Cannabis and the Brain: Friend or Foe?

Abstract

Legalization of cannabis in the US and other countries highlight the need to understand the health consequences of this substance use. Research indicates that some cannabis ingredients may play beneficial role in treating various medical conditions while other ingredients may pose health risks. This review is focused on the brain and mental health effects of cannabis use. The rationale for examining cannabis use in behavioral and neural conditions is that these conditions are highly widespread in the US and account for high level of medical healthcare and associated cost. The purpose of this review is to provide an overview of the known medicinal benefits of selected cannabis cannabinoids in conditions like pediatric epilepsy, attention deficit hyperactivity disorder, autism spectrum disorder, and the known side effects or contraindications in conditions such as addiction, cognition, and psychosis. Several recommendations are made as to studies that will help further understanding the increasing role of cannabis in neuropsychiatric health and disease.

1. Introduction

Legalization of cannabis in the US and other countries in conjunction with increases in various methods of consumption make it vital to understand the associated health consequences. The global legal cannabis market size is expected to reach $84B by the end of 2028, according to a report by Grand View Research [1]. The cannabis market is expected to expand at a compound annual growth rate (CAGR) of 14% from 2021 to 2028 according to the report. Gallup poll indicates that Americans support for legalizing marijuana has been around 66% in 2018, which represents 30% increase between 2005 and 2018 [2]. In a 2019 Gallup poll, 13% of the US adults reported smoking cannabis, a percentage which was almost double that reported 3 years earlier [3]. About 43% of adults in the US reported having tried cannabis in 2019, 44% in 2018, 38% in 2013, and 4% in 1969 [3].

The first evidence of cannabis medicinal effects dates to Chinese medicine in the first to second century B.C. [4]. The detrimental effects of cannabis on mental health were first reported by the physician Iban Beitar between the twelfth and the thirteenth century [5]. Later in 1845, the French psychiatrist Jacque-Joseph Moreau described such effects as acute psychotic reactions that could last a few hours up to a week. He identified that the reaction was dose-dependent, and its main characteristics were illusions, hallucinations, delusions, confusion, and restlessness; and potential disorientation and loss of consciousness [6]. Such evidence suggested a potential role of cannabis in the pathophysiology of psychosis and other mental disorders, as later confirmed by studies performed over the last 50 years [7, 8, 9]. Legalization of medical and recreational cannabis has incentivized consumer to develop novel forms of cannabis consumption. The methods have been described in a recent authors’ publication [10].

Here, we provide an overview of the known medicinal benefits of selected cannabis cannabinoids, the known side effects or contraindications and point out the many unknowns of cannabis use on the brain. We propose new cannabis research to answer questions as to why cannabis may be both a friend and a foe and uncover additional medicinal benefits and identify the health hazards with focus on brain and mental health.

1.1 National academies of science report

A committee on the Health Effects of cannabis consumption was formed at the National Academies of Science (NAS), Engineering and Medicine to extensively review the scientific literature and identify the research gaps. The committee formed by 16 experts in the areas of cannabis addiction, oncology, cardiology, neurodevelopment, respiratory disease, pediatric and adolescent health, immunology, toxicology, preclinical research, epidemiology, systematic review, and public health. Given the vast amount of scientific literature on cannabis, the committee decided to use published systematic reviews (since 2011) and high-quality primary research for 11 areas including brain and mental health conditions. The report was published in January 2017 [11]. The NAS committee summarized the effect of cannabis on brain and mental health literature published since 1999 [11]. The limitations of the reviewed studies included a lack of data on different methods of cannabis consumption [e.g., smoke, edible, etc.], inadequate dose information, little information on potential additives or contaminants, and lack of adequate data on total lifetime duration/dose of cannabis consumption [11]. The evidence committee found are summarized in the report [11].

