Damian Sendler: THC, one of the psychoactive compounds in cannabis, has been linked to a variety of long-term psychopathological outcomes when it is exposed to developing brains. As a result of this increased risk come an increased incidence of mental illnesses such as schizophrenia and other mood and anxiety disorders, in addition to possible cognitive declines. THC-related psychotic risk vulnerability may be explained by a variety of neuropathophysiological sequelae and mechanisms being studied in clinical and preclinical settings, particularly in adolescents who have had cannabis exposure. THC’s ability to induce long-term adaptations in the mesocorticolimbic system that resemble pathological endophenotypes associated with these disorders is common in these studies.
Damian Jacob Sendler: In terms of both recreational and medicinal use, cannabis is one of the most commonly used psychoactive substances. The growing acceptance of marijuana as a recreational drug around the world heightens the urgency of furthering clinical and preclinical research into the drug’s potentially harmful effects, particularly on the developing brain. Drug experimentation is common during the adolescent years as a result of the profound neurodevelopmental vulnerability during this time period. One-third of adolescents in Europe between the ages of 12 and 17 smoke cannabis, and 1.2 percent of them do so on a regular basis [1]. In the United States, however, the percentage of high school students who use cannabis has steadily increased from 14 percent to 44 percent. As a result of COVID-19, 31% of people aged 16 to 19 and 20 to 24 reported an increase in their cannabis consumption [3]. A decline in participants’ belief that daily cannabis smoke increases their risk of mental health disorders (from 76% in 2020 to 66 percent in 2019) coincided with these findings [3]. A wide range of cannabis-related pathophenotypes have been linked to factors such as the age at which exposure began, frequency, and duration. However, prolonged exposure to the main psychoactive marijuana phytochemical THC induces overstimulation of cannabinoid receptor type 1 (CB1Rs). This may profoundly affect the endocannabinoid system development and the endocannabinoid system’s physiological development (ECS). Anandamide (AEA) and other CB1R endogenous agonists are subject to metabolic control mechanisms, but THC escapes these neuroregulatory control mechanisms, leading to more long-lasting and unregulated neurophysiological effects [4].
Dr. Sendler: Chronic cannabis use in adolescents has been linked to a wide range of long-term health problems, according to both clinical and preclinical research. When it comes to the mesocorticolimbic system, developmental exposure to THC has been linked to numerous cognitive deficits and increased susceptibility to neurological disorders [5,6,7]. These findings are also accompanied by neuroanatomical abnormalities and maladaptations in the region.
The relative potency of THC appears to play an important role in the pathology of cannabis, as well. The concentration of THC in cannabis has steadily increased over the last few decades, while the concentration of cannabidiol (CBD), the main non-psychoactive constituent of cannabis, has not changed [8,9]. High-THC cannabis strains (e.g., sinsemilla) use in young people has been linked to an increased risk of anxiety and cannabis use disorder [13], as well as psychiatric-like symptoms [14,15] and relapses more frequently [16].
As a result, adolescence is a time when the brain is particularly vulnerable to the effects of external insults, which can lead to pathological phenotypes later in life. As a result of chronic cannabinoid exposure during adolescence in humans and animals, long-term behavioral and brain development abnormalities have been documented. As a result of our research, we’ve identified potential pharmacotherapeutic targets for treating these side effects of cannabis use.
Numerous epidemiological studies have found a link between adolescent cannabis use and an increased risk of developing various neuropsychiatric disorders in adulthood. According to Andréasson and colleagues in 1987, heavy cannabis users were six times more likely than non-users to develop schizophrenia in adulthood. There is a strong correlation between the onset of cannabis use and the development of psychopathological symptoms. Subjects who used cannabis for the first time before the age of 16 showed both positive and negative aspects of psychosis [18]. A higher risk of depression phenotypes and anxiety, as well as changes in cognition, have been linked to early cannabis use [19,20,21]. Long-term neurocognitive deficits in IQ, working memory, executive functioning, decision-making, impulsivity and attention, and scholastic performance have been linked to chronic cannabis use before the age of 17. During Jacobus and colleagues’ prospective studies, they found a correlation between cognitive impairments and neurostructural maladaptations. Researchers found that cannabis users had worse attention and memory, as well as reduced white and gray matter integrity and thicker frontal and temporal cortexes in the brain [25]. [25] Prefrontal, limbic, parietal and cerebellar tracts of young marijuana users showed reduced white matter integrity [26,27], and an opposite pattern in cortical thickness was associated with the onset of use, which highlighted thicker cortices in early- vs. late-onset users [27]. The right superior temporal, right inferior parietal, and left paracentral regions of the brain had increased thickness after heavy marijuana use, while the right caudal middle frontal, bilateral insula, and bilateral superior frontal cortices had decreased [28].
