No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Cannabinoid tolerance and dependence: A review of studies in laboratory animals
Abstract
Two are the issues on cannabis addiction that provoke more controversy from a research perspective. The first one is related to the development of tolerance phenomena and, in particular, of a dependence state after chronic cannabinoid consumption, with appearance of withdrawal signs when this is interrupted, that would be (or not) comparable to those observed for other drugs. A second controversial issue is related to the possibility that chronic cannabinoid consumption may increase the risk to consume other drugs of greater addictive power. Since the discovery in the 1990s of the endocannabinoid signaling system as the target for the action of plant-derived cannabinoids, many studies have addressed these two questions in laboratory animals and, although the results have resulted controversial in various aspects, the following conclusions seem evident: (i) prolonged exposure to plant-derived, synthetic or endogenous cannabinoid agonists in laboratory animals is currently associated with the development of tolerance for most of their pharmacological effects, (ii) tolerance is essentially due to adaptative phenomena consisting in pharmacodynamic events (down-regulation/desensitization of cannabinoid receptors), although some evidence exist on additional pharmacokinetic responses, (iii) the discontinuation of chronic cannabinoid treatment does not elicit abstinence responses spontaneously in most of the cases, presumably because the pharmacokinetic characteristics of cannabinoids, but these responses may be elicited after the blockade of cannabinoid CB1 receptors in cannabinoid-tolerant animals, (iv) these abstinent responses include mainly somatic signs and changes in various molecular processes affected during the abstinence to other drugs although the magnitude of these changes was currently lower in the case of cannabinoids, and (v) cannabinoid-tolerant animals do not appear to be more vulnerable to reinforcing properties of morphine, although the manipulation of the endocannabinoid signaling might serve to treat cannabis addiction and, in particular, the addiction to other drugs such as alcohol, nicotine or opioids. The present review article will address all these aspects trying to establish the bases for future research.
... Certain characteristics of CUD are thought to emerge, in part, due to molecular adaptations in the brain resulting from repetitive exposure to cannabis, particularly its primary psychoactive compound, THC. One of the most noteworthy and consistently observed findings of adaptations to chronic cannabis use is the desensitization of CB 1 receptors in preclinical models (40). CB 1 desensitization refers to a reduced responsiveness or sensitivity of CB 1 receptors to the binding of cannabinoids over time. ...
... In preclinical models, this phenomenon has been associated with the development of significant tolerance to cannabis and to the severity of withdrawal symptoms. As well, the reduction in CB 1 signaling is believed to impact various physiological and behavioral processes, including appetite, memory and learning, mood, pain perception, and sleep (40). CB 1 desensitization in preclinical models may also alter neurotransmitter release patterns and synaptic communication (40). ...
... As well, the reduction in CB 1 signaling is believed to impact various physiological and behavioral processes, including appetite, memory and learning, mood, pain perception, and sleep (40). CB 1 desensitization in preclinical models may also alter neurotransmitter release patterns and synaptic communication (40). Cannabis contains exogenous cannabinoids, including Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). ...
Cannabis has been legalized for medical and recreational purposes in multiple countries. A large number of people are using cannabis and some will develop cannabis use disorder (CUD). There is a growing recognition that CUD requires specific interventions. This Review will cover this topic from a variety of perspectives, with a particular emphasis on neurobiological findings and innovative treatment approaches that are being pursued. We will first describe the epidemiology and burden of disease of CUD, including risk factors associated with CUD (both in terms of general risk and genetic risk variants). Neurobiological alterations identified in brain imaging studies will be presented. Several psychosocial interventions that are useful for the management of CUD, including motivational enhancement therapy, behavioral and cognitive therapy, and contingency management, will be covered. Although no pharmacological interventions are yet approved for CUD, we present the most promising pharmacological interventions being tested.
... Figure 2 shows some of the major phytocannabinoids and terpenes present in the cannabis plant. Although THC has shown promising results in cellular and animal studies, its therapeutic applications have been limited due to its potential psychotropic effects [60][61][62]. There are, however, several other cannabinoids, such as CBD, which have demonstrated therapeutic benefits without mood-altering side-effects and have gained significant interest in the pharmaceutical and cosmetic industries [63]. ...
... With the discovery of the endocannabinoid system (ECS), specifically the expanded endocannabinoid system (endocannabinoidome), in the human body, it has become easier Although THC has shown promising results in cellular and animal studies, its therapeutic applications have been limited due to its potential psychotropic effects [60][61][62]. There are, however, several other cannabinoids, such as CBD, which have demonstrated therapeutic benefits without mood-altering side-effects and have gained significant interest in the pharmaceutical and cosmetic industries [63]. ...
Humans have employed cannabis for multiple uses including medicine, recreation, food, and fibre. The various components such as roots, flowers, seeds, and leaves have been utilized to alleviate pain, inflammation, anxiety, and gastrointestinal disorders like nausea, vomiting, diarrhoea, and inflammatory bowel diseases (IBDs). It has occupied a significant space in ethnomedicines across cultures and religions. Despite multi-dimensional uses, the global prohibition of cannabis by the USA through the introduction of the Marijuana Tax Act in 1937 led to prejudice about the perceived risks of cannabis, overshadowing its medicinal potential. Nevertheless, the discovery of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and the endocannabinoid system renewed scientific interest in understanding the role of cannabis in modulating different conditions, including gastrointestinal disorders. Preparations combining cannabidiol and THC have shown promise in mitigating gut symptoms through anti-inflammatory and motility-enhancing effects. This review revisits the ethnomedicinal use of cannabis in gastrointestinal diseases and emphasizes the need for further research to determine optimal dosages, formulations, and safety profiles of cannabis-based medicines. It also underscores the future potential of cannabinoid-based therapies by leveraging the role of the expanded endocannabinoid system, an endocannabinoidome, in the modulation of gastrointestinal ailments.
... Therefore, CB1 is highly expressed in cells with projections in dopaminergic pathways involved in drug abuse. In fact, several CNS tissues and dopaminergic pathways are implicated in cannabinoid tolerance, rewarding, and withdrawal-induced aversive-like effects [26]. ...
... Chronic cannabinoid use followed by discontinuation has been reported to cause cannabinoid withdrawal syndrome in both humans and animals, a major factor behind users not being able to quit successfully [9,26]. There are currently no approved medications to treat cannabis use disorder or cannabis withdrawal. ...
Cannabis is among the most widely consumed psychoactive drugs around the world and cannabis use disorder (CUD) has no current approved pharmacological treatment. Nicotine and cannabis are commonly co-used which suggests there to be overlapping neurobiological actions supported primarily by the co-distribution of both receptor systems in the brain. There appears to be strong rationale to explore the role that nicotinic receptors play in cannabinoid dependence. Preclinical studies suggest that the ɑ7 nAChR subtype may play a role in modulating the reinforcing and discriminative stimulus effects of cannabinoids, while the ɑ4β2* nAChR subtype may be involved in modulating the motor and sedative effects of cannabinoids. Preclinical and human genetic studies point towards a potential role of the ɑ5, ɑ3, and β4 nAChR subunits in CUD, while human GWAS studies strongly implicate the ɑ2 subunit as playing a role in CUD susceptibility. Clinical studies suggest that current smoking cessation agents, such as varenicline and bupropion, may also be beneficial in treating CUD, although more controlled studies are necessary. Additional behavioral, molecular, and mechanistic studies investigating the role of nAChR in the modulation of the pharmacological effects of cannabinoids are needed.
... On the other hand, the spontaneous withdrawal model is established by chronically administering the CB1 agonist, then abruptly ceasing treatment and observing the natural behavioral response to drug cessation. 17,[19][20][21] The spontaneous withdrawal model induces somatic symptoms, including decreased rubbing and grooming during drug withdrawal in mice. [22][23][24] In this study, we examined physical symptoms and changes in sleep after cannabis cessation in mice by assessing sleep disturbances using a more clinically relevant model of spontaneous withdrawal following cessation of ACPA administration, a CB1R agonist. ...
... 22 CB1R agonist withdrawal in mice also caused somatic symptoms including decreased rubbing and grooming. 17,[19][20][21][22] First, to assess whether ACPA affects behavior in mice, we observed the behavior of mice immediately after 1 week administration with ACPA (0.02 mg kg). As shown in Figure S1 (Row data of Figure S1: Table S1), the locomotor activity in the ACPA group Figure 1B-D). ...
Cannabis withdrawal syndrome (CWS) in humans is characterized by various somatic symptoms, including sleep disturbances. In the present study, we investigated sleep alterations in mice after the cessation of arachidonylcyclopropylamide (ACPA), a cannabinoid type 1 receptor agonist, administration. ACPA-administered mice (ACPA mice) displayed an increased number of rearings after the cessation of ACPA administration compared to saline-administered mice (Saline mice). Moreover, the number of rubbings was also decreased in ACPA mice compared with those of the control mice. Electroencephalography (EEG) and electromyography (EMG) were measured for 3 days after the cessation of ACPA administration. During ACPA administration, there was no difference in the relative amounts of total sleep and wake time between ACPA and Saline mice. However, ACPA-induced withdrawal decreased total sleep time during the light period in ACPA mice after ACPA cessation. These results suggest that ACPA cessation induces sleep disturbances in the mouse model of CWS.
... CHAPTER 5 Cannabinoid receptor interacting proteins cortex and cerebellum, where it is involved in the regulation of motor function, mood, memory, and pain (Fernández-Ruiz & González, 2005;Manzanares, Julian, & Carrascosa, 2006;Morena & Campolongo, 2014;Witkin, Tzavara, & Nomikos, 2005). CB 1 is most frequently expressed at the presynaptic terminals of both GABAergic and glutamatergic neurons, where activation inhibits neurotransmitter release (Castillo, Younts, Chávez, & Hashimotodani, 2012;Domenici et al., 2006;Irving et al., 2000;Szabo & Schlicker, 2005 Gowran, & Campbell, 2012). ...
... Following endocytosis, CB 1 has been described to undergo either recycling or degradation, with determination of this fate likely involving protein-protein interactions (e.g., Grimsey et al., 2010;Leterrier, Bonnard, Carrel, Rossier, & Lenkei, 2004;Martini et al., 2007;Wu et al., 2008). Regional differences in the development of tolerance and subsequent recovery of responsiveness following chronic cannabinoid exposure might be indicative of differential CB 1 regulation and protein-protein interactions between cell types (González, Cebeira, & Fernández-Ruiz, 2005). In the majority of contexts studied to date, CB 2 recycles following internalization and is refractory to agonist-induced degradation (Grimsey, Goodfellow, Dragunow, & Glass, 2011;Kleyer et al., 2012). ...
Proteins often do not function as a single biomolecular entity; instead, they frequently interact with other proteins and biomolecules forming complexes. There is increasing evidence depicting the essentiality of protein-protein interactions (PPIs) governing a wide array of cellular processes. Thus, it is crucial to understand PPIs. Commonly used approaches like genetic (e.g., Yeast Two-Hybrid, Y2H), optical (e.g., Surface Plasmon Resonance, SPR; Fluorescence Resonance Energy Transfer, FRET), and biochemical have rendered ease in developing interactive protein maps as freely available information in protein databases on the web. The underlying basis of traditional protein interaction analysis is the core of biochemical methodologies providing direct evidence of interactions. Co-Immunoprecipitation (Co-IP) is a powerful biochemical technique that facilitates identifying novel interacting partners of a protein of interest in vivo, allowing specific capture of their complexes on an immunoglobulin. Here, using Arf-like (Arl) GTPase-8b (Arl8b) and Pleckstrin Homology Domain-Containing Family M Member 1 (PLEKHM1) as an example of small GTPase-effector pair, we provide a detailed protocol for performing Y2H and Co-IP assays to confirm the interaction between a small GTPase and its effector protein.
... There is also evidence of tolerance developing for the HPA response, as evidence by reduced cortisol response to cannabis use (Murphy et al., 1998). Tolerance has also been found for other outcomes, including behavioral, subjective, and cognitive responses to cannabis (D'Souza et al., 2004(D'Souza et al., , 2008Ranganathan et al., 2009), which is consistent with preclinical evidence of tolerance (Murphy et al., 1998;González et al., 2005;Pagotto et al., 2006). ...
... Cannabinoids influence the hypothalamic-pituitary-gonadal (HPG) axis (López et al., 2010;Craft et al., 2013;Marusich et al., 2014;Wakley et al., 2014). Based on animal models, the density of endocannabinoid receptors in the brain, including hypothalamus and pituitary, change across the estrous cycle (González et al., 2000(González et al., , 2005López et al., 2010), suggesting that neuropsychological impacts of cannabis use may differ across the human menstrual cycle. Ovarian hormones impact drug-taking behaviors for a variety of substances, including cannabis (Lynch et al., 2002;Carroll and Anker, 2010;Becker and Koob, 2016). ...
Although research has only recently started to examine the impact of cannabis use on stress response, there is some evidence that indicates acute and chronic impacts of cannabis on these processes. In this paper, we review processes involved in regulating the stress response and we review the influence of acute and chronic exposure to cannabis on patterns and regulation of the stress response. We also highlight the role of stress as a risk factor for initiation and maintenance of cannabis use. In this context, we examine moderating variables, including sex and life adversity. In light of recent observations indicating increasing prevalence of cannabis use during pregnancy, we provide additional focus on cannabis use in this vulnerable population, including how acute and chronic stress may predispose some individuals to use cannabis during pregnancy. While this line of research is in its infancy, we review available articles that focus on the perinatal period and that examined the association between cannabis use and various life stressors, including partner violence, job loss, and lack of housing. We also review psychiatric co-morbidities (e.g., post-traumatic stress disorder, anxiety). A better understanding of the way stress and cannabis use relate within the general population, as well as within certain subgroups that may be at a greater risk of using and/or at greater risk for adverse outcomes of use, may lead to the development of novel prevention and intervention approaches.
... Research has mainly focused on the drug's pharmacodynamics and health risks (Vigil et al., 2022), particularly its acute effects, including impacts on motor control (González et al., 2005), cognition (Broyd et al., 2016), and its potential therapeutic use for some disorders (Adams and Martin, 1996;Castaño et al., 2017;Mauzay, 2021). A significant acute effect is changes in exploratory behavior (Abood and Martin, 1992;Hampson and Deadwyler, 1999;Hollister, 1998;Pertwee, 1995), with cannabis causing biphasic dose-dependent effects: low doses increase hyperactivity, while high doses reduce exploratory behavior (Bruijnzeel et al., 2016;Katsidoni et al., 2013). ...
Experimental evaluation of cannabis tolerance has lacked an associative learning approach, focusing primarily
on physiological variables. The present study assessed acute effects, chronic tolerance, and contextual specificity,
exploring a potential associative component underlying cannabis tolerance. Sixteen adult Sprague-Dawley rats of
both sexes were assigned to two groups, one receiving vaporized administrations of cannabis and the other
receiving the vehicle substance, in two different counterbalanced contexts. An initial measurement was performed
to assess acute effects, followed by four measurements to evaluate the development of chronic tolerance,
and a final measurement to test the context specificity of tolerance, comparing the responses to the usual
administration context and a novel context. Ten behaviors were analyzed in an open field. Acute effects were
observed in seven indicators, corresponding to greater exploration activity in the group that received the drug
compared to the control group. In five of these, the data also showed the development of chronic tolerance to the
effects of cannabis on exploration, which was indicated by a progressive decrease in exploratory activity in the
drug group. However, no evidence of context specificity was found in any variables in which chronic tolerance
was observed. We discuss factors that may be related to the lack of contextual specificity of cannabis tolerance.
Together, our findings show that a single administration of cannabis induces acute effects, and repeated exposure
leads to chronic tolerance, ultimately reducing exploratory behavior.
... In fact, regular cannabis users are highly likely to develop tolerance to cannabis effects (Colizzi and Bhattacharyya Fig. 11 Meta-analysis of Glx/Cre (Basal Ganglia) n = 60; p = 0.726 2018b). However, desensitization and tolerance can be reversed when cannabis use ceases (D'Souza et al. 2016), suggesting that neuro-adaptability changes do occur (González et al. 2005). ...