2. Mechanism of action for cannabis

A large literature exists on the effects of cannabis (plant-based cannabinoids), with many of the earlier studies conducted in human subjects [12]. Recently, research on plant-based cannabinoids has been stimulated by the recognition that specific receptors exist in the brain that recognize cannabinoids, and by the discovery of a series of endogenous cannabinoids which are made in the body that act as ligands for these receptors [13]. The endocannabinoid system consists of the endogenous cannabinoids, cannabinoids receptors and the enzymes that synthesize and degrade cannabinoids. Many of the effects of cannabinoids and endocannabinoids are mediated by two G protein-coupled receptors (GPCRs), CB₁ and CB₂, although additional receptors may be involved [14]. CB₁ receptors are present in extremely high levels in several brain regions and in lower amounts in a more widespread distribution. These receptors mediate many of the psychoactive effects of cannabinoids. All these compounds act as agonists at the CB1 cannabinoid receptor [15], which is the only one known to be expressed in the brain. A second cannabinoid receptor, CB2, is expressed only in peripheral tissues, principally in the immune system [16, 17, 18]. Both CB₁ and CB₂ coupled primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. Thus, partial agonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific cannabinoid receptor ligands. These receptors are crucial to utilizing the active components in cannabis that influence homeostasis. Various cannabinoids have diverse effects on the receptors, functioning as agonists, antagonists, or partial antagonists, as well as affecting the vanilloid receptor [14]. The identification of cannabinoid receptors grew out of a desire to understand the psychoactive effects of Δ⁹-tetrahydrocannabinol (THC), the principal psychoactive component of cannabis [18]. THC is the main activator of CB1 through allosteric modulators, which can potentially allow the therapeutic effects of THC without the intoxicating effects [18]. CNR1 gene produces the CB1 protein [19]. Since each individual carries a different version of the CNR1 gene, many people have a different experience with the use of compounds like THC and CBD [19]. THC and the synthetic cannabinoids also act to some extent as agonists at the CB2 receptor. Both cannabinoid receptors are members of the G-protein coupled class, and their activation is linked to inhibition of adenylate cyclase activity [20].

Smoking remains the most efficient means of using the drug and the users can adjust the dose by adjusting the frequency and depth of inhalation [21]. THC can also be taken orally in fat-containing foods with a delay in absorption [21]. Several man-made synthetic cannabinoids are also available [16].

3. Rationale for studies of cannabis effect on brain and mental health

Although cannabis use may impact numerous organ systems (cardiovascular, pulmonary, skeletal, etc.), we focus on the brain and mental health. There has recently been widespread interest in the relationship between cannabis use and psychosis, with over 100 papers addressing this topic each year since 2012, compared to fewer than 10 per year during the 1990s [22]. This intense interest is likely due to increasing approval within the USA of medicinal marijuana laws. Interest in this area is expected to continue to rise as cannabis becomes legally available to adults for recreational purposes. The concern is that more widespread cannabis use might increase the risk of schizophrenia [22]. Research studies indicated that heavy daily cannabis use across protracted periods exerts harmful effects on brain tissue and mental health [23]. Significant evidence exists that prenatal, perinatal, and adolescent cannabis exposure can induce a wide array of brain and behavioral alterations in adulthood [24].

4. Benefits associated with cannabis

Preliminary studies of medical marijuana suggest a variety of benefits, including improvement of chronic pain, inflammation, spasticity, and other conditions commonly seen in physical therapy practice [25]. There have been many clinical trials in a variety of conditions, including the neuropathic pain, schizophrenia, bipolar disorder, major depressive disorder, sleep deprivation and Tourette syndrome [25].

Although evidence suggests that heavy, recreational cannabis consumption is linked to cognitive deficits and potentially undesirable neural changes as outlined below, findings from studies of recreational cannabis consumption may not be applicable to medical marijuana [26]. One study examined whether patients receiving medical marijuana would exhibit improvement in cognitive functioning [27]. Further studies are warranted to clarify the specific neural and cognitive impact of medical marijuana use and how it compares to recreational use.

Investigators have evaluated the role of cannabinoids for neuroprotective role in injured brain with positive effect in acute neuronal injury [28, 29, 30, 31]. Human clinical trials are needed to validate these outcomes and to understand the underlying mechanism involved in brain injury with use of cannabinoids.