Other studies have shown that marijuana exposure may influence the development of the brain’s structure during neurodevelopmental periods. For example, a study of brain volume measurements found that marijuana users who began using before the age of 17 had smaller gray matter and larger white matter volumes in their brains [29]. There have been findings of morphological changes and profound impairments in connectivity in the corpus callosum and right fimbria of hippocampus in cannabis-related pathology [30–31,32–33]. These findings may explain the long-term cognitive impairments observed in cannabis-related pathology.
Cannabis-related symptoms may be caused by imbalances in the excitatory and inhibitory pathways in the brain, according to neurochemical studies. Repetition of CB1R stimulation during brain maturation may, in fact, interfere with normal neurodevelopmental processes, particularly in the frontal cortex, hippocampus, and striatum, where CB1Rs expression gradually increases until adulthood [35].. GABAergic and glutamatergic abnormalities in young chronic smokers and cannabis users in the early stages of psychosis were observed following adolescent cannabis exposure, but no clinical studies to our knowledge have reported long-lasting effects on these systems. It’s not unusual to see such anomalies in patients with neuropsychiatric disorders. A decrease in cortical glutamate decarboxylase (GAD-67) levels was found in schizophrenic patients’ post-mortem analyses [38]. This enzyme is involved in the synthesis and release of GABA. In addition, it has been shown that GAT-1 and GABAA receptor subunit levels have decreased [39,40,41]. Patients with major depression had similar changes in GAD-67 and GABAA receptors [42,43,44].
In addition, both clinical and pre-clinical studies have examined the effects of adolescent marijuana use on dopaminergic system function. As an example, studies have shown that long-term cannabis use is associated with decreased striatal dopamine (DA) release [45,46]. In addition, the COMT and Akt genes have been investigated because of their role in regulating DA and causing psychosis. Cannabis use during adolescence has been linked to an increased risk of developing psychotic symptoms in adulthood, according to Caspi and colleagues [47]. A genetic variation in the Akt gene [48] was found to be the mediating factor in the absence of this effect following acute consumption in young smokers. Cannabis-related psychopathology has been linked to the same polymorphism of the Akt gene [49]. [48, 49] Studies on the BDNF gene, a neurotrophin involved in the growth, differentiation, and survival of neurones, have shown that frequent cannabis use in adolescence deregulated BDNF production [50]. The onset of psychosis has also been linked to cannabis use at a young age and variations in BDNF [51].
New therapeutic approaches to prevent and/or reverse pathophysiological sequelae induced by chronic marijuana use during adolescence could be developed by examining the role of neuronal and genetic markers in the association between early cannabis consumption and vulnerability to neuropsychiatric disorders, as this evidence suggests. Correlational studies in humans, on the other hand, make it difficult to distinguish between causal and correlative measures, whether in terms of time or function. The role of cannabinoid biomarkers linked to adolescent brain development in pre-clinical studies using rodent models of adolescent brain development has been extremely important. Many pre-clinical studies and reported clinical effects are now beginning to align, allowing for greater opportunities to identify therapeutic interventions aimed at reversing the pathophysiological effects of cannabinoid exposure in adolescents.
To model cannabinoid-related endophenotypes similar to those reported in schizophrenia and other neuropsychiatric diseases, pre-clinical studies on adolescent neurodevelopmental cannabis exposure have been critical. Identifying cannabinoid-induced neuroadaptations, while precisely controlling drug concentration and the age window of exposure, as well as allowing mechanistic approaches to prevent or revert observed psychopathological phenotypes, are advantages of animal studies. Adolescence in rodents can be divided into three distinct phases, beginning at postnatal days (PNDs) 21, 34, and 46, in order to better translate these models into human health outcomes [52]. These three distinct stages are known as “early, middle, and late adolescence.”