Increased extracellular glutamate concentrations in the brain can cause neuronal injury. Cannabinoid use has been demonstrated to reduce extracellular glutamate levels in the brain in many animal models. However, there are no systematic reviews published evaluating the effect of cannabis on glutamate levels in the human brain. This review aimed to review studies that investigated the effect of cannabinoids on glutamate levels in the living human brain using neuroimaging methods and to provide evidence gathered from biomedical databases such as MEDLINE and EMBASE. Nine randomized controlled trials (RCTs) and ten observational studies met the eligibility criteria for this review. The articles included in the meta-analyses had a low risk of bias. Meta-analysis showed cannabis intake has no effects on the glutamate levels in human brain. However, there is limited evidence indicating that oral cannabidiol and cannabidivarin increased the glutamate/glutamine ratio in the basal ganglia while intravenous and vaped tetrahydrocannabinol increased glutamate in the basal ganglia. There is also some evidence showing oral cannabidiol increased glutamate in the hippocampus. Most of the observational studies in this review demonstrated a reduction in glutamate in the brain of chronic cannabis users. However, these findings are not definitive and will require further confirmations. This review suggests that acute cannabis administration may increase glutamate in the basal ganglia and hippocampus but not in other parts of the brain, while chronic cannabis use lead to a decrease in glutamate levels in some parts of the brain. The quality of this evidence is limited therefore further studies are needed.
... Preclinical studies have shown that THC can alleviate inflammation and promote tissue healing in models of colitis [14]. However, its therapeutic application is often limited by behavioural side effects such as anxiety, tolerance and cognitive impairment, which restrict its clinical utility [15][16][17]). Clinical trials on THC for inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC), have shown mixed results. ...
Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic effects limit clinical use. ZCZ011, a CB1R allosteric modulator, and cannabidiol (CBD), a non-psychoactive cannabinoid, offer alternatives. This study investigated combining sub-therapeutic THC doses with ZCZ011 or CBD in a murine model of dextran sodium sulphate (DSS)-induced colitis. Methods: Acute colitis was induced with 4% DSS for 7 days, followed by 3 days of water. Chronic colitis was modelled over 24 days with alternating DSS concentrations. The combination of 2.5 mg/kg THC with 20 mg/kg ZCZ011 or 10 mg/kg CBD was evaluated. Key markers were assessed to determine efficacy and safety, including disease activity index (DAI), inflammation, cytokine levels, GLP-1, and organ health. Results: DSS-induced colitis resulted in increased DAI scores, cytokines, organ inflammation and dysregulation of GLP-1 and ammonia. THC at 10 mg/kg significantly improved colitis markers but was ineffective at 2.5 and 5 mg/kg. ZCZ011 alone showed transient effects. However, combining 2.5 mg/kg THC with either 20 mg/kg ZCZ011 or 10 mg/kg CBD significantly alleviated colitis markers, restored colon integrity and reestablished GLP-1 homeostasis. This combination also maintained favourable haematological and biochemical profiles, including a notable reduction in colitis-induced elevated ammonia levels. Conclusions: This study demonstrates the synergistic potential of low-dose THC combined with CBD or ZCZ011 as a novel, effective and safer therapeutic strategy for ulcerative colitis.
... This may also indicate the administrations of D. stramonium and N. tabacum alkaloids at those doses had lower drug cue preferences. This corresponds with previous studies that reported that chronic exposure to psychoactive substances at high doses will induce rapid development of tolerance and aversion, despite their potency to induce addictiveness at very low doses (González et al., 2005;Zernig et al., 2007;Hur et al., 2020;Fasakin et al., 2022b). Thus, the CS, DS, NT, and CM possess the potential to be both addictive and neurotoxic. ...
... Cannabis, primarily through the psychoactive compound delta-9-tetrahydrocannabinol (THC), interacts with the developing endocannabinoid system (ECS) during adolescence, a period marked by ECS maturation and a higher density of CB1 receptors in the brain. Preclinical evidence suggests that the activation of CB1 receptors may play a crucial role in regulating structural brain development, influencing synaptic plasticity and impacting processes like synaptic pruning, dendritic arborization, and synaptogenesis, thereby shaping the brain's structural organization [51,52]. Studies involving adolescents and emerging adults have reported varying findings regarding the impact of cannabis use [53]. ...
Early life substance use, including cannabis and nicotine, may result in deleterious effects on the maturation of brain tissue and gray matter cortical development. The current study employed linear regression models to investigate the main and interactive effects of past-year nicotine and cannabis use on gray matter cortical thickness estimates in 11 bilateral independent frontal cortical regions in 223 16–22-year-olds. As the frontal cortex develops throughout late adolescence and young adulthood, this period becomes crucial for studying the impact of substance use on brain structure. The distinct effects of nicotine and cannabis use status on cortical thickness were found bilaterally, as cannabis and nicotine users both had thinner cortices than non-users. Interactions between nicotine and cannabis were also observed, in which cannabis use was associated with thicker cortices for those with a history of nicotine and tobacco product (NTP) use in three left frontal regions. This study sheds light on the intricate relationship between substance use and brain structure, suggesting a potential modulation of cannabis’ impact on cortical thickness by nicotine exposure, and emphasizing the need for further longitudinal research to characterize these interactions and their implications for brain health and development.
... The CB1 and CB2 receptors, widely distributed in the central nervous system, dorsal ganglia, hypothalamus, hippocampus, and cerebellum, as well as in the enteric nervous system and presynaptic ganglia of the parasympathetic nervous system, are responsible for mediating the effects of cannabinoids. They do so by reducing the release of anterior pituitary hormones and increasing corticotropin secretions [74][75][76]. The disruption of normal thermoregulation due to cannabis use, facilitated by CB1 receptors located in the preoptic area and their involvement in the cooling effects of cannabinoids, might provide an explanation for the relief of symptoms experienced by many CHS patients who find relief through compulsive hot baths. ...
Cannabis, a plant known for its recreational use, has gained global attention due to its widespread use and addiction potential. Derived from the Cannabis sativa plant, it contains a rich array of phytochemicals concentrated in resin-rich trichomes. The main cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with CB1 and CB2 receptors, influencing various physiological processes. Particularly concerning is its prevalence among adolescents, often driven by the need for social connection and anxiety alleviation. This paper provides a comprehensive overview of cannabis use, its effects, and potential health risks, especially in adolescent consumption. It covers short-term and long-term effects on different body systems and mental health and highlights the need for informed decision making and public health initiatives, particularly regarding adolescent cannabis use.
... Differences in CB 1 R density, downregulation, and/or desensitization are all mechanisms that have been proposed as potential reasons for observed sex differences in cannabinoid sensitivity and/or tolerance. Previous work has also found differences in CB 1 R density and desensitization between male and female rodents (Castelli et al. 2014;de Fonseca et al. 1994b;Farquhar et al. 2019;González et al. 2005 but see Wiley et al. 2021). It is possible that sex differences in cannabinoid response are also response specific. ...
Cannabinoids are increasingly used to alleviate pain; however, tolerance to their antinociceptive effects, including those of delta-9-tetrahydrocannabinol (Δ⁹-THC), may limit their therapeutic utility. With more women than men using medical cannabis for pain relief, it is crucial to understand how sex influences cannabinoid-mediated antinociception and tolerance. Though studies in rats consistently find females are more sensitive to the acute antinociceptive effects of cannabinoids, our work with mice consistently finds the converse. The present study examined whether our observed sex differences in Δ⁹-THC-induced antinociception and tolerance are consistent across multiple mouse strains or are strain-dependent. Male and female C57BL/6J (B6), DBA/2, AKR, and CBA/J mice were assessed for differences in acute Δ⁹-THC-induced antinociception and hypothermia prior to and following seven days of once-daily Δ⁹-THC administration. Consistent with our previous findings, male B6 mice were more sensitive to the acute antinociceptive effects of Δ⁹-THC than female littermates, an effect which dissipated with age. B6 males had decreased cannabinoid expression in the PAG compared to females. While DBA and CBA female mice showed increased Δ⁹-THC-antinociception compared to male littermates at 30 and 10 mg/kg Δ⁹-THC, respectively, these differences were less pronounced at higher doses, revealing that dose of Δ⁹-THC may also be important. Overall, CBA mice were more sensitive to Δ⁹-THC-induced antinociception while AKR mice were less responsive. These studies highlight the therapeutic potential of Δ⁹-THC in pain management and underscore the importance of considering not only Δ⁹-THC dose as a function of sex, but potentially genetic differences when evaluating their clinical utility.
... In contrast, CB users had increased functional connectivity compared to controls from the right I to IV of the cerebellum to the left posterior cingulate and to the right fusiform gyrus. While speculative, these alterations in connectivity may be secondary to downregulation and desensitization of CB1 receptors after chronic exposure (González et al., 2005;Sim-Selley, 2003). Contrary to our hypotheses, CB use features, such as age of CB initiation and total lifetime use were unrelated to rsFC. ...
... Unlike Food and Drug Association (FDA) approved medications, treatments approved by voter initiatives or legislative action come with little evidence to guide dosing to optimize benefits and minimize adverse effects. Further, recent US national data reports that 3 in 10 adults who use cannabis develop cannabis use disorder (CUD), with 23% developing severe CUD (36) often with tolerance to 9-tetrahydrocannabinol (THC) and withdrawal symptoms (37,38). Data are lacking on whether adults using cannabis for medical purposes develop similar rates of CUD to those who use cannabis for recreational purposes. ...
Background
Evidence for long-term effectiveness of commercial cannabis products used to treat medical symptoms is inconsistent, despite increasingly widespread use.
Objective
To prospectively evaluate the effects of using cannabis on self-reported symptoms of pain, insomnia, anxiety, depression, and cannabis use disorder (CUD) after 12 months of use.
Methods
This observational cohort study describes outcomes over 9 months following a 12-week randomized, waitlist-controlled trial (RCT: NCT03224468) in which adults (N = 163) who wished to use cannabis to alleviate insomnia, pain, depression, or anxiety symptoms were randomly assigned to obtain a medical marijuana card immediately (immediate card acquisition group) or to delay obtaining a card for 12 weeks delay (delayed card acquisition group). During the 9-month post-randomization period, all participants could use cannabis as they wished and choose their cannabis products, doses, and frequency of use. Insomnia, pain, depression, anxiety, and CUD symptoms were assessed over the 9-month post-randomization period.
Results
After 12 months of using cannabis for medical symptoms, 11.7% of all participants (n = 19), and 17.1% of those using cannabis daily or near-daily (n = 6) developed CUD. Frequency of cannabis use was positively correlated with pain severity and number of CUD symptoms, but not significantly associated with severity of self-reported insomnia, depression, or anxiety symptoms. Depression scores improved throughout the 9 months in all participants, regardless of cannabis use frequency.
Conclusions
Frequency of cannabis use was not associated with improved pain, anxiety, or depression symptoms but was associated with new-onset cannabis use disorder in a significant minority of participants. Daily or near-daily cannabis use appears to have little benefit for these symptoms after 12 months of use.
... It is both one of the diagnostic criteria for cannabis use disorder (CUD) and a distinct diagnosis in the fifth edition of the Diagnostic and Statistical Manual (DSM-5) of the American Psychiatric Association 1 and the 11th edition of the International Classification of Diseases (ICD-11) of the World Health Organization. 2 The validity and clinical significance of cannabis withdrawal syndrome (CWS), which occurs upon substantially decreased use or abstinence among persons with chronic, heavy cannabis use, is well established. [3][4][5][6] The typical symptoms of CWS include irritability, anxiety, sleep difficulties, decreased appetite, restlessness, depressed mood, and somatic complaints, such as abdominal pain, sweating, fever, chills, tremors, and headache. ...
Background
Cannabis withdrawal syndrome (CWS) is a recognized psychiatric disorder that can interfere with recovery from cannabis use disorder (CUD).
Objectives
To identify factors differentially associated with the prevalence of lifetime and past-year CWS.
Methods
We conducted a secondary analysis of a 2020 systematic literature review on the prevalence of CWS among people with regular cannabis use or moderate-severe CUD and conducted new meta-analyses separately for lifetime and current (past-year) CWS prevalence.
Results
The meta-analyses used 51 studies, including 4 additional studies not used in the 2020 meta-analyses. The overall prevalence of CWS was 65.4% (95% CI, 50.1%–78.1%) for lifetime (based on 22 studies) and 30.1% (95% CI, 23.4%–37.7%) for current (based on 29 studies). The only 2 factors that were significantly associated with lifetime CWS prevalence in multivariable meta-regression were sample source (inpatient >outpatient >nonclinical populations) and cannabis use frequency at baseline (daily >less-than-daily >not reported). However, current CWS prevalence was associated with 9 additional factors: study design (longitudinal cohort >cross-sectional), source of CWS diagnostic information (self-related or informant-rated >clinician-rated), geographic region (South America >rest), method of CWS diagnosis (multi-item rating instrument >generic question), lifetime tobacco use disorder comorbidity (present >absent), treatment-seeking status for CUD (treatment-seeking >nonseeking), race/ethnicity (Latino/Hispanic or Black >White), sex (male >female), and age (younger >older).
Conclusions
Our study found that current CWS had 11 factors associated with prevalence, while lifetime CWS had only 2. These different associations do not imply causality but suggest possible differences in factors that promote or protect against the development of CWS, which warrants further study.
Contexte
Le syndrome de sevrage du cannabis (SSC) est un trouble psychiatrique reconnu qui peut interférer avec le rétablissement d'un trouble lié à l'usage du cannabis (TCC).
Objectifs
Identifier les facteurs et leurs différences associés à la prévalence du SSC au cours de la vie et de l'année précédente.
Méthodes
Nous avons effectué une analyze secondaire d'une revue systématique de la littérature de 2020 sur la prévalence du SSC chez les personnes ayant une consommation régulière de cannabis ou un trouble de consommation de cannabis modéré à sévère et nous avons effectué de nouvelles méta-analyses distinctes pour la prévalence du SSC au cours de la vie entière et du SSC actuel (année passée).
Résultats
Les méta-analyses ont utilisé 51 études, dont quatre études supplémentaires non utilisées dans la méta-analyses de 2020. La prévalence globale du SSC était de 65,4 % (IC à 95%, 50,1–78,1%) pour la vie entière (basé sur 22 études) et 30,1 % (IC à 95%, 23,4%–37,7%) pour la vie actuelle (basé sur 29 études). Les deux seuls facteurs significativement associés à la prévalence du SSC au cours de la vie dans la méta-régression multivariable était la source de l'échantillon (patient hospitalisé; patient externe; populations non cliniques) et la fréquence de la consommation de cannabis au départ (quotidienne; moins que quotidiennement; non déclaré). Cependant, la prévalence actuelle du SSC était associée à neuf facteurs supplémentaires: le plan d’étude (cohorte longitudinale et transversale), la source d’information sur le diagnostic du SSC (auto-évaluées ou évaluées par un intervenant; évaluées par un clinicien), région géographique (Amérique du Sud; autre), méthode de diagnostic du SSC (instrument d'évaluation multi-items; question générique), comorbidité du trouble du tabagisme au cours de la vie (présent; absent), le statu de recherche de traitement pour le TCC (recherche de traitement; non-recherche de traitement), race/ethnicité (Latino/Hispanique ou Noir; Blanc), le sexe (homme; femme) et l’âge (jeune; âgé).
Conclusion
Notre étude a révélé que le SSC actuel comportait 11 facteurs associés à la prévalence, tandis que le SSC au cours de la vie entière n'en avait que deux. Ces associations différentes n'impliquent pas de causalité mais suggèrent des différences possibles dans les facteurs qui favorisent ou protègent contre le développement du SSC, ce qui justifie une étude plus approfondie.
... It is well-reported that exposure to CB 1 orthosteric agonists produces tolerance to the antiallodynic effects (Gonzalez et al., 2005). We observed that the antinociceptive efficacy of GAT229 was sustained over 28 days of repeated daily administration, which suggests that long-term exposure to GAT229 does not produce tolerance. ...