The US Food and Drug Administration (FDA) has approved Dronabinol, the generic name for synthetic THC, is marketed under the trade name of Marinol® and is clinically indicated to counteract the nausea and vomiting associated with chemotherapy and to stimulate appetite in AIDS patients affected by wasting syndrome. A synthetic analog of THC, nabilone (Cesamet®), is prescribed for similar indications. Both dronabinol and nabilone are given orally and have a slow onset of action. In July 2016, the FDA approved Syndros®, a liquid formulation of dronabinol, for the treatment of patients experiencing chemotherapy-induced nausea and vomiting who have not responded to conventional therapies. The agent is also indicated for treating anorexia associated with weight loss in patients with AIDS. Nabiximols (Sativex®) is a combination drug standardized in composition, formulation, and dose. The principal active cannabinoid components of Sativex are the cannabinoids: tetrahydrocannabinol (THC) and cannabidiol (CBD) which was approved by UK in 2010 [32]. Nabiximols is administered as an oromucosal spray and is indicated in the symptomatic relief of multiple sclerosis [32]. Each spray delivers a dose of 2.7 mg THC and 2.5 mg CBD [32]. As of 2018, nabiximols has been launched in several countries. There are other promising applications for CBD like smoking cessation [33], drug withdrawal treatment [34], treating seizures and epilepsy [35], anxiety treatment [36], reducing some of the effects of Alzheimer’s [37], and antipsychotic effects on patients with schizophrenia [38].

4.1 Pediatric epilepsy

There is significant need for safe and effective treatment of intractable childhood epilepsy, especially in cases of devastating epileptic encephalopathies, such as infantile spasms, Lennox-Gastaut syndrome [39] and Dravet syndrome [40]. Despite limited preclinical data and a lack of well-designed clinical trials, CBD, and CBD-enriched whole cannabis plant extracts, have generated excitement as potential treatments for epilepsy [41]. Following anecdotal reports of potential efficacy from parents who have administered these products to their children [42, 43], clinical trials of multiple preparations of CBD were undertaken [43, 44, 45]. The results showed strong efficacy for treatment of Lennox-Gastaut syndrome [46], Dravet syndrome [46], and highly-treatment resistant epilepsy in children and young adults [45] and confirmed reports from open-label studies [47]. Among patients with Dravet syndrome, CBD treatment resulted in a greater reduction in convulsive-seizure frequency than placebo but was associated with higher rates of adverse events [48]. The adverse effect are a risk of liver damage, lethargy, and possibly depression and thoughts of suicide from patient information leaflet, but these are also true of other treatments for epilepsy. FDA approved Epidiolex® (brand name), a purified CBD-based oral solution based on collected evidence, for the treatment of Lennox-Gastaut syndrome and Dravet syndrome in June 2018. Epidiolex® has been assigned to Schedule V of the Controlled Substances Act. Longitudinal studies are required to provide further clarification of the effects of this product in the population of interest, especially with respect to the young developing brains.

4.2 Attention deficit hyperactivity disorder (ADHD)

There are some non-scientific evidence that support the use of cannabis to treat ADHD for children and adolescents [49]. Functional Magnetic Resonance Imaging (fMRI) was employed to investigate the relation between ADHD diagnosis and cannabis consumption in young adults [50]. No impact on behavioral response inhibition on a Go/No-Go task (the Go/No-Go task is a computerized test used to assess inhibitory control, a cognitive process that enables humans to rapidly cancel motor activity even after its initiation) was observed but did find that cannabis consumption was associated with increased signal in the hippocampus and cerebellum during the fMRI only in cannabis-using control subjects, but not in cannabis-using ADHD participants [50]. This may reflect a delayed maturation trajectory in ADHD participants according to the authors and suggested further studies related to hippocampal and cerebellar function to gain more information into how this circuitry is changed by ADHD and cannabis consumption. One of the important long-term implications of a childhood diagnosis of ADHD is an increased risk for substance use, abuse, or dependence in adolescence and adulthood [51]. Longitudinal study was designed to address this research gap by recruiting a sample of 75 individuals aged 21–25 years with and without a childhood diagnosis of ADHD, who were either frequent users or non-users of cannabis. These participants were followed since age 7–9.9 [51]. The results indicated that cannabis consumption did not exacerbate ADHD-related symptoms and larger samples study was proposed. Students (n = 1738) completed an online survey containing measures of ADHD symptoms, cannabis use, perceived effects of cannabis on ADHD symptoms and medication side effects, as well as executive dysfunction [52]. They reported that cannabis has acute beneficial effects on several symptoms of ADHD (e.g., hyperactivity, impulsivity). They also perceived cannabis to improve most of their medication side effects (e.g., irritability, anxiety). Cannabis use frequency was a significant moderator of the associations between symptom severity and executive dysfunction. Results suggest people with ADHD may be using cannabis to self-medicate for many of their symptoms and medication side effects and that more frequent use may mitigate ADHD-related executive dysfunction [52].

