural analogue of ketamine. CASE DESCRIPTION: A 30-year-old man with no history of illness was presented to the accident and emergency department. He had lost his balance and could not move. He was in a dissociative psychosis, felt he had no control over his body and was extremely frightened. Most of this symptoms disappeared within two hours of arrival. The next day there were no indications of a psychosis, and only headache and nausea remained. The state of dissociative psychosis was caused by MXE, which was sold to him as an ecstasy tablet. CONCLUSION: Whether mixed with alcohol and other drugs or not, MXE can cause serious feelings of dissociation resulting in extreme anxiety and psychosis. This might cause severely lowered consciousness in these patients. Currently, use of MXE in the Netherlands is limited, but ketamine or MXE intoxication should be considered in patients with these symptoms.

Therapeutic satisfaction and subjective effects of different strains of pharmaceutical-grade cannabis.

In The Netherlands, pharmaceutical-grade cultivated cannabis is distributed for medicinal purposes as commissioned by the Ministry of Health. Few studies have thus far described its therapeutic efficacy or subjective (adverse) effects in patients. The aims of this study are to assess the therapeutic satisfaction within a group of patients using prescribed pharmaceutical-grade cannabis and to compare the subjective effects among the available strains with special focus on their delta-9-tetrahydrocannabinol and cannabidiol content. In a cross-sectional and natural design, users of pharmaceutical-grade cannabis were investigated with questionnaires. Medical background of the patients was asked as well as experienced therapeutic effects and characteristics of cannabis use. Subjective effects were measured with psychometric scales and used to compare among the strains of cannabis used across this group of patients. One hundred two patients were included; their average age was 53 years and 76% used it for more than a year preceding this study. Chronic pain (53%; n = 54) was the most common medical indication for using cannabis followed by multiple sclerosis (23%; n = 23), and 86% (n = 88) of patients (almost) always experienced therapeutic satisfaction when using pharmaceutical cannabis. Dejection, anxiety, and appetite stimulation were found to differ among the 3 strains of cannabis. These results show that patients report therapeutic satisfaction with pharmaceutical cannabis, mainly pain alleviation. Some subjective effects were found to differ among the available strains of cannabis, which is discussed in relation to their different tetrahydrocannabinol/cannabidiol content. These results may aid in further research and critical appraisal for medicinally prescribed cannabis products.

Does Cannabidiol Protect Against Adverse Psychological Effects of THC?

The recreational use of cannabis can have persistent adverse effects on mental health. Delta-9-tetrahydrocannabinol (THC) is the main psychoactive constituent of cannabis, and most, if not all, of the effects associated with the use of cannabis are caused by THC. Recent studies have suggested a possible protective effect of another cannabinoid, cannabidiol (CBD). A literature search was performed in the bibliographic databases PubMed, PsycINFO, and Web of Science using the keyword "cannabidiol." After removing duplicate entries, 1295 unique titles remained. Based on the titles and abstracts, an initial selection was made. The reference lists of the publications identified in this manner were examined for additional references. Cannabis is not a safe drug. Depending on how often someone uses, the age of onset, the potency of the cannabis that is used and someone's individual sensitivity, the recreational use of cannabis may cause permanent psychological disorders. Most recreational users will never be faced with such persistent mental illness, but in some individuals cannabis use leads to undesirable effects: cognitive impairment, anxiety, paranoia, and increased risks of developing chronic psychosis or drug addiction. Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC. However, the question remains of how the laboratory results translate to the types of cannabis that are encountered by real-world recreational users.