Chemotherapy-induced peripheral neuropathy (CIPN) is one of chemotherapies’ most often documented side effects. Patients with CIPN experience spontaneous burning, numbness, tingling, and neuropathic pain in their feet and hands. Currently, there is no effective pharmacological treatment to prevent or treat CIPN. Activating the cannabinoid receptor type 1 (CB1) by orthosteric agonists has shown promising results in alleviating the pain and neuroinflammation associated with CIPN. However, the use of CB1 orthosteric agonists is linked to undesirable side effects. Unlike the CB1 orthosteric agonists, CB1 positive allosteric modulators (PAMs) don’t produce any psychoactive effects, tolerance, or dependence. Previous studies have shown that CB1 PAMs exhibit antinociceptive effects in inflammatory and neuropathic rodent models. This study aimed to investigate the potential benefits of the newly synthesized GAT229, a pure CB1 PAM, in alleviating neuropathic pain and slowing the progression of CIPN. GAT229 was evaluated in a cisplatin-induced (CIS) mouse model of peripheral neuropathic pain (3 mg/kg/d, 28 d, i.p.). GAT229 attenuated and slowed the progression of thermal hyperalgesia and mechanical allodynia induced by CIS, as evaluated by the hotplate test and von Frey filament test. GAT229 reduced the expression of proinflammatory cytokines in the dorsal root ganglia (DRG) neurons. Furthermore, GAT229 attenuated nerve injuries by normalizing the brain-derived neurotrophic factor and the nerve growth factor mRNA expression levels in the DRG neurons. The CB1 receptor antagonist/inverse agonist AM251 blocked GAT229-mediated beneficial effects. According to our data, we suggest that CB1 PAMs might be beneficial in alleviating neuropathic pain and slowing the progression of CIPN.
... The logic behind using an escalating dose of THC is to overcome the potential desensitization of CB1 receptors after chronic exposure [63]. Furthermore, this protocol has been demonstrated to reliably modify dopamine-related behaviors and increase the mesocorticolimbic dopaminergic activity when rats are tested during adulthood [52,53,64,65]. ...
Adolescence is a gradual transition period between childhood and adulthood, characterized by greater sensitivity to rewarding stimuli. Consistently, demographic studies have shown that teenagers show a high prevalence of rewarding drugs use, mainly nicotine-containing products and cannabis. Clinical researches have associated the adolescence consume of nicotine and cannabis with a higher vulnerability to develop neuropsychiatric diseases in adulthood such as depression, schizophrenia, and drug addiction. Despite these evidence, it is difficult to conclusively prove causal relationships with longitudinal and retrospective clinical research in humans. Accordingly, preclinical animal models are indispensable tools to determine the causal relationship between early neurodevelopmental drug exposure and psychiatric disease risk. Preclinical rodent models have been widely used to research the neurobiological mechanisms underlying the vulnerability of the adolescent brain because the similarities in behavioral patterns and brain maturation processes with human adolescents. Particularly, both human teenager and adolescent rodents show similar patterns of DA maturation, and dysregulations in these neuronal circuits may induce phenotypes associated with psychiatric diseases.This chapter will describe the THC and nicotine adolescent exposure methods in rats that induce a long-term dysregulation of the dopaminergic system. Furthermore, this chapter will detail the experimental protocol used in our laboratory to test the electrical activity of dopaminergic neurons. In addition, these methodologies include preclinical testing protocols for several neuropsychiatric behavioral phenotypes related to social cognition and motivation, memory processing, and anhedonia-like behaviors.Key wordsAdolescenceDopamineNicotineTHCDepressionWorking memorySocial interaction
... CB 1 Rs are downregulated or desensitized with prolonged exposure to ligand (Kouznetsova et al., 2002), making tolerance an obstacle to drug development. Indeed, heavy cannabis use can lead to D 9 -THC tolerance and dependence in humans (Colizzi and Bhattacharyya, 2018) and rodents (Gonz alez et al., 2005), and the CB 1 R is downregulated in postmortem human brain tissue from frequent cannabis users relative to nonusers (Villares, 2007). Previous studies have investigated JZL 184-induced CB 1 R desensitization in rodents, with mixed results. ...
The endocannabinoid system (ECS) modulates synaptic function to regulate many aspects of neurophysiology. It adapts to environmental changes and is affected by disease. Thus, the ECS presents an important target for therapeutic development. Despite recent interest in cannabinoid-based treatments, few preclinical studies are conducted in human systems. Human induced pluripotent stem cells (hiPSCs) provide one possible solution to this issue. However, it is not known if these cells have a fully functional ECS. Here, we show that hiPSC-derived neuron/astrocyte cultures exhibit a complete ECS. Using Ca2+ imaging and a genetically encoded endocannabinoid sensor, we demonstrate that they not only respond to exogenously applied cannabinoids but also produce and metabolize endocannabinoids. Synaptically driven [Ca2+]i spiking activity was inhibited (EC50 = 48 ± 13 nM) by the efficacious agonist [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate] (Win 55,212-2) and by the endogenous ligand 2-arachidonoyl glycerol (2-AG; EC50 = 2.0 ± 0.6 µm). The effects of Win 55212-2 were blocked by a CB1 receptor-selective antagonist. Δ9-Tetrahydrocannabinol acted as a partial agonist, maximally inhibiting synaptic activity by 47 ± 14% (EC50 = 1.4 ± 1.9 µm). Carbachol stimulated 2-AG production in a manner that was independent of Ca2+ and blocked by selective inhibition of diacylglycerol lipase. 2-AG returned to basal levels via a process mediated by monoacylglycerol lipase as indicated by slowed recovery in cultures treated with 4-[Bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester (JZL 184). Win 55,212-2 markedly desensitized CB1 receptor function following a 1-day exposure, whereas desensitization was incomplete following 7-day treatment with JZL 184. This human cell culture model is well suited for functional analysis of the ECS and as a platform for drug development. SIGNIFICANCE STATEMENT: Despite known differences between the human response to cannabinoids and that of other species, an in vitro human model demonstrating a fully functional endocannabinoid system has not been described. Human induced pluripotent stem cells (hiPSCs) can be obtained from skin samples and then reprogrammed into neurons for use in basic research and drug screening. Here, we show that hiPSC-derived neuronal cultures exhibit a complete endocannabinoid system suitable for mechanistic studies and drug discovery.
... 148,149 The endocannabinoid system is thought to be involved in the modulation of circadian rhythm and the sleep/wake cycle, 150,151 particularly through the influence of cannabinoids on CB1 receptors. 152,153 Heavy cannabis activity is linked to desensitization, and decreased CB1 efficacy 154,155 and blocking of the CB1 receptors have been found to facilitate waking in rodent models specifically. 156,157 There is limited evidence to suggest that cannabis use might influence aspects of the sleep cycle such as slow-wave sleep (SWS) [158][159][160] and rapid eye movement sleep. ...
The current review highlights the available research related to cannabis and indicators of physical health in a variety of domains. Various studies have found associations between cannabis use with pulmonary, cardiovascular, gastrointestinal, and endocrine function as well as body mass index and sleep. At this time, more research is needed to understand the influence of cannabis use on physical health, particularly among adolescent samples.
... It is known that chronic cannabis use is associated with CB 1 receptor desensitization and downregulation of endocannabinoid signaling. 43 Reduction of endocannabinoid levels in chronic cannabis users have been explained by the impact of externally administered cannabinoids that cause the ECS to adapt. In our study, we observed that also more occasional use of cannabis is associated with lower endocannabinoid levels. ...
Background
Although current treatments for Post-Traumatic Stress Disorder (PTSD) in war veterans are effective, unfortunately 30–50% still do not benefit from these treatments. Trauma-focused therapies, eg exposure therapy, are primarily based on extinction processes in which the endocannabinoid system (ECS) plays a significant role. Therefore, it can be hypothesized that poor treatment response on trauma-focused therapy due to extinction deficits may be associated with a poorly functioning ECS. The present study examined whether the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) are associated with post-treatment symptom reduction.
Methods
Blood plasma levels of AEA and 2-AG were determined in war veterans with a PTSD diagnosis ( n = 54) and combat controls ( n = 26) before and after a 6–8 month interval. During this period veterans with PTSD received trauma-focused therapy (eg cognitive behavioral therapy with exposure or eye-movement desensitization and reprocessing). Clinical symptoms were assessed before and after therapy with the Clinician Administered PTSD Scale (CAPS), State-Trait Anxiety Inventory (STAI) and Mood and Anxiety Symptom Questionnaire (MASQ).
Results
Regression analysis demonstrated that pretreatment endocannabinoid levels were not predictive of PTSD symptom reduction. Additionally, baseline endocannabinoid levels did not differ between either PTSD and combat controls or between combat controls, treatment responders, and non-responders. Only cortisol levels significantly decreased over time from pre- to posttreatment ( p = .041). Endocannabinoid levels were significantly lower in individuals who reported cannabis use during their lifetime, independent of PTSD diagnosis. Furthermore, correlation analysis revealed that pretreatment 2-AG levels in PTSD were positively correlated with anxious arousal ( r = .354, p = .015) and negatively with avoidance symptoms ( r = -.271, p = .048). Both posttreatment AEA and 2-AG were positively correlated with trait anxiety (AEA r = .459, p = .003; 2-AG r = .423, p = .006), anxious arousal (AEA r = .351, p = .024; 2-AG r = .311, p = .048) and general distress depression symptoms (AEA r = .414, p = .007; 2-AG r = .374, p = .016).
Conclusion
Since endocannabinoids are mainly generated ‘on demand’, future work could benefit by investigating endocannabinoid circulation under both baseline and stressful conditions. In line with previous research cannabis use was associated with lower endocannabinoid levels. The correlation analysis between pre- and posttreatment endocannabinoid levels and pre- and posttreatment clinical symptomatology were exploratory analysis and should be replicated in future research.
... Ramaekers et al. showed that neurocognitive performance was significantly impaired after smoking in occasional cannabis users compared to chronic, heavy users, indicating the development of tolerance 13,14 . The development of tolerance may involve multiple pharmacodynamic mechanisms including the downregulation and desensitization of CB 1 receptors in various brain regions [15][16][17] and the recruitment of alternate neural networks to compensate for the impairing effects of ∆ 9 -THC during the performance of neurocognitive tasks 18,19 . It has also been shown that the development of tolerance to ∆ 9 -THC may reduce the sensitivity of standardized field sobriety tests in the detection of cannabis impairment 20 . ...
Previous investigators have found no clear relationship between specific blood concentrations of ∆9-tetrahydrocannabinol (∆9-THC) and impairment, and thus no scientific justification for use of legal “per se” ∆9-THC blood concentration limits. Analyzing blood from 30 subjects showed ∆9-THC concentrations that exceeded 5 ng/mL in 16 of the 30 subjects following a 12-h period of abstinence in the absence of any impairment. In blood and exhaled breath samples collected from a group of 34 subjects at baseline prior to smoking, increasing breath ∆9-THC levels were correlated with increasing blood levels (P < 0.0001) in the absence of impairment, suggesting that single measurements of ∆9-THC in breath, as in blood, are not related to impairment. When post-smoking duration of impairment was compared to baseline ∆9-THC blood concentrations, subjects with the highest baseline ∆9-THC levels tended to have the shortest duration of impairment. It was further shown that subjects with the shortest duration of impairment also had the lowest incidence of horizontal gaze nystagmus at 3 h post-smoking compared to subjects with the longest duration of impairment (P < 0.05). Finally, analysis of breath samples from a group of 44 subjects revealed the presence of transient cannabinoids such as cannabigerol, cannabichromene, and ∆9-tetrahydrocannabivarin during the peak impairment window, suggesting that these compounds may be key indicators of recent cannabis use through inhalation. In conclusion, these results provide further evidence that single measurements of ∆9-THC in blood, and now in exhaled breath, do not correlate with impairment following inhalation, and that other cannabinoids may be key indicators of recent cannabis inhalation.
... An obvious caveat of precipitated withdrawal is that humans undergo spontaneous withdrawal, so the translational relevance of precipitated CWS is unclear. While spontaneous cannabis or THC withdrawal does reliably induce somatic withdrawal symptoms (e.g., wet dog and head shaking, front paw tremor, hunched posture, body tremor, etc.) [38][39][40][41], indicating its potential to drive CWS, previous studies have struggled to provide strong evidence for spontaneous THC withdrawal symptoms that more closely model human CWS. ...
Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors like irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during abstinence in a mouse model of chronic THC exposure. Using a THC treatment regimen known to produce tolerance, we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance to THC. Altered striatal DA release, sleep, and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. These findings provide a foundation for preclinical study of directly translatable non-precipitated THC withdrawal symptoms and the neural mechanisms that affect them.
... Ramaekers et al. showed that neurocognitive performance was signi cantly impaired after smoking in occasional cannabis users compared to chronic, heavy users, indicating the development of tolerance [11,12]. The development of tolerance may involve multiple pharmacodynamic mechanisms including the downregulation and desensitization of CB 1 receptors in various brain regions [13][14][15] and the recruitment of alternate neural networks to compensate for the impairing effects of D 9 -THC during the performance of neurocognitive tasks [16,17]. It has also been shown that the development of tolerance to D 9 -THC may reduce the sensitivity of standardized eld sobriety tests in the detection of cannabis impairment [18]. ...
Previous investigators have found no clear relationship between specific blood concentrations of D ⁹ -tetrahydrocannabinol (D ⁹ -THC) and impairment, and thus no scientific justification for use of legal “per se” D ⁹ -THC blood concentration limits. Analyzing blood from 30 subjects showed D ⁹ -THC concentrations that exceeded 5 ng/mL in 16 of the 30 subjects following a 12-hour period of abstinence in the absence of any impairment. In blood and exhaled breath samples collected from a group of 34 subjects at baseline prior to smoking, increasing breath D ⁹ -THC levels were related to increasing blood levels in the absence of impairment, suggesting that single measurements of D ⁹ -THC in breath, as is blood, are not related to impairment. When post-smoking duration of impairment was compared to baseline D ⁹ -THC blood concentrations, subjects with the highest baseline D ⁹ -THC levels tended to have the shortest duration of impairment. It was further shown that subjects with the shortest duration of impairment also tended to have the lowest incidence of horizontal gaze nystagmus at 3 h post-smoking. Finally, analysis of breath samples from these subjects revealed the presence of transient cannabinoids such as cannabigerol, cannabichromene, and D ⁹ -tetrahydrocannabivarin during the peak impairment window, suggesting that these compounds may be key indicators of recent cannabis use through inhalation. In conclusion, these results provide further evidence that single measurements of D ⁹ -THC in blood, and now in exhaled breath, do not correlate with impairment following inhalation, and that other cannabinoids may be key indicators of recent cannabis inhalation.
... Drug doses are based on previous studies (Puighermanal et al., 2009;Puighermanal et al., 2013;Rubino, Realini, Braida, Alberio, et al., 2009;Rubino, Realini, Braida, Guidi, et al., 2009). Increasing doses of THC were administered to counter the development of drug tolerance (Gonz alez et al., 2005) and were chosen based on previous studies demonstrating THC-induced long-term behavioural deficits in rats (Renard et al., 2017;). ...
Long‐lasting cognitive impairment is one of the most central negative consequences related to the exposure to cannabis during adolescence and particularly of Δ‐9‐tetrahydrocannabinol (THC). The aim of this study was to compare the protracted effects of adolescent versus late‐adolescent chronic exposure to THC on short‐term memory and plasticity and to examine whether rapamycin, a blocker of the mammalian target of rapamycin (mTOR) pathway, can restore THC‐induced deficits in memory and plasticity. Male rats were injected with ascending doses of THC [2.5, 5, 10 mg/kg; intraperitoneally (i.p.)] during adolescence and late‐adolescence (post‐natal days 30–41 and 45–56, respectively), followed by daily injections of rapamycin (1 mg/kg, i.p.) during the first 10 days of cessation from THC. Thirty days after the last injection, rats were tested for short‐term and working memory, anxiety‐like behaviour, and plasticity in the pathways projecting from the ventral subiculum (vSub) of the hippocampus to the prefrontal cortex (PFC) and nucleus accumbens (NAc). THC exposure in adolescence, but not late‐adolescence, was found to induce long‐term deficits in object recognition short‐term memory and synaptic plasticity in the hippocampal‐accumbens pathway. Importantly, rapamycin rescued these persistent effects of THC administered during adolescence. Our findings show that some forms of memory and plasticity are sensitive to chronic THC administration during adolescence and that rapamycin administered during THC cessation may restore cognitive function and plasticity, thus potentially protecting against the possible long‐term harmful effects of THC.