4.3 Autism spectrum disorder (ASD)

Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. The endocannabinoid system is often affected in ASD patients with comorbidities, such as seizures, anxiety, cognitive impairments, and sleep disturbances [53]. There is increasing interest in cannabinoids, especially CBD as add-on treatment for the core symptoms and comorbidities of ASD. In a preclinical study that tested the efficacy of CBD in a mouse model for Dravet syndrome, CBD reduced both seizures and ASD behaviors [54]. They found that when mice were administered CBD 1 hour before induced seizures, the seizures were shorter and less severe than in the mice who did not receive CBD. The authors also found that CBD improved inhibitory neuron function, and this action could be replicated by a GPR55 antagonist, suggesting another potential therapeutic option. Presently no clinical studies have examined the effects of any cannabinoid on epilepsy reduction specifically in ASD patients. Further preclinical and clinical studies are needed to investigate the pros and cons of CBD and other cannabinoids in ASD before they are established as treatment for symptoms and co-morbidities.

5. Problems associated with cannabis

5.1 Cognition

Although cannabis and cannabinoid-based products are increasingly being accepted worldwide, there is currently limited understanding of the effect of the various cannabinoid compounds on the brain. Exogenous cannabinoids interact with the endogenous cannabinoid system that underpins vital functions in the brain to perturb key brain and cognitive function. Chye et al. [55] reviewed existing brain imaging evidence related to cannabis consumption and its major cannabinoids (THC, CBD etc.) including synthetic cannabinoid. They concluded that neuroimaging research has been limited to observational studies of cannabis users, not considering the specific role of the various cannabinoids.

Research to date has suggested that cannabis consumption leads to cognitive impairments [56] classified as acute and chronic cognition. There is strong evidence that acute administration of cannabis adversely affects executive function. Impaired performance of occasional, moderate, and heavy users was documented in some, but not all studies, on functions like reasoning, decision-making, and problem solving [57, 58, 59, 60, 61, 62, 63, 64, 65]. As an example, double blind experiment on 35 male mild cannabis users showed that THC administration may be a useful pharmacological cannabinoid model for psychotic effects in healthy volunteers [57]. It was found that high potency marijuana (13% THC) consistently impairs executive function and motor control in contrast with low potency marijuana (4% THC) [60]. Use of higher doses of THC in controlled experiments may offer a reliable indication of THC induced impairment as compared to lower doses of THC that have traditionally been used in performance studies [60]. Cannabis consumption has been associated with increased risk of becoming involved in traffic accidents. Ramaekers et al. [61] designed a study to investigate performance impairment as a function of THC in serum. The results indicated that serum THC concentrations between 2 and 5 ng/ml establish the lower and upper range of a THC limit for impairment.

The effects of marijuana consumption on women’s cognition have been studied [64]. Anderson et al. examined sex differences in the acute effects of marijuana on cognition in 70 (35 male and 35 female) occasional users of marijuana [64]. The tasks chosen to study were divided attention, cognitive flexibility, time estimation, and visuospatial processing affected by sex and/or marijuana. The results indicated that acute marijuana use impaired performance on divided attention, time estimation, and cognitive flexibility. Although there did not appear to be sex differences in marijuana’s effects on cognition, but women requested to discontinue the smoking session more often than men that led to unconclusive results.

Performance impairment during THC intoxication has been described in heavy users of cannabis [64]. Twenty-four subjects participated in a double-blind, placebo controlled, two-way mixed model design. Both groups received single doses of THC placebo and 500 μg/kg THC by smoking. Performance tests were conducted at regular intervals between 0 and 8 hrs after smoking and included measures of perceptual motor control (critical tracking task), dual task processing (divided attention task), motor inhibition (stop signal task) and cognition (Tower of London). THC significantly impaired performance of occasional cannabis users on critical tracking task, divided attention task, and the stop signal task. THC did not affect the performance of heavy cannabis users except in the stop signal task; i.e., stop reaction time increased, particularly at high THC concentrations. The comparisons of overall performance in occasional and heavy users did not reveal any persistent performance differences due to residual THC in heavy users. These data suggest that cannabis consumption history strongly determines the behavioral response to single doses of THC.