Many behavioral paradigms with high validity have been used to investigate schizophrenia-like features following adolescent cannabinoid exposure, although schizophrenia is unquestionably an exclusively human disease. Prepulse inhibition (PPI) is one of the most commonly used assays to investigate sensory filtering impairments in a variety of neuropsychiatric disorders, including schizophrenia and autism. In fact, one of the hallmark symptoms of schizophrenia is an inability to discriminate between relevant and unimportant stimuli [53]. Sensorimotor gating has been shown to be significantly disrupted in adult rodents after chronic THC exposure during middle adolescence (PND 35–45) [54,55]. However, this effect was not observed when THC was administered to adult rats (PND 65–75) directly after adolescent THC exposure [55].
Damian Sendler
Schizophrenia is characterized by impairments in social cognition and memory [56]. Animal studies have shown that adolescent exposure to neurodevelopmental THC causes deficits in cognition similar to those seen in schizophrenia [57,58]. THC-treated adolescent rats, for example, showed significant long-term abnormalities in social interaction memory [54,59]. Additionally, both males and females were affected by specific tasks (e.g. novel and spatial object recognition; radial arm maze; T maze; Morris water maze) when they were tested. The memory-enhancing effects of THC have not been consistently reported across studies [64,65,66,67]. Disparities in THC administration methods and dosing regimens, as well as differences in behavioral paradigm techniques, may be to blame for these inconsistencies. The paired-associates learning task, which assesses for associative learning and visual memory deficits, also yielded relevant long-lasting deficits. Adult THC-exposed rats needed more trials than controls to meet a criterion of 80% at adulthood [55].
Anxiety and depression-like symptoms have been linked to long-term cannabinoid exposure during adolescence in rodents, according to extensive research. THC-exposed adolescent rats, on the other hand, were more likely to become immobilized in a water cylinder during the Porsolt Forced Swim Test (FST) if they were placed in an inescapable water cylinder. Females are more likely to engage in these behaviors, which are seen as indicators of despair and resignation [69,70]. Adolescent THC exposure has been shown to induce anhedonia-like behaviors, as demonstrated by decreased interest in rewarding stimuli measured by sucrose and palatable food preference tests [68,70,71]. Moreover Furthermore, these findings support the role of cannabis use during adolescence in the development of mood disorders in adulthood, which is consistent with the remarkable gender differences in depression observed.
Damian Jacob Markiewicz Sendler: Adolescent THC exposure has been linked to a variety of anxiety disorders, but the evidence is inconsistent. It was found that chronic THC treatment in adolescents resulted in long-lasting anxiety in the light-dark box test [54], which is an experimental paradigm built on rodents’ natural aversion to bright light. Adolescent THC has been found to induce either no changes, anxiety- or anxiolytic-like effects when other assays are used. Adult rats given low doses of THC from PND 30 to 50 during the Elevated Plus Maze test spent less time and made fewer entries into the open arms [68]. THC-exposed males and females [71,72] as well as C57Bl/6J and DBA/2J male mice [63,65] showed no long-term differences. The strain-specific anxiolytic effects of THC were also found in Lewis rats, which spent more time open arms compared to their vehicle counterpart and THC-exposed Fischer344 rats [73]. THC-induced maladaptations might have been influenced by genetic differences and differences in vulnerability. In fact, one study found that chronic adolescent THC exposure had no effect on adult Long-Evans rats in terms of affective dysregulation [74]. According to the Open Field test, there have been conflicting results on whether or not tigmotaxis occurs. As a result of their natural instinct to avoid predators, rodents prefer to stay close to the walls of an enclosed test environment rather than venture out into the open arena. This anxiety index is based on this preference. Adolescent THC exposure was found to either increase [60] or maintain [68,71] the thigmotaxis index in adulthood using this assay. This suggests a complex interaction between a person’s genetic background and their relative vulnerability to THC-induced anxiety phenotypes.