... Following endocytosis, CB 1 has been described to undergo either recycling or degradation, with determination of this fate likely involving protein-protein interactions (e.g., Grimsey et al., 2010;Leterrier, Bonnard, Carrel, Rossier, & Lenkei, 2004;Martini et al., 2007;Wu et al., 2008). Regional differences in the development of tolerance and subsequent recovery of responsiveness following chronic cannabinoid exposure might be indicative of differential CB 1 regulation and protein-protein interactions between cell types (González, Cebeira, & Fernández-Ruiz, 2005). In the majority of contexts studied to date, CB 2 recycles following internalization and is refractory to agonist-induced degradation (Grimsey, Goodfellow, Dragunow, & Glass, 2011;Kleyer et al., 2012). ...
Cannabinoid receptors 1 and 2 (CB1 and CB2) are implicated in a range of physiological processes and have gained attention as promising therapeutic targets for a number of diseases. Protein-protein interactions play an integral role in modulating G protein-coupled receptor (GPCR) expression, subcellular distribution and signaling, and the identification and characterization of these will not only improve our understanding of GPCR function and biology, but may provide a novel avenue for therapeutic intervention. A variety of techniques are currently being used to investigate GPCR protein-protein interactions, including Förster/fluorescence and bioluminescence resonance energy transfer (FRET and BRET), proximity ligation assay (PLA), and bimolecular fluorescence complementation (BiFC). However, the reliable application of these methodologies is dependent on the use of appropriate controls and the consideration of the physiological context. Though not as extensively characterized as some other GPCRs, the investigation of CB1 and CB2 interacting proteins is a growing area of interest, and a range of interacting partners have been identified to date. This review summarizes the current state of the literature regarding the cannabinoid receptor interactome, provides commentary on the methodologies and techniques utilized, and discusses future perspectives.
... Previous work has also found differences in CB 1 R density and desensitization between male and female rodents (Castelli et al. 2014;de Fonseca et al. 1994;Farquhar et al. 2019;González andCebeira 2005 but see Wiley et al. 2020). Another possibility that could explain our findings is that sex differences in cannabinoid response might be strain dependent and that our observations might be specific for the C57BL/6 strain upon which our mice are backcrossed. ...
Rationale
Tolerance to cannabinoids could limit their therapeutic potential. Male mice expressing a desensitization-resistant form (S426A/S430A) of the type-1 cannabinoid receptor (CB1R) show delayed tolerance to delta-9-tetrahydrocannabinol (∆⁹-THC) but not CP55,940. With more women than men using medical cannabis for pain relief, it is essential to understand sex differences in cannabinoid antinociception, hypothermia, and resultant tolerance.
Objective
Our objective was to determine whether female mice rely on the same molecular mechanisms for tolerance to the antinociceptive and/or hypothermic effects of cannabinoids that we have previously reported in males. We determined whether the S426A/S430A mutation differentially disrupts antinociceptive and/or hypothermic tolerance to CP55,940 and/or Δ⁹-THC in male and female S426A/S430A mutant and wild-type littermates.
Results
The S426A/S430A mutation conferred an enhanced antinociceptive response for ∆⁹-THC and CP55,940 in both male and female mice. While the S426A/S430A mutation conferred partial resistance to ∆⁹-THC tolerance in male mice, disruption of CB1R desensitization had no effect on tolerance to ∆⁹-THC in female mice. The mutation did not alter tolerance to the hypothermic effects of ∆⁹-THC or CP55,940 in either sex. Interestingly, female mice were markedly less sensitive to the antinociceptive effects of 30 mg/kg ∆⁹-THC and 0.3 mg/kg CP55,940 compared with male mice.
Conclusions
Our results suggest that disruption of the GRK/βarrestin2 pathway of desensitization alters tolerance to Δ⁹-THC but not CP55,940 in male but not female mice. As tolerance to Δ⁹-THC appears to develop differently in males and females, sex should be considered when assessing the therapeutic potential and dependence liability of cannabinoids.
Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder marked by persistent gastrointestinal inflammation and a spectrum of systemic effects, including extraintestinal manifestations (EIMs) that impact the joints, skin, liver, and eyes. Conventional therapies primarily target intestinal inflammation, yet they frequently fail to ameliorate these systemic complications. Recent investigations have highlighted the complex interplay among the immune system, gut, and nervous system in IBD pathogenesis, thereby underscoring the need for innovative therapeutic approaches. Methods: We conducted a comprehensive literature search using databases such as PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Keywords including “cannabinoids”, “endocannabinoid system”, “endocannabinoidome”, “inflammatory bowel disease”, and “extraintestinal manifestations” were used to identify peer-reviewed original research and review articles that explore the role of the endocannabinoidome (eCBome) in IBD. Results: Emerging evidence suggests that eCBome—a network comprising lipid mediators, receptors (e.g., CB1, CB2, GPR55, GPR35, PPARα, TRPV1), and metabolic enzymes—plays a critical role in modulating immune responses, maintaining gut barrier integrity, and regulating systemic inflammation. Targeting eCBome not only improves intestinal inflammation but also appears to mitigate metabolic, neurological, and extraintestinal complications such as arthritis, liver dysfunction, and dermatological disorders. Conclusions: Modulation of eCBome represents a promising strategy for comprehensive IBD management by addressing both local and systemic disease components. These findings advocate for further mechanistic studies to develop targeted interventions that leverage eCBome as a novel therapeutic avenue in IBD.
An impact of legalization and decriminalization of marijuana is the gradual increase in the use of cannabis for recreational purposes, which poses a potential threat to society and healthcare systems worldwide. However, the discovery of receptor subtypes, endogenous endocannabinoids, and enzymes involved in synthesis and degradation, as well as pharmacological characterization of receptors, has led to exploration of the use of cannabis in multiple peripheral and central pathological conditions. The role of cannabis in the modulation of crucial events involving perturbed physiological functions and disease progression, including apoptosis, inflammation, oxidative stress, perturbed mitochondrial function, and the impaired immune system, indicates medicinal values. These events are involved in most neurological diseases and prompt the gradual progression of the disease. At present, several synthetic agonists and antagonists, in addition to more than 70 phytocannabinoids, are available with distinct efficacy as a therapeutic alternative in different pathological conditions. The present review aims to describe the use of cannabis in neurological diseases and psychiatric disorders.
Background
Cannabis and tobacco co-use is prevalent, and individuals who co-use have elevated cannabis relapse rates compared with those using cannabis alone. Research demonstrates that individuals who co-use experience greater cannabis withdrawal severity, a strong predictor of cannabis relapse, compared with those using cannabis alone. In this secondary analysis, we compared the trajectory of cannabis withdrawal severity during 28 days of cannabis abstinence in individuals with cannabis use disorder parsed according to tobacco co-use status.
Methods
Men with cannabis use disorder (N=20) were parsed according to tobacco co-use: those with heavy (CT-H ≥10 cigarettes/day, n=11) and light tobacco co-use (CT-L ≤5 cigarettes/day, n=9). Participants completed 28 days of cannabis abstinence encouraged by contingency management and supportive therapy. Cannabis withdrawal severity was assessed weekly using the Marijuana Withdrawal Checklist. Abstinence was biochemically verified using urine analyzed by gas chromatography-mass spectrometry.
Results
Fourteen participants achieved 28 days of biochemically verified cannabis abstinence and 4 participants significantly reduced their cannabis use (>70%); 2 participants relapsed and were excluded from the analyses. In the included participants (CT-H, n=9; CT-L, n=9), there was a significant interaction (group x time) effect for Marijuana Withdrawal Checklist severity ( P =0.03). Relative to CT-L, CT-H exhibited elevated cannabis withdrawal severity across multiple time points during cannabis abstinence.
Conclusions
CT-H experiences elevated cannabis withdrawal severity that persists throughout 28 days of cannabis abstinence, relative to CT-L. Since withdrawal symptoms that remain elevated in severity over time prolong cannabis relapse risk, personalized approaches that target heavy tobacco co-use in CT-H may improve rates of cannabis cessation.
Contexte
La consommation simultanée de cannabis et de tabac est répandue, et les personnes qui la pratiquent ont des taux de rechute élevés pour le cannabis par rapport à celles qui consomment seulement du cannabis. Les recherches démontrent que les personnes qui font un usage conjoint éprouvent une plus grande intensité de sevrage du cannabis, un facteur prédictif important de rechute, par rapport à celles qui ne consomment que du cannabis. Dans cette analyse complémentaire, nous avons comparé la courbe d’intensité du sevrage du cannabis pendant 28 jours d’abstinence chez des personnes souffrant de troubles liés à l’usage du cannabis et classées en fonction de leur statut de consommateur simultané de tabac.
Méthodes
Les hommes souffrant de troubles liés à la consommation de cannabis (N=20) ont été répartis en fonction de leur consommation simultanée de tabac : ceux ayant une forte consommation de tabac (CT-H ≥10 cigarettes/jour, n=11) et ceux ayant une faible consommation de tabac (CT-L ≤5 cigarettes/jour, n=9). Les participants ont suivi 28 jours d’abstinence de cannabis, encouragés par une gestion des contingences et une thérapie de soutien. La sévérité du sevrage du cannabis a été évaluée chaque semaine à l’aide de la liste de contrôle du sevrage de la marijuana (Marijuana Withdrawal Checklist-MWC). L’abstinence a été vérifiée biochimiquement en analysant l’urine par chromatographie en phase gazeuse et spectrométrie de masse.
Résultats
Quatorze participants ont atteint 28 jours d’abstinence de cannabis vérifiée biochimiquement et quatre participants ont réduit de manière significative leur consommation de cannabis (>70%); deux participants ont rechuté et ont été exclus des analyses. Parmi les participants inclus (CT-H, n=9; CT-L, n=9), il y avait un effet d’interaction significatif (groupe x temps) pour la sévérité de la MWC ( P =0,03). Par rapport à CT-L, CT-H a présenté une sévérité de sevrage du cannabis élevée sur plusieurs points temporels pendant l’abstinence de cannabis.
Conclusions
Les CT-H présentent une sévérité de sevrage du cannabis élevée qui persiste pendant les 28 jours d’abstinence, par rapport aux CT-L. Étant donné que les symptômes de sevrage dont la gravité reste élevée au fil du temps prolongent le risque de rechute de consommation de cannabis, les approches personnalisées qui ciblent la forte consommation conjointe avec le tabac chez les CT-H peuvent améliorer les taux d’abandon du cannabis.
While current analytical methodologies can readily identify cannabis use, definitively establishing recent use within the impairment window has proven to be far more complex, requiring a new approach. Recent studies have shown no direct relationship between impairment and Δ9-tetra-hydrocannabinol (Δ9-THC) concentrations in blood or saliva, making legal “per se” Δ9-THC limits scientifically unjustified. Current methods that focus on Δ9-THC and/or metabolite concentrations in blood, saliva, urine, or exhaled breath can lead to false positive results for recent use due to the persistence of Δ9-THC well outside of the typical three to four-hour window of potential impairment following cannabis inhalation. There is also the issue of impairment due to other intoxicating substances– just because a subject exhibits signs of impairment and cannabis use is detected does not rule out the involvement of other drugs. Compounding the matter is the increasing popularity of hemp-derived cannabidiol (CBD) products following passage of the 2018 Farm Bill, which legalized industrial hemp in the U.S. Many of these products contain varying levels of Δ9-THC, which can lead to false positive tests for cannabis use. Furthermore, hemp-derived CBD is used to synthesize Δ8-THC, which possesses psychoactive properties similar to Δ9-THC and is surrounded by legal controversy. For accuracy, analytical methods must be able to distinguish the various THC isomers, which have identical masses and exhibit immunological cross-reactivity. A new testing approach has been developed based on exhaled breath and blood sampling that incorporates kinetic changes and the presence of key cannabinoids to detect recent cannabis use within the impairment window without the false positive results seen with other methods. The complexity of determining recent cannabis use that may lead to impairment demands such a comprehensive method so that irresponsible users can be accurately detected without falsely accusing responsible users who may unjustly suffer harsh, life-changing consequences.
Cannabis has been used recreationally and medically for centuries, yet research into understanding the mechanisms of its therapeutic effects has only recently garnered more attention. There is evidence to support the use of cannabinoids for the treatment of chronic pain, muscle spasticity, nausea and vomiting due to chemotherapy, improving weight gain in HIV-related cachexia, emesis, sleep disorders, managing symptoms in Tourette syndrome, and patient-reported muscle spasticity from multiple sclerosis. However, tolerance the risk for cannabis use disorder are two significant disadvantages for cannabinoid-based therapies in humans. Recent work has revealed prominent sex differences in the acute response and tolerance to cannabinoids in both humans and animal models. This review will discuss evidence demonstrating cannabinoid tolerance in rodents, non-human primates, and humans and our current understanding of the neuroadaptations occurring at the cannabinoid type 1 receptor (CB1R) that are responsible tolerance. CB1R expression is downregulated in tolerant animals and humans while there is strong evidence of CB1R desensitization in cannabinoid tolerant rodent models. Throughout the review, critical knowledge gaps are indicated and discussed, such as the lack of a neuroimaging probe to assess CB1R desensitization in humans. The review discusses the intracellular signaling pathways that are responsible for mediating CB1R desensitization and downregulation including the action of G protein-coupled receptor kinases, β-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and the intracellular trafficking of CB1R. Finally, the review discusses approaches to reduce cannabinoid tolerance in humans based on our current understanding of the neuroadaptations and mechanisms responsible for this process.
Background:
As greater numbers of states in the United States and countries in the world continue to legalize cannabis for medical use, it has become increasingly important to assess patterns of cannabis use in individuals using cannabis for medical symptoms over time. A public health concern is that, like recreational cannabis, some individuals using cannabis for medical reasons may develop detrimental patterns of use, leading to the development of a cannabis use disorder (CUD).
Methods:
In a 9-month longitudinal cohort study following a 12-week randomized, waitlist-controlled trial in 149 adults who used cannabis to alleviate insomnia, pain, depressed mood, or anxiety (RCT: NCT03224468), we assessed whether patterns of cannabis use for the 9 months following the RCT were associated with the development of CUD.
Results:
We identified five unique trajectories of use; 31 participants (21%) had low stable or no use, 50 (34%) had medium stable use, 19 (13%) had high stable use, 26 (17%) showed de-escalating and 23 (15%) showed escalating use over 9 months following the RCT. Of 149 participants enrolled, 19 (13%) met diagnostic criteria for CUD at 12 months. Only the escalating cannabis use pattern predicted significantly higher rates of CUD compared to the low or no use category (OR = 4.29, 95% CI = 1.21 to 10.87, p = 0.02).
Conclusions:
These data indicate that most individuals using cannabis for medical symptoms have a stable pattern of use over the first year. Escalation of use may be a detrimental pattern that warrants further concern.
Endocannabinoids (eCBs) and the expanded endocannabinoid system (ECS)-“endocannabinoidome”, consists of the endogenous ligands, eCBs, their canonical and non-canonical receptor subtypes, and their synthesizing and metabolizing enzymes. This system modulates a wide range of body functions and acts as a retrograde signaling system within the central nervous system (CNS) by inhibition of classical transmitters, and plays a vital modulatory function on dopamine, a major neurotransmitter in the CNS. Dopamine is involved in different behavioral processes and contributes to different brain disorders—including Parkinson’s disease, schizophrenia, and drug addiction. After synthesis in the neuronal cytosol, dopamine is packaged into synaptic vesicles until released by extracellular signals. Calcium dependent neuronal activation results in the vesicular release of dopamine and interacts with different neurotransmitter systems. The ECS, among others, is involved in the regulation of dopamine release and the interaction occurs either through direct or indirect mechanisms. The cross-talk between the ECS and the dopaminergic system has important influence in various dopamine-related neurobiological and pathologic conditions and investigating this interaction might help identify therapeutic targets and options in disorders of the CNS associated with dopamine dysregulation.
Background and objectives:
Rates of cannabis use disorder (CUD) are higher in people with schizophrenia than in the general population. Irrespective of psychiatric diagnosis, tobacco co-use is prevalent in those with CUD and leads to poor cannabis cessation outcomes. The cannabis withdrawal syndrome is well-established and increases cannabis relapse risk. We investigated whether cannabis withdrawal severity differed as a function of high versus no/low tobacco dependence and psychiatric diagnosis in individuals with CUD.