A large body evidence points to cognitive impairment after chronic, heavy cannabis consumption [66, 67, 68], lasting beyond the acute effects. There is also substantial evidence with negative findings in cannabis users [69, 70, 71]. Consistency in experimental design remains a challenging aspect of studying the long-term effects of chronic cannabis consumption on cognition [72].

Memory has been the cognitive domain most consistently impaired, with verbal learning [67, 73, 74]. In chronic users, impairments in memory and attention deteriorates with increasing years of cannabis use [68, 75, 76, 77]. Contrary to these findings, recent studies have shown that THC can promote neurogenesis, restore memory, and prevent neurodegenerative processes and cognitive decline in animal models of Alzheimer’s disease [78, 79, 80]. Literature search indicates [81] that CBD improves cognition in multiple preclinical models of cognitive impairment, including models of neuropsychiatric [schizophrenia], neurodegenerative (Alzheimer’s disease), neuro-inflammatory (meningitis, sepsis, and cerebral malaria) and neurological disorders (hepatic encephalopathy and brain ischemia). There is only one clinical investigation into the effects of CBD on cognition in schizophrenia patients, with negative results for the Stroop test [81]. The efficacy of CBD to improve cognition in schizophrenia cannot be explained due to lack of clinical evidence. Further investigation into its efficacy in schizophrenia is justified given the ability of CBD to restore cognition in multiple impairment studies.

Studies performed on effect of cannabis on young users and showed that regular consumption during the adolescent may produce lasting adverse effects on cognitive and IQ [75, 82, 83]. On the other hand, another group found little evidence that cannabis use was related to impaired cognitive performance and hypothesized that family background may explain the lower cognitive function often reported in cannabis users [84]. Another study found no relation between adolescent cannabis consumption and educational achievement [85]. It is not clear, however, whether impairment will emerge later in life. Cyrus et al. [86] reviewed the literature on the relationship between adolescent cognitive function and academic performance with cannabis consumption. The conclusion was that frequency and quantity of cannabis consumption were related with decreased functional connectivity of the brain, poorer executive control and academic performance. Factors such as minimal parental monitoring, peer cannabis consumption, social isolation, and race/ethnicity were positively correlated with more frequent adolescent use of cannabis. Interventions to prevent early initiation of cannabis use that can lead to chronic use in youth who may be more at risk was recommended.

There have been studies of the degree of cognitive function recovery with abstinence. In a study of adolescents (16–25 years of age), improvements were found in verbal memory in the first week of abstinence whose abstinence was monitored for 1 month following regular consumption [87]. Cross-sectional studies indicate improvement on attention and verbal memory but not on other cognitive domains for adolescents abstinent for 4–5 weeks [88, 89]. Further research to monitor cognitive performance improvement during prolonged periods of abstinence from chronic cannabis use are recommended to address these questions including the neural mechanisms.

The lack of assurance about the effects of cannabis consumption on cognition may be due to composition of cannabis [90]. One study showed greater memory impairment as well as signs of depression and anxiety associated with using cannabis of higher THC content compared to cannabis containing lower THC and higher levels of CBD [76]. These studies should be repeated with known THC contents to evaluate mental behavior.

A review was conducted to study the long-standing consequences regarding regular cannabis use on cognition, brain structure, and function in adults [91]. The review suggested that the neuropsychological studies provided evidence for mild cognitive deficits at least 7 days after heavy cannabis consumption. The fMRI studies showed growing evidence of abnormalities in hippocampus volume and gray matter density of cannabis users relative to controls; however, morphological changes in other brain regions were more controversial. The fMRI studies suggested an altered pattern of brain activity associated with cannabis consumption. It should be noted that there are several limitations for study comparison and substantial heterogeneity in the findings [91]. The morphological alterations could ultimately affect brain organization and function, but the associated time course for neuronal recovery as well as the real impact on cognitive functioning remain unknown. The application of fMRI is beginning to advance the understanding of the neural mechanisms associated with the cognitive consequences observed in cannabis users to establish relationship between cannabis consumption, brain function and cognitive output. Factors to be included are age of onset, mode of consumption, frequency and extent of consumption, recovery of function with abstinence with different compositions of the cannabis product. Changes in brain activity may be an early indicator of long-term consequences before cognitive deficits can be measured [56]. Application of fMRI is also important for the adolescent brain reorganization study after prolonged usage and whether these changes reverses during adulthood after abstinence.