Consistent with a disruption of the GABA/Glutamate balance within this region, chronic THC exposure in adolescents leads to a remarkable potentiation of firing and bursting activity in PFC pyramidal neurons in addition to loss of GABAergic inhibition [54,59]. As a result, pharmacological interventions aimed at preventing or reversing THC-induced psychopathology involve modulating glutamatergic dysfunction. There has been particular interest in L-theanine, a green tea analogue of L-glutamate and L-glutamine that has been shown to have therapeutic properties in anxiety and schizophrenia as well as depressive phenotypes L-theanine has been shown to effectively block a wide range of THC-induced behavioral abnormalities into adulthood, including anhedonia, anxiety, and impairments in memory and sensorimotor gating in a neurodevelopmental rodent model of adolescent THC exposure [96]. As DAergic hyperactivity in the VTA is normalized, L-ability theanine’s to normalize the cortical hyper-bursting state and restore the inhibitory/excitatory balance and the oscillation patterns within the PFC may be responsible for these preventative effects. Furthermore, L-theanine was able to completely prevent the overactivation of DAergic neuronal activity in the subcortical VTA DAergic neurons as well as in the cortical PFC activity states and gamma-oscillatory dysregulation caused by the adolescent THC exposure. L-theanine also reversed the down-regulation of cortical GSK-3/ and Akt-Thr308, two critical molecular biomarkers for THC-related neuropsychiatric side effects [96]. (Table 1). It has previously been shown that sustained activation of DA D2 receptors causes decreases in the expression of GSK-3/ and Akt-Thr308 associated with hyperdAErgic states [97]. The glutathione levels in astrocytes are modulated by L-theanine in an in vitro study, which protects against DA-related neurotoxicity [98]. Astrocytic-glutathione mechanisms may play a role in the dysregulation of the PFC/VTA following adolescent THC exposure, according to this study.
Teenage THC use was found to cause long-term dysregulation of serotonin transmission [60,68], indicating that this system could be a target for new therapeutic approaches beyond DA alone. Adolescent co-administration of THC and the 5HT6 receptor antagonist SB258585, as well as changes in the intrinsic properties of cortical pyramidal neurons and LTD, have been shown by Berthoux and colleagues [99] to prevent long-lasting cognitive impairments and aberrations in cortical networks (Table 1). Moreover, the mTOR inhibitor rapamycin reversed these THC-induced abnormalities, and 5HT6 receptor deficient mice lacked these abnormalities, indicating the critical role of these receptors in THC-related pathology. The antagonism of the 5HT6 receptor has previously been found to be effective in the development of schizophrenia models [100]. This study shows that mTOR dysregulation is a key molecular mechanism in THC-induced neurodevelopmental pathophysiology [54,81].
Damien Sendler: CBD’s antipsychotic profile and apparent lack of side-effects have also prompted a number of studies to investigate its potential protective properties. Although CBD has been found to have opposite effects on various neurophysiological measures compared to THC, it is a promising treatment for various neuropsychiatric conditions. CBD, for example, has been shown to alleviate amphetamine-induced deficits in PPI, hyperlocomotion, and increased VTA DA activity. In a study by Norris and colleagues [103], it was found that CBD reduces spontaneous DAergic firing and bursting rates by functional interaction with the 5HT1A receptor system. This could be the mechanism behind the CBD effects. Serotonin modulation by CBD in adolescents prevented hyper-motility, sensorimotor gating impairments and contextual fear memory loss in spontaneously hypertensive rats [104]. Additionally, CBD has been shown to have beneficial effects on memory and cognition in chronic cannabis users, as well as decreasing depressive-like symptoms without causing any side effects [105]. The abnormalities in the hippocampal anatomy and neurochemistry caused by long-term cannabis use were also normalized by CBD [106,107]. In pre-clinical studies, CBD has been shown to have similar anti-schizophrenia-like effects on long-term symptoms. Even in adolescent mice, CBD and THC co-administration prevented deficits in working memory, anxiety, and compulsive-like behavior [108]. (Table 1). CBR allosteric site modulation or interactions with other molecular substrates may allosterically antagonize THC effects [109,110,111,112], but the mechanisms are not yet fully understood. Increasing serum levels of endogenous AEA, which may be inhibited by CBD, has been found to have therapeutic effects in animal studies [113]. Adult female rats treated with the FAAH inhibitor URB597 were able to recover from THC-induced cognitive and depressive symptoms after receiving the drug, which lends credence to this finding. An increased CB1R density and restoration of THC-related functional aberrations in PFC and DG were associated with these effects. [70,87] (Table 1). The activation of nuclear peroxisome proliferator-activated receptors alpha (PPAR), an isoform of the nuclear ligand-activated transcription factors family, has previously been shown to have neuroprotective effects in several neurodevelopmental models [114,115].