Method:
Men with CUD (N = 55) were parsed into four groups according to schizophrenia diagnosis and tobacco dependence severity using the Fagerstrom Test for Nicotine Dependence (FTND): men with schizophrenia with high tobacco dependence (SCT+, n = 13; FTND ≥ 5) and no/low tobacco dependence (SCT-, n = 22; FTND ≤ 4), and nonpsychiatric controls with high (CCT+, n = 7; FTND ≥ 5) and no/low (CCT-, n = 13; FTND ≤ 4) tobacco dependence. Participants completed the Marijuana Withdrawal Checklist following 12-h of cannabis abstinence.
Results:
There was a significant main effect of tobacco dependence on cannabis withdrawal severity (p < .001). Individuals with high tobacco dependence had significantly greater cannabis withdrawal severity (M = 13.85 [6.8]) compared to individuals with no/low tobacco dependence (M = 6.49, [4.9]). Psychiatric diagnosis and the interaction effects were not significant. Lastly, cannabis withdrawal severity positively correlated with FTND (r = .41, p = .002).
Conclusion and scientific significance:
Among individuals with CUD and high tobacco dependence, cannabis withdrawal severity was elevated twofold, irrespective of diagnosis, relative to individuals with CUD and no/low tobacco dependence. Findings from this study emphasize the importance of addressing tobacco co-use when treating CUD.
Here we present methodology to simulate the electrical activity of dopamine neurons by using a freely available software package to numerically integrate a set of coupled nonlinear equations that describe the equivalent circuit that generates the membrane potential, the nonlinear dynamics of channel gating, and a material balance on Ca2+ ions. The general methodology is conductance-based single-neuron computational models. We begin with Hodgkin-Huxley (H-H)-type conductance-based single-compartment models of pacemaking in vitro, which is described mathematically as a limit cycle. We illustrate phase plane methods to gain insight into this activity. Next, we address modeling rhythmic bursting activity. To illustrate that the methodology can be extended beyond the H-H formalism in which activation and inactivation gates operate independently of each other, we include a Markov model of a K+ channel in which they are dependent on each other. We then add random synaptic input to the model to illustrate the hypothesized balanced state in dopamine neurons, which is quite distinct from the balanced state of neocortical pyramidal neurons. We use this model to explain transient bursts and pauses. A major advantage of models is that parameter sweeps can be conducted quickly to determine the robustness of predicted activity. Finally, we move to a multi-compartmental model that captures the full morphology of a dopamine neuron to illustrate the role of the axon initial segment (AIS) in action potential initiation.Key wordsComputational modelNonlinear dynamicsPacemakingBurstingDepolarization blockOscillationsSubstantia nigraVentral tegmental areaDopaminergic neuron
The intoxicating and medicinal properties of cannabis have been known since the human species domesticated the plant, at least 11,000 years before present. Its psychotropic constituent, (−)- trans-Δ9-tetrahydrocannabinol (Δ9-THC), exerts its pharmacological effects by binding to selective receptors present on the surface of most cells of the human body, including neurons. These receptors are normally engaged by a family of lipid-derived mediators, called endocannabinoids, which participate in the regulation of a diversity of physiological functions, including pain, mood, hunger, and memory. The endocannabinoid system (ECS) is comprised of two lipid-derived ligands, anandamide (arachidonoylethanolamide) and 2-arachidonoyl-sn-glycerol (2-AG), enzymes and transporters that control their formation and deactivation, and receptors (CB1 and CB2) that transduce their actions. All key components of the ECS are found in the brain and spinal cord but also in most if not all peripheral organs and tissues. In this chapter, we outline current views on how endocannabinoid substances are produced, act on cannabinoid receptors, and are deactivated in the brain. In addition, we review progress on the development of pharmacological agents that interfere with endocannabinoid deactivation and discuss their potential utility in the treatment of disease.
The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.
Cannabinoid hyperemesis syndrome (CHS) was first described in 2004 as a cyclic vomiting illness in cannabis users. It is a puzzling condition because cannabis is a well characterized antiemetic. Cannabis acts through cannabinoid receptors of the endocannabinoid system, which is expressed throughout the body, including the gut-brain axis, where it influences neural, immune, and epithelial mechanisms involved in digestive and defensive functions of the gut. This chapter outlines the pathways of the gut-brain axis involved in nausea and emesis that are regulated by cannabinoid receptors and examines the cannabinoid receptor biology that is central to an understanding of the emetic and antiemetic actions of cannabis. In the final section, potential mechanisms for development of CHS are described based on preclinical literature, case studies, and clinical findings that constitute our understanding of this condition. Chronic cannabis consumption is the precipitating factor for CHS development in susceptible individuals. Many factors may contribute to mechanisms of CHS, including downregulation of cannabinoid-1 receptors, hypothalamic–pituitary–adrenal axis dysregulation, concomitant mood disorders, and altered endocannabinoid system genetics or epigenetics. Evidence for these potential mechanisms is limited. Future research aimed at understanding CHS pathophysiology is required to provide a better understanding of the biology and epidemiology of this debilitating condition.
Importance:
Despite the legalization and widespread use of cannabis products for a variety of medical concerns in the US, there is not yet a strong clinical literature to support such use. The risks and benefits of obtaining a medical marijuana card for common clinical outcomes are largely unknown.
Objective:
To evaluate the effect of obtaining a medical marijuana card on target clinical and cannabis use disorder (CUD) symptoms in adults with a chief concern of chronic pain, insomnia, or anxiety or depressive symptoms.
Design, setting, and participants:
This pragmatic, single-site, single-blind randomized clinical trial was conducted in the Greater Boston area from July 1, 2017, to July 31, 2020. Participants were adults aged 18 to 65 years with a chief concern of pain, insomnia, or anxiety or depressive symptoms. Participants were randomized 2:1 to either the immediate card acquisition group (n = 105) or the delayed card acquisition group (n = 81). Randomization was stratified by chief concern, age, and sex. The statistical analysis followed an evaluable population approach.
Interventions:
The immediate card acquisition group was allowed to obtain a medical marijuana card immediately after randomization. The delayed card acquisition group was asked to wait 12 weeks before obtaining a medical marijuana card. All participants could choose cannabis products from a dispensary, the dose, and the frequency of use. Participants could continue their usual medical or psychiatric care.
Main outcomes and measures:
Primary outcomes were changes in CUD symptoms, anxiety and depressive symptoms, pain severity, and insomnia symptoms during the trial. A logistic regression model was used to estimate the odds ratio (OR) for CUD diagnosis, and linear models were used for continuous outcomes to estimate the mean difference (MD) in symptom scores.
Results:
A total of 186 participants (mean [SD] age 37.2 [14.4] years; 122 women [65.6%]) were randomized and included in the analyses. Compared with the delayed card acquisition group, the immediate card acquisition group had more CUD symptoms (MD, 0.28; 95% CI, 0.15-0.40; P < .001); fewer self-rated insomnia symptoms (MD, -2.90; 95% CI, -4.31 to -1.51; P < .001); and reported no significant changes in pain severity or anxiety or depressive symptoms. Participants in the immediate card acquisition group also had a higher incidence of CUD during the intervention (17.1% [n = 18] in the immediate card acquisition group vs 8.6% [n = 7] in the delayed card acquisition group; adjusted odds ratio, 2.88; 95% CI, 1.17-7.07; P = .02), particularly those with a chief concern of anxiety or depressive symptoms.
Conclusions and relevance:
This randomized clinical trial found that immediate acquisition of a medical marijuana card led to a higher incidence and severity of CUD; resulted in no significant improvement in pain, anxiety, or depressive symptoms; and improved self-rating of insomnia symptoms. Further investigation of the benefits of medical marijuana card ownership for insomnia and the risk of CUD are needed, particularly for individuals with anxiety or depressive symptoms.
Trial registration:
ClinicalTrials.gov Identifier: NCT03224468.
Cannabis is now legal in many countries and while numerous studies have reported on its impact on cognition and appetite regulation, none have examined fatty acid metabolism in young cannabis users. We conducted an exploratory analysis to evaluate cannabis impact on fatty acid metabolism in cannabis users (n = 21) and non‐cannabis users (n = 16). Serum levels of some saturated and monounsaturated fatty acids, including palmitic, palmitoleic, and oleic acids were higher in cannabis users compared to nonusers. As palmitic acid can be derived from diet or lipogenesis from sugars, we evaluated lipogenesis using a de novo lipogenesis index (palmitate/linoleic acid) and carbon‐specific isotope analysis, which allows for the determination of fatty acid 13C signature. The significantly higher de novo lipogenesis index in the cannabis users group along with a more enriched 13C signature of palmitic acid suggested an increase in lipogenesis. In addition, while serum glucose concentration did not differ between groups, pyruvate and lactate were lower in the cannabis user group, with pyruvate negatively correlating with palmitic acid. Furthermore, the endocannabinoid 2‐arachidonoylglycerol was elevated in cannabis users and could contribute to lipogenesis by activating the cannabinoid receptor 1. Because palmitic acid has been suggested to increase inflammation, we measured peripheral cytokines and observed no changes in inflammatory cytokines. Finally, an anti‐inflammatory metabolite of palmitic acid, palmitoylethanolamide was elevated in cannabis users. Our results suggest that lipogenic activity is increased in cannabis users; however, future studies, including prospective studies that control dietary intake are required.
Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is known to be affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors, e.g., irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during withdrawal in a mouse chronic cannabis exposure model. Using a THC treatment regimen known to produce tolerance we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance inducing THC treatment. Sex differences were observed in nearly all metrics. Altered striatal DA release, sleep and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. To our knowledge these findings provide the first model of directly translatable non-precipitated cannabis withdrawal symptoms, in particular, sleep disruption.
Cannabis (i.e., marijuana and cannabinoids) is the most commonly used illicit drug in developed countries, and the lifetime prevalence of marijuana dependence is the highest of all illicit drugs in the United States. To provide clues for finding effective pharmacological treatment for cannabis-dependent patients, we examined the effects and possible mechanism of lithium administration on the cannabinoid withdrawal syndrome in rats.
A systemic injection of the mood stabilizer lithium, at serum levels that were clinically relevant, prevented the cannabinoid withdrawal syndrome. The effects of lithium were accompanied by expression of the cellular activation marker Fos proteins within most oxytocin-immunoreactive neurons and a significant increase in oxytocin mRNA expression in the hypothalamic paraventricular and supraoptic nuclei. Lithium also produced a significant elevation of oxytocin levels in the peripheral blood. We suggest that the effects of lithium against the cannabinoid withdrawal syndrome are mediated by oxytocinergic neuronal activation and subsequent release and action of oxytocin within the CNS. In support of our hypothesis, we found that the effects of lithium against the cannabinoid withdrawal syndrome were antagonized by systemic preapplication of an oxytocin antagonist and mimicked by systemic or intracerebroventricular injection of oxytocin.
These results demonstrate that oxytocinergic neuronal activation plays a critical role in the action of lithium against the cannabinoid withdrawal syndrome in rats, thus providing a potentially novel strategy for the treatment of cannabis dependence in humans.
Chronic 9-tetrahydrocannabinol (9-THC) administration produces tolerance to cannabinoid effects, but alterations in signal transduction that mediate these changes are not yet known. The present study uses in vitro autoradiography of agonist-stimulated [ 35 S]GTPS binding to localize cannabinoid receptor-activated G-proteins after chronic 9-THC treatment. Cannabinoid (WIN 55212-2)-stimulated [ 35 S]GTPS binding was performed in brain sections from rats treated chronically with 10 mg/kg 9-THC for 21 d. Control animals received saline or an acute injection of 9-THC. Acute 9-THC treatment had no effect on basal or WIN 55212-2-stimulated [ 35 S]GTPS binding. After chronic 9-THC treatment, net WIN 55212-2-stimulated [ 35 S]GTPS binding was reduced significantly (up to 70%) in most brain regions, including the hippocampus, caudate-putamen, perirhinal and entorhinal cortex, globus pal-lidus, substantia nigra, and cerebellum. In contrast, chronic 9-THC treatment had no effect on GABA B-stimulated [ 35 S]GTPS binding. In membranes and brain sections, 9-THC was a partial agonist, stimulating [ 35 S]GTPS by only 20% of the level stimulated by WIN 55212-2 and inhibiting WIN 55212-2-stimulated [ 35 S]GTPS at high concentrations. Because the EC 50 of WIN 55212-2-stimulated [ 35 S]GTPS binding and the K D of cannabinoid receptor binding were unchanged by chronic 9-THC treatment, the partial agonist actions of 9-THC did not produce the decrease in cannabinoid-stimulated [ 35 S]GTPS binding. These results suggest that profound desensitization of cannabinoid-activated signal transduction mechanisms occurs after chronic 9-THC treatment.
The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive
role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates
were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced.
These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the
concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.
The authors review the literature examining the validity and significance of cannabis withdrawal syndrome. Findings from animal laboratory research are briefly reviewed, and human laboratory and clinical studies are surveyed in more detail. Converging evidence from basic laboratory and clinical studies indicates that a withdrawal syndrome reliably follows discontinuation of chronic heavy use of cannabis or tetrahydrocannabinol. Common symptoms are primarily emotional and behavioral, although appetite change, weight loss, and physical discomfort are also frequently reported. The onset and time course of these symptoms appear similar to those of other substance withdrawal syndromes. The magnitude and severity of these symptoms appear substantial, and these findings suggest that the syndrome has clinical importance. Diagnostic criteria for cannabis withdrawal syndrome are proposed.
We have found that phosphorylation of a G-protein-coupled receptor by protein kinase C (PKC) disrupts modulation of ion channels by the receptor. In AtT-20 cells transfected with rat cannabinoid receptor (CB1), the activation of an inwardly rectifying potassium current (Kir current) and depression of P/Q-type calcium channels by cannabinoids were prevented by stimulation of protein kinase C by 100 nM phorbol 12-myristate 13-acetate (PMA). In contrast, activation of Kir current by somatostatin was unaffected, and inhibition of calcium channels was only modestly attenuated. The possibility that PKC acted by phosphorylating CB1 receptors was confirmed by demonstrating that PKC phosphorylated a single serine (S317) of a fusion protein incorporating the third intracellular loop of CB1. Mutating this serine to alanine did not affect the ability of CB1 to modulate currents, but it eliminated disruption by PMA, demonstrating that PKC can disrupt ion channel modulation by receptor phosphorylation.
The hypothesis was tested that the development of tolerance in man to the pharmacological effects of delta 9-tetrahydrocannabinol (THC) is due in part to changes in metabolism and disposition. Tolerance developed in six subjects following p.o. administration of 30 mg of THC every 4 hr for 10 to 12 days. Evaluation of THC pharmacokinetics was based on plasma levels of unchanged THC following i.v. administration of [14C] THC before and after the chronic p.o. THC. Development of tolerance was paralleled by pharmacokinetic changes: 1) average total metabolic clearance and the initial apparent volume of distribution increased from 605 to 977 ml/min and from 2.6 to 6.4 liters, respectively; 2) steady-state volume of distribution, averaging 684 liters, was unaltered; 3) the majority of model-dependent pharmacokinetic parameters as well as the time course of total metabolites in plasma were unchanged; 4) the percent dose excreted in urine decreased from 23.2 to 17.5%, but total elimination (urine plus feces) was not significantly changed; and 5) metabolites were rapidly formed (t 1/2 = 2.8-4.4 min), but slowly eliminated (t 1/2 = 49-53 hours) because of extensive protein binding. Renal clearance values of total metabolites were surprisingly low (maximum of 18-20 ml/min) and decreased with time (approximately 1 ml/min after 4-5 days), indicating the accumulation of highly bound metabolites. We conclude that such pharmacokinetic and metabolic changes cannot account for the development of tolerance to the cardiovascular, psychological and skin hypothermic effects of THC.
Although tolerance to cannabinoids has been well established, the question of cannabinoid dependence had been very controversial until the discovery of a cannabinoid antagonist, SR141716A. The objective of this study was to develop and characterize a mouse model of precipitated withdrawal indicative of cannabinoid dependence. Using a dosing regimen known to produce pharmacological and behavioral tolerance, mice were treated with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) twice a day for 1 wk. SR141716A administration after the last Delta(9)-THC injection promptly precipitated a profound withdrawal syndrome. Typical withdrawal behavior was an increase in paw tremors and head shakes that was accompanied with a decrease in normal behavior such as grooming and scratching. Of the three Delta(9)-THC regimens tested, daily Delta(9)-THG injections of 10 and 30 mg/kg produced the greatest number of paw tremors and head shakes and the least number of grooms after challenge with SR141716A. Precipitated withdrawal was apparent after 2, 3, 7 and 14 days of treatment based on an increase in paw tremors in Delta(9)-THC-treated mice as compared with vehicle-treated mice. These findings are consistent with SR141716A-precipitated withdrawal in rats. Moreover, these results suggest that mice are a viable model for investigating dependence to cannabinoids.