Eadie et al. [92] determined the duration of acute neurocognitive impairment associated with medical cannabis consumption, and to identify differences between medical cannabis patients and recreational consumers. It resulted in evidence that cognitive performance in medical cannabis patients declined after THC consumption, with steady resolution of impairment in the hours following THC consumption. The degree of impairment is predominantly dose-dependent where higher doses of THC were generally more impairing than the lower doses. There was no difference on any neurocognitive test between placebo and the active THC groups at 4-hrs of recovery, irrespective of the THC dose inhaled, although the duration of neurocognitive impairment varied between studies, partly due the differences in design of experiments. More research is needed to directly relate levels of cognitive impairment to THC levels in the patients’ plasma employing fMRI.

5.2 Addiction

Zehra et al. [93] reviewed the acute and long-term addiction effects of cannabis users. Cannabis use disorder (CUD) appears to correlate with the general patterns of changes described in the Koob and Volkow [94] addiction model. Previous pre-clinical and clinical studies seem to indicate that features of the three stages of drug addiction described by Koob and Volkow [94] are also prevalent in cannabis addiction. The model describes most drugs of abuse result in the hyperactivation of the mesocorticolimbic pathway in the binge-intoxication stage of addiction. This hyperactivation seems to be present in cannabis addiction but to a lower extent [93].

The stimulant-induced dopamine reactivity has been associated with negative emotionality, an important characteristic of withdrawal/negative affect stage explained by Koob and Volkow [94]. With the addition of withdrawal as a symptom of CUD, it is perceived that cannabis addiction development parallels addiction to other drugs of abuse. Additionally, Spechler et al. [95] found that chronic cannabis consumption has been associated with affect dysregulation that may involve changes in amygdala functioning. Cuttler et al. [96] reported that cannabis seems to disrupt hypothalamic–pituitary–adrenal (HPA) axis function as with other drugs of abuse, another key neuroadaptation of the withdrawal/negative affect stage.

Norberg et al. [97] reported that chronic cannabis consumption is also associated with the presence of cannabis cue-induced craving after abstinence, a feature of the preoccupation/anticipation stage of the Koob and Volkow framework [94]. They hypothesize that the presence of cannabis cue-induced craving seems to be related to the loss of executive control over excessive salience for cannabis. They additionally found that chronic cannabis consumption has been related to impaired memory and IQ , resulting in changes in executive functioning after chronic cannabis use.

It is imperative to investigate if there are other features of the addiction framework proposed by Koob and Volkow [94] in cannabis addiction through longitudinal studies to address behavioral and mood changes (such as changes in IQ or the presence of a mood disorder). This study should also include the synthesized cannabis due to its high potency. The relationship of addiction with the effect of THC use on neurons and microglia should also be instigated. Melis et al. [98] research result indicates that chronic THC exposure in animals seems to activate microglia and produce neuroinflammation that may underlie some of the cognitive deficits associated with CUD. Kolb et al. [99] studied changes in neuron and glia morphology after chronic cannabis exposure and concluded that it may contribute to the persistent cognitive and behavioral deficits related to CUD. Future research should investigate whether chronic THC exposure in animals and humans is related to changes in various cell types in the brain that contribute to cannabis addiction through neuroinflammation.

Combined consumption of cannabis and alcohol has increased in recent years, and it is well established that individuals who use both alcohol and cannabis are at increased risk for substance-related harms relative to individuals who use only one substance [100]. The studies provide evidence that combined consumption of alcohol and cannabis is associated with unique characteristics and psychological processes relative to single-substance use. Research in this area must continue considering recent trend toward increasingly liberal cannabis policies in the U.S. and other countries.

5.3 Psychosis

There has recently been widespread interest in the relationship between cannabis consumption and psychosis, with over 100 publications addressing this topic each year since 2012, compared to fewer than 10 per year during the 1990s [22]. This intense interest is likely due to increasing approval within the USA of medicinal marijuana laws. Cannabis consumption has seen a large increase in its licit production, growing from 1.4 tons in 2000 to 211 tons by 2016, due to the increasing implementation of medicinal programs with cannabis-related medicinal products for a wide range of neuropsychiatric conditions.