Damian Jacob Sendler
Cannabis-related neurodevelopmental pathology can be exacerbated by genetic polymorphisms, as previously stated. Anxiolytic behaviors and memory impairments were observed in transgenic mice with DN-DISC1 mutations that had been exposed to THC in late adolescence, which were linked to reduced synaptic plasticity in HC. There were significant differences in BDNF levels between wild type (WT) mice and those with the DN-DISC1 THC treatment. This suggests that the WT response to environmental insults is a protective mechanism that fails to work if there are also other vulnerability factors in the mix. Indeed, in DN-DISC1-THC mice, BDNF over-expression prevented cognitive deficits [116]. (Table 1). An additional recent study found that THC-induced memory impairments are linked to astrocytic mechanisms. THC treatment in adolescents activates the proinflammatory NF-kB-COX-2 pathway in mice expressing DN-DISC1 specifically in astrocytes, resulting in increased glutamate levels and decreased parvalbumin-positive boutons in HC in these mice. These cognitive and glutamatergic abnormalities following adolescent THC exposure were prevented by selective inhibition of COX-2 signaling aimed to counteract this neuroinflammatory state (Table 1).
Further studies have suggested that the modulation of Neuregulin 1 (Nrg1), another gene linked to schizophrenia and the neuropsychiatric effects of cannabis, may have protective properties. It has previously been shown that transgenic mice heterozygous for the Nrg1 transmembrane domain exhibit less anxiety following acute THC exposure, whereas chronic THC exposure does not reduce exploratory sniffing behavior during social interaction in WT control groups [118]. For example, THC had a different effect on CB1 and 5-HT2A receptor binding density between Nrg1 HET and WT groups in brain areas linked to schizophrenia. A number of proteins associated with NMDA receptor trafficking and glutamatergic transmission, excitotoxicity, and apoptosis were found in Nrg1 HET THC-exposed mice compared to WT mice [119]. (Table 1). Although the Nrg1 mutation has been shown to be protective against THC-induced neurodevelopmental pathology, further research is needed.
Finally, epigenetic interventions have been proposed as a possible therapeutic target for THC-related neurodevelopmental abnormalities. Suv39H was found to be upregulated in the brains of adolescent female rats exposed to THC, which increased a repressive histone H3 marker. THC-induced cognitive impairments could be prevented by normalizing these selective histone modifications if a selective blocker of this enzyme was administered during adolescence [69]. (Table 1). Heterodimerization of the histone H3 methylation appears to be a promising strategy for treating the cortical inhibitory/excitatory imbalance brought on by chronic adolescent THC exposure [120]. These possibilities will need to be explored in greater depth in future research.
Chronic cannabis use during adolescence has been linked to an increased risk of developing a wide range of mental health issues and cognitive abnormalities. In addition to memory and learning impairments and mental health issues like schizophrenia-related psychosis, depressive and anxiety disorders are also possible. There has been remarkable agreement between translational animal models’ studies into the neurodevelopmental exposure to THC and clinical findings, and these studies have provided insight into various neural pathways and biomarkers involved in pathological outcomes associated with THC, pointing to several molecular targets for new pharmacotherapeutic approaches. We recently discovered that normalizing the hyper-DAergic state and restoring the excitatory/inhibitory balance in the mesocorticolimbic system can prevent or reverse the long-lasting behavioral, neural, and molecular consequences of adolescent THC use [59,96].
THC formulations that minimize potential side effects and tiered early interventions are becoming increasingly important in light of the rapid rise in marijuana use among youth. Many factors can contribute to the long-term effects of cannabis use during adolescence. It is possible that co-occurrence with other multivariate factors, as well as exposure to THC during brain development, increases vulnerability to psychiatric disorders’ (see [121] for an extensive review). This review found that while some genetic polymorphisms were protective, others induced adverse and synergistic effects and increased vulnerability to cannabis-related developmental insults, for example. Emerging findings on early-life interferences, such as maternal deprivation or immune system activation, and adolescent THC exposure [122,123], highlight the complexity of such interactions and call for further investigation.