Although the proposition that repeated marijuana use can lead to marijuana dependence has long been accepted, only recently has evidence emerged suggesting that abstinence leads to clinically significant withdrawal symptoms. Converging evidence from human and animal studies has increased our understanding of cannabinoid dependence. One of the most powerful tools to advance this area of research is the CB1 cannabinoid receptor antagonist SR 141716A, which reliably precipitates withdrawal syndromes in mice, rats, and dogs that have been treated repeatedly with cannabinoids. In addition, the use of CB1 receptor knockout mice has revealed that not only cannabinoid dependence is mediated through a CB1 receptor mechanism of action, but CB1 receptors also modulate opioid dependence. Moreover, the results of other genetically altered mouse models suggest the existence of a reciprocal relationship between cannabinoid and opioid systems in drug dependence. Undoubtedly, these animal models will play pivotal roles in further characterizing cannabinoid dependence and elucidating the mechanisms of action, as well us developing potential pharmacotherapies for cannabinoid dependence. Journal of Clinical Pharmacology, 2002.
The effects of chronic exposure to the psychoactive cannabinoid derivative delta-9-THC were evaluated on a spatial discrimination version of a delayed-match-to-sample (DMTS), short-term memory task in rats. An initially severe disruption of DMTS performance, produced by injections of 10 mg/kg delta-9-THC immediately prior to the session, was completely eliminated following 30-35 days of continuous exposure to the drug. The timecourse of adaptation to the disruptive effects of delta-9-THC were characterized and analyzed. Performance at the shortest delay intervals (1-5 sec) was reduced least during the 35 day exposure. At delays longer than 5 sec, performance was severely reduced to near chance levels upon initial exposure. Performance recovered systematically over the 35 day exposure period to criterion levels. Recovery between days 5-16 of exposure was most pronounced at delays of 6-20 sec, after which (days 17-30) recovery at all delays occurred at the same rate. Withdrawal from the drug after the 35 day exposure produced a slight but significant reduction in performance at all delays which dissipated within 2 days. There were no subsequent residual effects of the 35 day exposure on DMTS performance measured up to 15 days after withdrawal from drug treatment. These results suggest that the effects of cannabinoid substances on short-term memory are consistent with those produced by damage to the hippocampus in this same task, and that adaptation to an initial debilitating dose was consistent with recovery from a hippocampal deficit. Upon repeated exposure, performance returned to criterion levels even though the high dose and drug concentration were similar to when performance was severely disrupted. It is therefore possible that cannabinoid induced disruption of DMTS performance was susceptible to changes in receptor-coupled biochemical systems (1) that mediated adaptation to the deleterious effects of delta-9-THC.
Context Cognitive impairments are associated with long-term cannabis use, but
the parameters of use that contribute to impairments and the nature and endurance
of cognitive dysfunction remain uncertain.Objective To examine the effects of duration of cannabis use on specific areas
of cognitive functioning among users seeking treatment for cannabis dependence.Design, Setting, and Participants Multisite retrospective cross-sectional neuropsychological study conducted
in the United States (Seattle, Wash; Farmington, Conn; and Miami, Fla) between
1997 and 2000 among 102 near-daily cannabis users (51 long-term users: mean,
23.9 years of use; 51 shorter-term users: mean, 10.2 years of use) compared
with 33 nonuser controls.Main Outcome Measures Measures from 9 standard neuropsychological tests that assessed attention,
memory, and executive functioning, and were administered prior to entry to
a treatment program and following a median 17-hour abstinence.Results Long-term cannabis users performed significantly less well than shorter-term
users and controls on tests of memory and attention. On the Rey Auditory Verbal
Learning Test, long-term users recalled significantly fewer words than either
shorter-term users (P = .001) or controls (P = .005); there was no difference between shorter-term
users and controls. Long-term users showed impaired learning (P = .007), retention (P = .003), and retrieval
(P = .002) compared with controls. Both user groups
performed poorly on a time estimation task (P<.001
vs controls). Performance measures often correlated significantly with the
duration of cannabis use, being worse with increasing years of use, but were
unrelated to withdrawal symptoms and persisted after controlling for recent
cannabis use and other drug use.Conclusions These results confirm that long-term heavy cannabis users show impairments
in memory and attention that endure beyond the period of intoxication and
worsen with increasing years of regular cannabis use.
Five chimpanzees were given Delta 9-tetrahydrocannabinol (Delta 9THC): 1.0 milligram per kilogram of body weight for 21 days and 4.0 milligrams per kilogram of body weight for 42 days. Although accuracy and speed of performance on a delayed matching-to-sample task were significantly affected by both doses, tolerance to Delta 9THC THC did not develop. No long-term behavioral effects of Delta 9 THC were observed after termination of the drug regimens.
Most data on effects of natural and synthetic cannabinoids on anterior pituitary hormone secretion point out to a primary impact on the hypothalamus. There is also some evidence, however, of possible direct actions of these compounds on the anterior pituitary, although the presence of cannabinoid receptors in the pituitary has not been documented as yet. In the present study, we evaluated the presence of cannabinoid CB1 receptor-mRNA transcripts in the pituitary gland by in situ hybridization. We observed CB1 receptor-mRNA transcripts in the anterior pituitary and to a lesser extent in the intermediate lobe whereas they were absent in the neural lobe. We then examined whether CB1 receptor-mRNA levels in both pituitary lobes responded to chronic activation by a specific agonist, as did receptors located in adjacent hypothalamic nuclei and in other brain regions. Daily administration of CP-55,940 for 18 days produced a small, but statistically significant paradoxical increase in CB1 receptor-mRNA levels in the anterior pituitary, with no changes in the intermediate lobe, in contrast to reduced CB1 receptor-mRNA levels observed in the ventromedial hypothalamic nucleus (VMN), and to decreased CB1 receptor binding in the VMN and the arcuate nucleus. The time-course of up-regulation of CB1 receptor-mRNA transcripts in the anterior lobe was biphasic; daily administration of Δ9-tetrahydrocannabinol produced an early and marked decrease in CB1 receptor-mRNA levels after 1 and 3 days, followed by normalization after 7 days and by a small increase after 14 days. We also checked whether endogenous cannabinoid ligands are present in the anterior pituitary and the hypothalamus. Although anandamide itself was detected only in trace amounts, concentrations of its precursor N-arachidonoyl-phosphatidyl-ethanolamine and of 2-arachidonoyl-glycerol were found in both tissues, suggesting that endocannabinoids may be synthetized in the anterior pituitary. In summary, CB1 receptors and corresponding ligands seem to be expressed in cells of the anterior and intermediate lobes of the pituitary, but the response of CB1 receptor-mRNA transcripts in the anterior lobe to chronic agonist activation is different than the desensitization observed in hypothalamic nuclei.
New data strengthen the idea of a prominent role for endocannabinoids in the modulation of a wide variety of neurobiological functions. Among these, one of the most important is the control of movement. This finding is supported by 3 lines of evidence: (1) the demonstration of a powerful action, mostly inhibitory in nature, of synthetic and plant-derived cannabinoids and, more recently, of endocannabinoids on motor activity; (2) the presence of the cannabinoid CB1 receptor subtype and the recent description of endocannabinoids in the basal ganglia and the cerebellum, the areas that control movement; and (3) the fact that CB1 receptor binding was altered in the basal ganglia of humans affected by several neurological diseases and also of rodents with experimentally induced motor disorders. Based on this evidence, it has been suggested that new synthetic compounds that act at key steps of endocannabinoid activity (i.e., more-stable analogs of endocannabinoids, inhibitors of endocannabinoid reuptake or metabolism, antagonists of CB1 receptors) might be of interest for their potential use as therapeutic agents in a variety of pathologies affecting extrapyramidal structures, such as Parkinson's and Huntington's diseases. Currently, only a few data exist in the literature studying such relationships in humans, but an increasing number of journal articles are revealing the importance of this new neuromodulatory system and arguing in favour of the funding of more extensive research in this field. The present article will review the current knowledge of this neuromodulatory system, trying to establish the future lines for research on the therapeutic potential of the endocannabinoid system in motor disorders.
Cannabinoids, the active components of marijuana and their endogenous counterparts, exert many of their actions in brain through the seven-transmembrane receptor CB1. This receptor is coupled to the activation of the extracellular signal-regulated kinase (ERK) cascade. However, the precise molecular mechanism for CB1-mediated ERK activation is still unknown. Here, we show that in U373 MG human astrocytoma cells, CB1 receptor activation with the cannabinoid agonist Δ⁸-tetrahydrocannabinol dimethyl heptyl (HU-210) was coupled to ERK activation and protection from ceramide-induced apoptosis. HU-210-induced ERK activation was inhibited by tyrphostin AG1478 and PP2, widely employed inhibitors of the epidermal growth factor receptor (EGFR) and the Src family of cytosolic tyrosine kinases, respectively. However, HU-210 stimulation resulted in neither EGFR phosphorylation, Src tyrosine phosphorylation, nor increased Src activity. In addition, dominant-negative forms of both proteins were unable to prevent cannabinoid-induced ERK activation, thus excluding the existence of CB1-mediated EGFR transactivation or Src activation. Wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294,002), inhibitors of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, blocked cannabinoid-induced ERK activation. Likewise, HU-210 stimulated the PI3K downstream targets protein kinase B (PKB), as shown by its phosphorylation in Thr 308 and Ser 473 residues, and Raf-1. Moreover, βγ subunit release mimicked ERK and PI3K/PKB activation, suggesting that activation of class IB PI3K mediates cannabinoid action. Pro-survival HU-210 action also required activation of both PI3K and ERK signaling pathways. In conclusion, CB1-induced ERK activation was mediated by PI3KIB and this effect may have important consequences in the control of cell death/survival decision.
Δ9-Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB1 in the brain, and CB2 in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the “endocannabinoid” agonists for these receptors. CB1 receptors are abundant in basal ganglia, hippocampus and cerebellum, and their functional activity can be mapped during behaviors using cerebral metabolism as the neuroimaging tool. CB1 receptors couple to Gi/o to inhibit cAMP production, decrease Ca2+ conductance, increase K+ conductance, and increase mitogen-activated protein kinase activity. Functional activation of G-proteins can be imaged by [35S]GTPγS autoradiography. Post-synaptically generated endocannabinoids form the basis of a retrograde signaling mechanism referred to as depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Under circumstances of sufficient intracellular Ca2+ (e.g., burst activity in seizures), synthesis of endocannabinoids releases a diffusible retrograde messenger to stimulate presynaptic CB1 receptors. This results in suppression of γ-aminobutyric acid (GABA) release, thereby relieving the post-synaptic inhibition. Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB1, CB2 and related receptors. One very important role for CB1 antagonists will be in the treatment of craving in the disease of substance abuse.
SummaryA nationally representative sample (n=1997) of young people (17-20 years of age) was examined twice with an interval of two years using postal questionnaires supplemented by telephone interviews of non-responders. Sixty-eight per cent of the original sample participated in both surveys. Factors found to increase the probability of having ever used cannabis were sex, place of residence, divorced parents, earlier problems with education and employment, and mental and somatic health problems. However, these factors could not predict the persistence/cessation of cannabis use which was significantly related to the establishment of an adult social role with a partner/spouse and/or having children, and negatively correlated to long-term unemployment. Among men, high aspirations as to future occupational activity predicted cessation of cannabis use. The hypothesis that alcohol consumption would be increased amongst those individuals who stopped using cannabis was not supported. The results replicate some of the main findings of Kandel and coworkers (1984,1986,1989) supporting the role incompatibility theory of Thornton (1975) as an explanation of the cessation of cannabis use.
Region-specific up-regulation of the cyclic AMP pathway is considered an important molecular mechanism in the origin of the somatic manifestations of the withdrawal syndrome to known drugs of abuse. Nevertheless, the existence of a withdrawal syndrome after prolonged cannabinoid administration has long been a controversial issue. Recent studies, in different species, have shown that withdrawal to prolonged cannabinoid exposure precipitated by the cannabinoid antagonist SR141716A is characterized by physical signs underlying impairment of motor coordination. Interestingly, cannabinoid withdrawal is accompanied by an increase of adenylyl cyclase activity in the cerebellum. Here, we investigate the functional role of the cyclic AMP pathway in the cerebellum in the establishment of cannabinoid withdrawal. We show that after SR141716A precipitation of cannabinoid withdrawal, basal and calcium-calmodulin-stimulated adenylyl cyclase activities as well as active PKA in the cerebellum increase in a transient manner with a temporal profile which matches that of the somatic expression of abstinence. Selectively blocking the up-regulation of the cyclic AMP pathway in the cerebellum, by microinfusing the cyclic AMP blocker Rp-8Br-cAMPS in this region, markedly reduced both PKA activation and the somatic expression of cannabinoid withdrawal. Our results (i) directly link the behavioural manifestations of cannabinoid withdrawal with the up-regulation of the cyclic AMP pathway in the cerebellum, pointing towards common molecular adaptive mechanisms for dependence and withdrawal to most drugs of abuse; (ii) suggest a particular role for the cerebellum as a major neurobiological substrate for cannabinoid withdrawal.
To examine the relationship between cannabis use in adolescence and the onset of other illicit drug use.
Data were gathered over the course of a 21-year longitudinal study of a birth cohort of 1265 New Zealand children. Measures analysed included: (a) frequency of cannabis use and other illicit drugs from 15-21; (b) family, social, educational and behavioural backgrounds of cohort members prior to 15; and (c) adolescent life-style variables.
(i) By 21, nearly 70% of cohort members and used cannabis and 26% had used other illicit drugs. (ii) In all but three cases, the use of cannabis had preceded the use of illicit drugs. (iii) Those using cannabis on more than 50 occasions a year had hazards of other illicit drug use that were 140 times higher than non-users. (iv) After adjustment for covariate factors, including childhood factors, family factors and adolescent life-style factors, cannabis use remained strongly related to the onset of other forms of illicit drug use. Those using cannabis on more than 50 occasions per year had hazards of other illicit drug use that were 59.2 times higher than non-users.
Findings support the view that cannabis may act as a gateway drug that encourages other forms of illicit drug use. None the less, the possibility remains that the association is non-causal and reflects factors that were not adequately controlled in the analysis.
This study examined if (1) there is an association in the general population between cannabis use, DSM-IV abuse and dependence, and other substance use and DSM-IV substance abuse/dependence; (2) if so, is it explained by demographic characteristics or levels of neuroticism? It used data from the Australian National Survey of Mental Health and Well-Being (NSMHWB), a stratified, multistage probability sample of 10 641 adults, representative of the general population. DSM-IV diagnoses of substance abuse and dependence were derived using the Composite International Diagnostic Interview (CIDI). There was a strong bivariate association between involvement with cannabis use in the past 12 months and other substance use, abuse and dependence. In particular, cannabis abuse and dependence were highly associated with increased risks of other substance dependence. These associations remained after including other variables in multiple regression. Cannabis use without disorder was strongly related to other drug use, an association that was not explained by other variables considered here. The high likelihood of other substance use and substance use disorders needs to be considered among persons seeking treatment for cannabis use problems.
Marijuana has a long history of abuse yet, as described here by Mary Abood and Billy Martin, there is little evidence that animals will self-administer the primary psychoactive constituent, tetrahydrocannabinol, or that marijuana stimulates brain reward pathways. While marked tolerance develops to marijuana, it has been difficult to demonstrate physical dependence, and until recently the mechanisms by which cannabinoids produced their behavioral effects were poorly defined. The development of new synthetic analogs played a critical role in the characterization and cloning of the cannabinoid receptor. Insight into cannabinoid receptors may lead to a better understanding of marijuana abuse in humans and provide new therapeutic strategies for several disorders.
The effect of repetitive administration of delta-9-tetrahydrocannabinol (Δ9-THC) in mice on behavioral and biochemical tolerance was determined in this study. Mice were injected twice daily with 10 mg/kg Δ9-THC for 6.5 days. On day 8, spontaneous activity was assessed or whole-brain homogenates were prepared for the cannabinoid receptor binding and mRNA studies. Although a twenty-sevenfold tolerance to Δ9-THC was observed in the behavioral assay, there was no significant alteration in receptor binding or mRNA levels.