Yücel et al. [23] studied whether long-term heavy cannabis use is associated with gross anatomical abnormalities in 2 cannabinoid receptor–rich regions of the brain, the hippocampus, and the amygdala. They carefully selected 15 long-term (>10 years) and heavy (>5 joints daily) cannabis-using men (mean age, 39.8 years; mean duration of regular use, 19.7 years) with no history of polydrug abuse or neurologic/mental disorder and 16 matched non using control subjects (mean age, 36.4 years). The results indicated that cannabis users had bilaterally reduced hippocampal and amygdala volumes, with a relatively and significantly greater magnitude of reduction in the former (12.0% vs. 7.1%). Left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous 10 years and reduced positive psychotic symptoms. Positive symptom scores were also associated with cumulative exposure to cannabis. Although cannabis users performed significantly worse than controls on verbal learning, this did not correlate with regional brain volumes in either group. These results provide new evidence of exposure-related structural abnormalities in the hippocampus and amygdala in long-term heavy cannabis users with similar findings in the animal literature. The findings indicated that heavy daily cannabis consumption for long periods exerts harmful effects on brain tissue and mental health.

Hurd et al. [24] reviewed several investigations and concluded that strong evidence exists that prenatal, perinatal, and adolescent cannabis exposure can cause a series of brain and behavioral changes in adulthood. This happens through interfering with multiple neurobiological systems in brain regions involved in psychotic/affective disorders. Adolescent cannabis consumption is associated with an increased risk for psychosis later in life [101]. Whether such risk truly results in psychiatric, and substance use disorders will depend on various factors, such as genetics, age, frequency of use, concurrent use of other substances and sex, that will be better understood as research continues to expand. They recommended that policy makers need to apply the existing data to educate the public about the potential health risk and the long-term effects on adult mental health.

THC or other cannabinoid agonists all suffer from the problem of a narrow therapeutic window between the desired clinical benefits and the unwanted psychic side-effects. It is possible that the pharmacological manipulation of the endocannabinoid system by drugs that inhibited the inactivation of the endocannabinoids, may offer a safer and more subtle approach to cannabis-based medicines in the future [102].

Empirical evidence suggests that cannabis consumption is associated with both CUD and comorbid psychiatric illness, which is not perceived to be the case by the US general population. On the other hand, there is mixed evidence regarding the role of cannabis in the prognosis of a co-occurring disorder across all categories of psychiatric disorders [103]. It can be concluded that longitudinal effort needs to be performed to expand on the existing body of literature to better understand the acute and long-term effects of cannabis on comorbid psychiatric illness.

6. Unknowns associated with cannabis consumption/synthetic illicit drugs

It is imperative that cannabis legalization which will likely increase cannabis use, does not cause significant adverse effect like tobacco smoking. This topic was discussed in previous authors’ publication [10]. It is recommended that research be conducted on the long- and short-term health effects of exposure to second-hand marijuana smoking to confirm possible adverse effect on brain and mental health. The large market of cannabis has given rise to numerous potentially hazardous natural contaminants being reported in crude cannabis and preparations. This topic also was discussed in previous authors’ publication [10]. These drugs have detrimental effects on the brain and primarily affect the central nervous system. Understanding the mechanism of brain alteration due to synthetic drug abuse can help with early detection, diagnosis, and prognosis of brain tissue damage in the clinical setting. Furthermore, these drugs sometimes have severe, life-threatening adverse effects on the human body. A few structural MRI studies have been conducted in synthetic drug abusers to reveal the effects of these drugs on the brain [104] to offer treatment options for various class of synthetic drugs.

7. Conclusions and recommendations

Legalization of cannabis in the US and other counties in conjunction with increase in various methods of consumption makes it vital to understand the associated health consequences. There are indications to suggest that many compounds found in cannabis have potential therapeutic benefit, either alone or in combination with other cannabinoid or terpene compounds [105].