11-Methyl-Δ8-, 9-nor-Δ8-, and 9-nor-Δ9-tetrahydrocannabinol (THC), newly synthesized cannabinoids which are not 11-hydroxyated in vivo, were tested for cannabinoid activity. Δ8-, Δ9-THC and each synthetic analog produced static ataxia in unanesthetized dogs, hypotension and bradycardia in anesthetized dogs, and decreased spontaneous activity in mice. All synthetic analogs tested produced a greater degree of tolerance to the behavioral effect in dogs than did Δ8-THC. 11-Methyl-Δ8-THC was more effective than Δ8-THC in decreasing spontaneous activity in mice, but was less active in producing the behavioral and cardiovascular effects in dogs. 9-nor-Δ9-THC was less active than Δ9-THC, but 9-nor-Δ8-THC was as active as Δ8-THC in all observations. These results suggest that the 11-hydroxy metabolites of Δ8- and Δ9-THC are not solely responsible for the biological activity of tetrahydrocannabinols.
The clinical relevance of marijuana withdrawal has not been established. This study is the first to document the incidence and severity of perceived marijuana withdrawal symptoms in a clinical sample of marijuana-dependent adults.
Fifty-four people seeking outpatient treatment for marijuana dependence completed a 22-item Marijuana Withdrawal Symptom checklist based on their most recent period of marijuana abstinence.
The majority (57%) indicated that they had experienced > or = six symptoms of at least moderate severity and 47% experienced > or = four symptoms rated as severe. Withdrawal severity was greater in those with psychiatric symptomatology and more frequent marijuana use.
This study provides further support for a cluster of withdrawal symptoms experienced following cessation of regular marijuana use. The affective and behavioral symptoms reported were consistent with those observed in previous laboratory and interview studies. Since withdrawal symptoms are frequently a target for clinical intervention with other substances of abuse, this may also be appropriate for marijuana.
Tolerant and nontolerant dogs received one i.v. administration of 0.5 mg/kg of 3H-delta9-tetrahydrocannabinol 30 minutes before they were sacrificed. Plasma, peripheral and brain tissues, as well as subcellular fractions of brain tissues from both treatment groups, were analyzed for radioactivity. Throughout the time period before sacrifice, the plasma concentrations of radioactivity in the tolerant and nontolerant dogs were not significantly different. The percentage of radioactivity in brain and plasma that was due to either unchanged delta9-tetrahydrocannabinol or a major metabolite was the same in each group. Of the radioactivity in brain, 46% was identified as delta9-tetrahydrocannabinol. Regardless of treatment, there was a specific accumulation of radioactivity in adrenals, liver, kidney, heart and pancreas. The only significant differences in radioactivity between tolerant and nontolerant peripheral tissues were found in liver, kidney cortex, heart and lymph nodes. Although all brain areas from tolerant dogs contained less radioactivity than the comparable brain areas from nontolerant animals, only pituitary and putamen were significantly less. There was a specific accumulation of radioactivity in some brain areas that could be associated with behavioral effects. The concentration in cerebellar and cerebral gray was significantly greater than that in white, and there was a marked reduction in the concentration in gray after tolerance developed. The mean percentage of radioactivity in each subcellular fraction was as follows: 23% crude nuclei, 44% mitochondria, 8% cholinergic nerve endings, 7% noncholinergic nerve endings, 2% free mitochondria and 6% synaptic vesicles. The quantity of radioactivity in homogenates of brains from tolerant dogs was 17% less than brains of nontolerant animals, which was merely a reflection of the respective plasma concentrations. The distribution of radioactivity was similar in both groups, although most of the subcellular fractions from tolerant dogs contained a lesser amount of radioactivity. The most notable difference was observed in the synaptic vesicle fraction. The synaptic vesicle fraction of tolerant dogs contained 40% less radioactivity than did the same fraction from nontolerant dogs, which implied a possible mechanism of action. A comparison of the remaining subcellular fractions did not appear to explain the development of tolerance.
The effects of chronic delta 9-tetrahydrocannabinol (delta 9-THC) and marijuana administration on the properties of brain cannabinoid receptor populations of the rat and monkey, respectively, were examined in this study. It was determined that the properties of the cannabinoid receptors in the striatum, cerebral cortex, cerebellum, hippocampus, and brainstem/spinal cord of the rat do not appear to be irreversibly altered by chronic exposure to delta 9-THC. Similarly, the cannabinoid receptors in the caudate, prefrontal cortex, and cerebellum of the monkey do not appear to be irreversibly altered by chronic exposure to marijuana smoke.
Six healthy male, paid volunteers smoked one NIDA cigarette containing 1.0% THC each day for 13 consecutive days. They were tested before and after the period of drug administration by the following procedure: the subjects smoked one NIDA marijuana cigarette containing 1.0% THC followed 15 minutes later by the intravenous infusion of 52 micrograms/min of deuterated THC for 50 minutes. The THC plasma concentrations, ratings of "high" and heart rate effects produced by the combined drug administration were measured, and absolute bioavailability of smoked THC was calculated on Days 1 and 22. Statistical analyses indicate that the only significant changes induced by daily marijuana exposure were in cardioacceleration.
Previous studies have shown that the secretion of several stress-related hormones can be altered by exposure to marihuana or its purified constituents. The purpose of this study was to examine changes in adrenal medullary function caused by acute, subchronic and chronic treatments with two different doses of delta-9-tetrahydrocannabinol (THC). Acute exposure to THC caused a significant decrease in the adrenal medulla contents of both norepinephrine (NE) and epinephrine (E) and a significant increase in the E/NE ratio. These effects were mainly observed with the highest dose of THC, but they were not accompanied by a statistically significant decrease in adrenal medulla tyrosine hydroxylase activity, the rate-limiting enzyme in the catecholamine (CA) synthesis. These effects disappeared after seven or fourteen days of a daily THC treatment, which suggests the development of tolerance to this drug. Analysis of plasma PRL, ACTH and corticosterone levels showed some THC-related changes in these hormones. THC-induced modifications in ACTH and corticosterone were not in parallel to the changes in the adrenal medulla function, whereas those effects of acute THC on PRL release were statistically correlated with decreases of CA contents following acute THC. In conclusion, acute exposure to THC caused an alteration in the adrenal medullary function, reflected by a fall in endogenous stores of both CAs which could influence the adrenal medullary response to stress situations. This acute effect of THC could be mediated by the pituitary secretion of PRL, although the possibility of an effect directly exerted on the adrenal medulla chromaffin cells should be also considered.(ABSTRACT TRUNCATED AT 250 WORDS)
A nationally representative sample (n = 1997) of young people (17-20 years of age) was examined twice with an interval of two years using postal questionnaires supplemented by telephone interviews of non-responders. Sixty-eight per cent of the original sample participated in both surveys. Factors found to increase the probability of having ever used cannabis were sex, place of residence, divorced parents, earlier problems with education and employment, and mental and somatic health problems. However, these factors could not predict the persistence/cessation of cannabis use which was significantly related to the establishment of an adult social role with a partner/spouse and/or having children, and negatively correlated to long-term unemployment. Among men, high aspirations as to future occupational activity predicted cessation of cannabis use. The hypothesis that alcohol consumption would be increased amongst those individuals who stopped using cannabis was not supported. The results replicate some of the main findings of Kandel and coworkers (1984, 1986, 1989) supporting the role incompatibility theory of Thornton (1975) as an explanation of the cessation of cannabis use.
Previous studies in this laboratory have demonstrated that a cloned neuroblastoma cell line (N18TG2) responds to delta 9-tetrahydrocannabinol (THC), the major psychoactive product of marihuana, with an attenuation of cyclic AMP accumulation that results from an inhibition of adenylate cyclase. The requirement for the Gi regulatory protein, stereoselectivity, pharmacologic specificity and cell selectivity of this response suggest that a receptor for cannabimimetic compounds may be associated with adenylate cyclase in the neuroblastoma cell. Presented here is a comprehensive investigation of cellular effects of chronic exposure to cannabimimetic agents. Short-term exposure to either delta 9-THC or the more potent nantradol analog, desacetyllevonantradol (DALN), at doses up to 100 microM did not compromise the plating efficiency of the cells. Cells that were exposed to 1 microM delta 9-THC (maximally effective for inhibiting cyclic AMP production) for 24 hr in a serum-free medium were shown to accumulate the drug but not to metabolize it. Exposure to 10 microM delta 9-THC or DALN for up to 48 hr failed to significantly affect cell growth rate or protein content per cell. The gross morphology of cannabinoid-treated cells was not altered at the light or the electron microscope level. The cellular organelles and membranes appeared intact, with no remarkable differences from control cells. The inhibition of cyclic AMP accumulation in response to cannabimimetic drugs was diminished in cells treated with delta 9-THC or DALN for 24 hr. This desensitization was homologous because both delta 9-THC and DALN responses were attenuated after exposure to either cannabimimetic drug.(ABSTRACT TRUNCATED AT 250 WORDS)
The present studies examined whether dependence could be induced by continuous infusion of delta-9-tetrahydrocannabinol (THC), as evidenced by behavioral disruptions during withdrawal of THC administration. Four rhesus monkeys lever pressed under fixed-ratio schedules for their daily food rations during four, daily, 0.5 -hr sessions. Initially, the monkeys were tested before, during and after continuous i.v. infusions of THC. A dosage regimen of 0.05 mg/kg/hr for 10 days for three of the monkeys and a somewhat greater regimen in the fourth had little direct effect on rates of respondings for food during THC infusion, but marked decreases in response rates occurred in each monkey during withdrawal. These effects generally did not occur until the second day of withdrawal, and often lasted for over a week. These initial demonstrations were replicated subsequently with lower solvent concentrations. In the final study, THC was administered for a greater number of days and at higher dosages than during any of the previous studies. Response rate reductions again occurred within 2 to 3 days of withdrawal. When THC was readministered, reversal of the withdrawal effects occurred in that withdrawal-induced rate decreases were halted and rates increased subsequently. Administration of THC was discontinued after 2 to 3 days of its readministration. Response rates again decreased within the first 3 days after this withdrawal and then recovered slowly with time. Withdrawal of THC administration can disrupt operant behavior, and these disruptions can be reversed by resumption of THC administration, indicating that dependence upon this drug can be produced in rhesus monkeys.
Marijuana seems firmly established as another social drug in Western countries, regardless of its current legal status. Patterns of use vary widely. As with other social drugs, the pattern of use is critical in determining adverse effects on health. Perhaps the major area of concern about marijuana use is among the very young. Using any drug on a regular basis that alters reality may be detrimental to the psychosocial maturation of young persons. Chronic use of marijuana may stunt the emotional growth of youngsters. Evidence for an amotivational syndrome is largely based on clinical reports; whether marijuana use is a cause or effect is uncertain. A marijuana psychosis, long rumored, has been difficult to prove. No one doubts that marijuana use may aggravate existing psychoses or other severe emotional disorders. Brain damage has not been proved. Physical dependence is rarely encountered in the usual patterns of social use, despite some degree of tolerance that may develop. The endocrine effects of the drug might be expected to delay puberty in prepubertal boys, but actual instances have been rare. As with any material that is smoked, chronic smoking of marijuana will produce bronchitis; emphysema or lung cancer have not yet been documented. Cardiovascular effects of the drug are harmful to those with preexisting heart disease; fortunately the number of users with such conditions is minimal. Fears that the drug might accumulate in the body to the point of toxicity have been groundless. The potential deleterious effects of marijuana use on driving ability seem to be self-evident; proof of such impairment has been more difficult. The drug is probably harmful when taken during pregnancy, but the risk is uncertain. One would be prudent to avoid marijuana during pregnancy, just as one would do with most other drugs not essential to life or well-being. No clinical consequences have been noted from the effects of the drug on immune response, chromosomes, or cell metabolites. Contamination of marijuana by spraying with defoliants has created the clearest danger to health; such attempts to control production should be abandoned. Therapeutic uses for marijuana, THC, or cannabinoid homologs are being actively explored. Only the synthetic homolog, nabilone, has been approved for use to control nausea and vomiting associated with cancer chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)
The pharmacology of the cannabinoids is characterized by at least two very provocative phenomena. First, the multiplicity of effects. As I have mentioned throughout this review, most of these effects are due to actions on the central nervous system. The major problem in the search for a therapeutic agent in this series has been due to the inability to find a cannabinoid with the therapeutic action at doses below those that produce side effects. The high lipid solubility of the cannabinoids allows them to be distributed throughout the brain at reasonable doses. The second aspect of their pharmacology worthy of special mention is their low toxicity. Throughout this review, I have indicated that the minimal effective dose of delta 9-THC for a particular pharmacological effect in animals was higher than that usually consumed by man. Yet, in almost all cases, it was much lower than the dose which produced toxic effects in the same species. These two characteristics of the animal pharmacology of cannabinoids carry over to humans. For instance, each of the cannabinoids tested in man causes many side effects at active doses and lethal effects of overdose by humans are nonexistent or rare. Toxicity following chronic use may be a different issue. A great deal of work has been carried out in an attempt to characterize the pharmacological effects of cannabinoids. It is clear from the material reviewed in this article that most if not all of the predominant effects of cannabinoids in whole animals are due to the direct effects of these compounds on the central nervous system. Our state of knowledge is too limited to rule out the possibility that they also produce effects on certain peripheral organs. It is expected that the majority of these effects will be shown to be due to the interaction of the cannabinoids with the neuronal innervation of the organ rather than directly with the organ tissue itself. Very high doses of cannabinoids just like all active drugs have an effect on many organ systems. These are toxicologic not pharmacologic and are nonspecific. The effects of cannabinoids at the molecular level have been reviewed by Martin (182a) in this series. This type of research is expected to elucidate the mechanism of action of cannabinoids at the cellular level. It is clear that the cannabinoids produce a unique behavioral syndrome in laboratory animals and in man.(ABSTRACT TRUNCATED AT 400 WORDS)
Psychoactive drugs are often widely used before tolerance and dependence is fully appreciated. Tolerance to cannabis-induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, mood and behavioral changes is acquired and, to a great degree, lost rapidly with optimal conditions. Mechanisms appear more functional than metabolic. Acquisition rate depends on dose and dose schedule. Dependence, manifested by withdrawal symptoms after as little as 7 days of THC administration, is characterized by irritability, restlessness, insomnia, anorexia, nausea, sweating, salivation, increased body temperature, altered sleep and waking EEG, tremor, and weight loss. Mild and transient in the 120 subjects studied, the syndrome was similar to sedative drug withdrawal. Tolerance to drug side effects can be useful. Tolerance to therapeutic effects or target symptoms poses problems. Clinical significance of dependence is difficult to assess since drug-seeking behavior has many determinants. Cannabis-induced super sensitivity should be considered wherever chronic drug administration is anticipated in conditions like epilepsy, glaucoma or chronic pain. Cannabis pharmacology suggests ways of minimizing tolerance and dependence problems.
Long-term exposure of sexually mature female rhesus monkeys (Macaca mulata) to thrice weekly injections of delta 9-tetrahydrocannabinol resulted in a disruption of menstrual cycles that lasted for several months. This period was marked by an absence of ovulation and decreased basal concentrations of gonadotropin and sex steroids in the plasma. After this period, normal cycles and hormone concentrations were reestablished. These studies demonstrate that in rhesus monkeys subjected to long-term treatment with delta 9-tetrahydrocannabinol tolerance develops to the disruptive effects of the drug on the menstrual cycle.
Precipitated withdrawal in rats chronically exposed to delta 9-tetrahydrocannabinol, the major psychoactive principle of the marijuana plant, was unequivocally demonstrated for the first time using a selective antagonist, SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2,4- dichloro-phenyl)-4-methyl-1H-pyrazole carboxamide.HCl). This demonstration should provide a powerful stimulus for the systematic study of dependency on the psychoactive cannabinoids.
A brain constituent, the N-amide derivative of arachidonic acid, termed anandamide, has been recently proposed as a possible endogenous ligand for the cannabinoid receptor. The present study has been designed to examine whether the acute or chronic exposure to anandamide affected the binding of cannabinoid receptors in specific brain areas as occurred with the exogenous cannabinoid agonist, delta 9-tetrahydrocannabinol (THC). To this end, we measured the maximum binding capacity (Bmax) and the affinity (Kd) of cannabinoid receptors, by using [3H]CP-55,940 binding assays, in membranes obtained from several brain areas of male rats acutely or chronically treated with anandamide or THC. Results were as follows. The acute administration of either anandamide or THC increased the Bmax of cannabinoid receptors in the cerebellum and, particularly, in the hippocampus. This effect was also observed after 5 days of a daily exposure to either anandamide or THC. However, whereas the increase in the Bmax after the acute treatment seems to be caused by changes in the receptor affinity (high Kd), the increase after the chronic exposure may be attributed to an increase in the density of receptors. On the contrary, the [3H]CP-55,940 binding to cannabinoid receptors in the striatum, the limbic forebrain, the mesencephalon, and the medial basal hypothalamus was not altered after the acute exposure to anandamide or THC. However, the chronic exposure to THC significantly decreased the Bmax of these receptors in the striatum and nonsignificantly in the mesencephalon. This effect was not elicited after the chronic exposure to anandamide and was not accompanied by changes in the Kd.(ABSTRACT TRUNCATED AT 250 WORDS)
Using in situ hybridization we found that chronic treatment with CP-55,940 (0.4 mg kg-1, i.p. daily for 11 days), a synthetic cannabinoid receptor ligand, changed cannabinoid receptor mRNA levels in rat brain. CP-55,940 produced the expected tolerance: the decrease in locomotor activity (75%) caused by an acute dose was diminished to 25% after the 11 days of treatment. Thirty minutes after the last injection the animals were killed and in situ hybridization indicated that the levels of cannabinoid receptor mRNA in the caudate-putamen were reduced by 33%, with no alteration in the other brain areas. We suggest that the altered cannabinoid receptor expression is part of the adaptive changes underlying cannabinoid tolerance.
The antinociceptive effects of the putative endogenous cannabinoid ligand anandamide (ANA) and its fluorinated analog, fluoroanandamide (FA), were determined as measured by the tail-flick and p-phenylquinone (PPQ) stretch tests. The ED50 values (confidence limits) for ANA and FA were 77 (52-13) and 7 (2-21) micrograms/mouse, respectively, for the tail-flick test and 30 (23-41) and 0.5 (0.1-2) micrograms/mouse, respectively, for the PPQ test after intrathecal (i.t.) administration. ANA was not significantly less potent than delta 9-tetrahydrocannabinol (THC) in the tail-flick test, but it was less potent in the PPQ test. FA was more potent than either ANA or THC in tail-flick test. The antinociceptive effects of all drugs (administered i.t.) were blocked significantly or nearly abolished by the pretreatment of the mice with pertussis toxin (i.t.). Pretreatment of the mice with 5 and 25 micrograms forskolin per mouse or 10 micrograms 8-(4-chlorophenyl-thio)-adenosine-3',5'-monophosphate cyclic monosodium salt per mouse (both i.t.) significantly attenuated the antinociception produced by THC but not by ANA or FA. Various calcium modulators were tested in combination with THC, ANA, and FA, but they failed to alter the antinociceptive effects of the drugs. Various potassium channel blockers were tested in combination with the drugs. Apamin, a blocker of small (low)-conductance calcium-gated potassium channels that attenuates THC-induced antinociception, failed to alter ANA- or FA-induced antinociception. In contrast to THC, which is blocked by the kappa antagonist nor-binaltorphimine, ANA- and FA-induced antinociception was not altered by classic opioid antagonists. Also in contrast to THC, which enhances mu and delta opioid-induced antinociceptive effects, ANA failed to significantly alter opioid antinociception. ANA significantly shifted the THC dose-effect curve to the right. Thus, ED50 for DMSO/THC in the tail-flick test was shifted from 14 (7-29) to 54 (38-77) micrograms/mouse and was shifted in the hot-plate test from 22 (12-42) to 63 (43-92) micrograms/mouse. The magnitude of the shift in the ED50 was 3.8-fold in the tail-flick test and 2.9-fold in the hot-plate test. The shifts were parallel and significant. The Ki for the displacement of 3H-CP 55,940 binding by ANA and FA was 214 nM (+/- 45 S.E.M.) and 72 nM (+/- 5 S.E.M.), respectively, in pure spinal cord synaptosomes from the rat. ANA and FA were significantly cross-tolerant to THC. Although similarities between ANA and cannabinoids were shown, several marked differences were observed between ANA and the classic cannabinoids. ANA appears to function as both a cannabimimetic and a blocker of cannabinoid-induced antinociception.
The duration of behavioral impairment after marijuana smoking remains a matter of some debate. Alcohol and marijuana are frequently used together, but there has been little study of the effects of this drug combination on mood and behavior the day after use. The present study was designed to address these issues. Fourteen male and female subjects were each studied under four conditions: alcohol alone, marijuana alone, alcohol and marijuana in combination, and no active treatment. Mood and performance assessments were made during acute intoxication and twice the following day (morning and mid-afternoon). Acutely, each drug alone produced moderate levels of subjective intoxication and some degree of behavioral impairment. The drug combination produced the greatest level of impairment on most tasks and "strong" overall subjective ratings. There were few significant interactions between the two drugs, indicating that their effects tended to be additive. Only weak evidence was obtained for subjective or behavioral effects the day after active drug treatments, although consistent time-of-day effects (morning versus afternoon) were observed on several subjective and behavioral measures. In sum, this study provided little evidence that moderate doses of alcohol and marijuana, consumed either alone or in combination, produce behavioral or subjective impairment the following day.
In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,940 and WIN 55,212 produced more or less the same pharmacological effects and interacted with the same cannabinoid receptor. However, their potencies vary across a number of pharmacological assays, suggesting that a single mechanism may not account for all of their actions. To further explore possible differences among these cannabinoids, cross-tolerance studies were conducted. Specifically, the ability of delta 9-THC, CP 55,940 and WIN 55,212 to produce hypoactivity, hypothermia, antinociception and catalepsy was assessed in mice that had been chronically treated with either delta 9-THC or CP 55,940. The results indicated the delta 9-THC-treated mice were tolerant to delta 9-THC. The degrees of tolerance were 15.9, 7.8, and 13.4 for spontaneous activity, hypothermia and antinociception, respectively. Mice chronically treated with delta 9-THC also exhibited tolerance to some of the behavioral effects of CP 55,940 and WIN 55,212. The tolerance induced by repetitive administration of CP 55,940 was substantial. The ED50 for CP 55,940 was shifted 102 fold for spontaneous activity, 100 for hypothermia and 44 for catalepsy. Also, some cross-tolerance to delta 9-THC and WIN 55,212 was observed in CP 55,940 chronically treated mice. These findings indicate that cross-tolerance develops between delta 9-THC, CP 55,940 and WIN 55,212 and that these agents have some actions in common. However, quantitative differences in their development of cross-tolerance suggests that all of their actions may not be identical.
Cannabidiol (CBD) has been shown to be a selective inactivator of cytochromes P450 (P450s) 2C and 3A in the mouse and, like many P450 inactivators, it can also induce P450s after repeated administration. The inductive effects of CBD on mouse hepatic P450s 2B, 3A, and 2C were determined using cDNA probes, polyclonal antibodies, and specific functional markers. P450 2B10 mRNA was increased markedly after repeated CBD administration and correlated well with increased P450 2B immunoquantified content and functional activity. On the other hand, although the 2-fold increase in P450 3A mRNA detected after repeated CBD administration was consistent with the increased immunoquantified P450 3A protein content, the lack of an observable increase in P450 3A-specific functional activity suggested subsequent inactivation of the induced P450 3A. Repeated CBD treatment increased P450 2C mRNA content 2-fold, but did not increase either the P450 2C immunoquantified content or its functional activity. The effect of CBD treatment on the ability of tetrahydrocannabinol (THC) to induce P450 2B was also determined. A THC dose that did not induce P450 2B significantly was administered alone or in combination with a CBD dose that markedly inactivated P450s 2C- and 3A but submaximally increased P450 2B functional activity. The combination of THC and CBD did not increase P450 2B-catalyzed activity significantly over that observed after CBD treatment alone. Thus, prior CBD-mediated P450 inactivation does not appear to increase the ability of THC to induce P450 2B. To further characterize the relationship between P450 inactivation and induction, several structurally diverse CBD analogs with varying P450 inactivating potentials were tested for their ability to induce P450 2B. At least one CBD analog that is an effective P450 inactivator failed to induce P450 2B, while at least one CBD analog that is incapable of inactivating P450 was found to be a very good P450 2B inducer. It therefore appears that inherent structural features of the CBD molecule rather than its ability to inactivate P450 determine P450 2B inducibility. The complex effects of CBD treatment on P450 inactivation and induction have the potential to influence the pharmacological action of many clinically important drugs known to be metabolized by these various P450s. The mechanism of CBD-mediated P450 induction remains to be elucidated but does not appear to be related to CBD-mediated P450 inactivation.
Specific cannabinoid receptors have been recently described in extrapyramidal and limbic areas and presumably might mediate the effects of marijuana exposure on behavioral processes related to those areas. In this work, we examined whether cannabinoid receptors exhibit downregulation as a consequence of the chronic exposure to delta 9-tetrahydrocannabinol (THC), which might explain certain tolerance phenomena observed in relation to motor and limbic effects of marijuana. To this end, we first characterized the binding of cannabinoid receptors, by using [3H]CP-55,940 binding assays, in the striatum, limbic forebrain, and ventral mesencephalon of male rats, and, second, we measured the density and affinity of those receptors in these brain areas after 7 days of a daily treatment with THC. Development of a tolerance phenomenon was behaviorally tested by using an open-field technique. Results were as follows. The three areas studies presented specific and saturable binding for the cannabinoid ligand, as revealed by their corresponding association and dissociation curves, displacement by THC, saturation curves, and Scatchard plots. A chronic treatment with THC produced the expected tolerance phenomenon: The decrease caused by an acute dose in spontaneous locomotor (49.4%) and exploratory (59.7%) activities and, mainly, the increase in the time spent by the rat in inactivity (181.7%) were diminished after 7 days of daily treatment (39.4, 40.4, and 31.7%, respectively). This tolerance was accompanied by significant decreases in the density of cannabinoid receptors in the striatum and limbic forebrain, the areas where nerve terminals for nigrostriatal and mesolimbic dopaminergic systems, respectively, which play an important role in those processes, are located.(ABSTRACT TRUNCATED AT 250 WORDS)
Mice pretreated intraperitoneally for 2 days with delta‐9‐tetrahydrocannabinol (delta‐9‐THC) at a dose of 20 mg kg ⁻¹ day ⁻¹ and then challenged intravenously with this drug, 24 h after the second pretreatment, showed a 6 fold tolerance to the hypothermic effect of delta‐9‐THC. This pretreatment also induced tolerance to the hypothermic effects of the cannabimimetic agents, CP 55,940 (4.6 fold) and WIN 55,212‐2 (4.9 fold), but not to the hypothermic effect of the putative endogenous cannabinoid, anandamide.
Vasa deferentia removed from mice pretreated intraperitoneally with delta‐9‐THC twice at a dose of 20 mg kg ⁻¹ day ⁻¹ were less sensitive to its inhibitory effect on electrically‐evoked contractions than vasa deferentia obtained from control animals. The cannabinoid pretreatment induced a 30 fold parallel rightward shift in the lower part of the concentration‐response curve of delta‐9‐THC and a marked reduction in the maximal inhibitory effect of the drug. It also induced tolerance to the inhibitory effects on the twitch response of CP 55,940 (8.7 fold), WIN 55,212‐2 (9.6 fold) and anandamide (12.3 fold).
The results confirm that cannabinoid tolerance can be rapid in onset and support the hypothesis that it is mainly pharmacodynamic in nature. The finding that in vivo pretreatment with delta‐9‐THC can produce tolerance not only to its own inhibitory effect on the vas deferens but also to that of three other cannabimimetic agents, suggests that this tissue would be suitable as an experimental model for investigating the mechanisms responsible for cannabinoid tolerance.
Further experiments are required to establish why tolerance to anandamide‐induced hypothermia was not produced by a pretreatment with delta‐9‐THC that did induce tolerance to the hypothermic effects of delta‐9‐THC, CP 55,940 and WIN 55,212‐2 and to the inhibitory effects of delta‐9‐THC, CP 55,940, WIN 55,212‐2 and anandamide on the twitch response of the vas deferens.
The effects of delta-9-tetrahydrocannabinol (delta-9-THC) were studied during performance of a delayed match to sample (DMTS) task in rats. Correlated hippocampal cellular activity was also assessed in terms of the effects of cannabinoids on well characterized task specific changes in firing rate which occurred during various phases of a DMTS trial. Results show a surprising correlation between the delay and dose (0.75-2.0 mg/kg)-dependent behavioral deficit produced by delta-9-THC in this task and similar effects produced by damage to the hippocampus and related structures. However, unlike the effects of hippocampal lesions or neurotoxic damage, the effects of delta-9-THC were completely reversible within 24 hr of injection. Neither control injection of the vehicle nor equivalent concentrations of the nonpsychoactive cannabinoid, cannabidiol, produced alterations in DMTS performance levels. Simultaneous recordings from identified hippocampal complex spike cells at the highest dose of drug indicated that the DMTS deficit was associated with a specific decrease in hippocampal cell discharge during the Sample (but not the Match) phase of the task. In nine identified neurons (including four observed during both control and drug conditions) recorded from six different animals in which the effects of delta-9-THC were manifested, no indication of Sample phase firing was observed. Although there were slight but significant reductions in Match and Reinforcement phase related firing during THC sessions, highly significant increases in firing in these phases were still present, indicating that elimination of Sample phase firing did not reflect a nonspecific effect of delta-9-THC on hippocampal cell activity. These findings strongly suggest that performance of the DMTS task was selectively impaired by the lack of Sample phase discharge of hippocampal neurons during the DMTS trial, and that this effect could serve as the basis for the well characterized short-term memory and other cognitive deficits reported in humans after smoking marijuana.
The active ingredient of marijuana is (-)-delta 9-tetrahydrocannabinol (delta 9-THC). delta 9-THC and other natural and synthetic cannabinoids such as CP-55,940 inhibit spontaneous activity and produce catalepsy in animals in a receptor-mediated fashion. Tolerance develops to the motor effects of delta 9-THC after repeated administration. To test the hypothesis that tolerance is mediated by changes in cannabinoid receptor binding characteristics, we used quantitative in vitro autoradiography of [3H]CP-55,940 binding to striatal brain sections from rats treated either chronically or acutely with delta 9-THC, CP-55,940, or the inactive natural cannabinoid cannabidiol. In the chronic conditions, rats were given daily i.p. injections of delta 9-THC (10 mg/kg), cannabidiol (10 mg/kg), or CP-55,940 (1, 3, or 10 mg/kg) for 2 weeks and sacrificed 30 min after the last injection. In the acute condition, animals received a single dose (10 mg/kg) prior to sacrifice. Rats developed tolerance to the inhibitory effects of delta 9-THC and CP-55,940, assayed in an open field on days 1, 7, and 14. Cannabidiol had no effect on behavior. Densitometry of [3H]CP-55,940 binding to brain sections showed that delta 9-THC- and CP-55,940-treated animals had homogeneous decreases in binding in all structures measured at the selected striatal levels. Cannabidiol had no effect on binding. Analysis of binding parameters showed that alterations in the acute condition were attributed to changes in affinity (KD), whereas the major changes in the chronic condition were attributed to a lowering of capacity (Bmax). The effects in the 1, 3, and 10 mg/kg CP-55,940 conditions were dose-dependent and paralleled the behavioral data showing that the animals given the highest dose developed the greatest degree of tolerance. The data suggest that tolerance to cannabinoids results at least in part from agonist-induced receptor down-regulation.
Tolerance to delta 9-tetrahydrocannabinol (delta 9-THC) was produced in rats by twice daily injections (15 mg/kg i.p.) for 6.5 days. Administration of the cannabinoid antagonist SR141716A (i.p. or i.c.v.) induced a profound precipitated withdrawal syndrome in delta 9-THC-tolerant animals. The syndrome was characterized by a disorganized pattern of constantly changing brief sequences of motor behavior. Autonomic signs were not evident. THC-tolerant animals that were treated with vehicle remained quiet throughout the observation period.