Further pre-clinical and clinical studies are needed to examine the pros and cons of CBD and other cannabinoids in ASD, ADHD, and pediatric epilepsy before they are established as treatment. Further research is needed to better understand the acute and long-term effects of cannabis on comorbid psychiatric illness. Further application of fMRI is recommended to understand the adolescent brain reorganization after prolonged usage and whether these changes reverses during adulthood after abstinence. Future studies should investigate whether chronic THC exposure is linked to changes in various cell types in the brain that contribute to cannabis addiction. Cannabis addiction findings indicate that neurobiological changes in CUD seem to parallel those in other addictions. Further research is necessary in view of recent increase in cannabis consumption. Increasing number of new research concluded that significant evidence exists that prenatal, perinatal, and adolescent cannabis exposure can induce a wide array of brain and behavioral alterations in adulthood. New research is warranted to better understand the risk involved as function of various parameters such as genetics and sex. Research that identifies any potential effects of cannabis secondhand smoking (CSHS) on potential changes in cognitive function is important if consumption in public access areas is being considered.

Present research studies on how cannabis exposure can impact brain and mental health are beginning to inform public policy decision makers, including acceptable age of consumption, dose limits and directions for use. Nonetheless, additional investigation is required to fully understand the impact of cannabis on the cognition, especially for CBD where there may be various confounding biological variables unique to individual medical conditions. The impact of cannabis on the still-developing adolescent brain deserves special attention. While recreational use among adolescents and early onset users is relatively well studied, some areas remain understudied and need data to inform changing public policy. For example, additional effort is required to fully understand the impact of moderate cannabis consumption, short- and long-term consequences of using high-potency cannabis and new delivery methods, effects of cannabis consumption in older adults, and the efficacy and safety of existing and future products. Field-wide difficulties in quantification, methods of measuring cognitive constructs, and the influence of subacute effects seriously hamper the road ahead and require attention now. Multidisciplinary collaboration and investment in studies that solve these problems should be prioritized.

Although existing data suggest that there are findings regarding the chronic and acute effects of cannabis on brain activity, but refinements may help answer questions regarding potential differences between those persons who become dependent on cannabis versus those who use cannabis recreationally, potential residual effects of chronic use, consequences of earlier age of exposure to cannabis, acute and chronic effects on task performance, and possible neurobiological similarities between comorbid psychiatric disorders and cannabis consumption. Future effort using specific diagnostic criteria, and combining neurocognitive testing to functional imaging, may help address questions including the basis of any residual cognitive deficits from cannabis consumption and any potential factors differentiating cannabis-dependent subjects from cannabis users.

The mechanisms that underlie associations between cannabis consumption with psychiatric illness and cognitive impairment are still not well understood, although epidemiological and clinical studies have consistently established this relationship. It is well established that exposure during adolescence is a period of high risk, resulting in more severe and persistent adverse effects than exposure during adulthood. It is plausible that prolonged consumption during adolescence results in a disruption in the normative neuro-maturational processes. Eventually, this could result in long lasting changes to brain structure and function that underlie many of the adverse cognitive and emotional outcomes associated with heavy consumption. Spreading awareness regarding the potential risk of cognitive disturbance in adolescent cannabis users and screening them at an earlier age for potential risk factors of future cognitive damages should be encouraged among healthcare providers. Clearly, further investigation is needed to study the cognitive effects of synthetic cannabinoids to inform the public policy to curb the spread of synthetic cannabinoids and to keep the risk/benefit ratio of the medicinal consumption of cannabis as low as possible. Furthermore, the role of medicinal cannabis including benefits and potential risks with regards to brain management need to be studied in randomized experiments.

The emerging research on cannabis and alcohol co-use and associated outcomes has the potential to inform intervention efforts. As research on the combined use of cannabis and alcohol continues to evolve, next step would be to develop a program that target co-use as a specific high-risk behavior. We hope that new studies will help further understanding of the increasing role of cannabis in neuropsychiatric health and disease. We also hope to soon witness advances in the field of cannabis-related pharmacological treatments.

Finally, it is important to distinguish between scientifically studied and FDA approved cannabis benefits as opposed to potential benefits for indications not rigorously studied, e.g., attention deficit hyperactivity disorder. Conversely, there are situations where rigorous controlled clinical studies have been successfully completed to establish the scientific credibility of cannabis for certain indications but has not yet completed regulatory approval. It is essential that both scientific rigor and regulatory approval support a specific therapy for cannabis.

Conflict of interest

The authors have no financial conflicts of interest to declare.

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Consent for publication: The authors have given their consent for publication.

Funding: The work is funded by 3DTholdings, LLC.