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Article

Relationship between the Polymorphism of the AKT1 Gene and the Consumption of Cannabis in the Appearance of Psychosis

by
Mónica López-Martín
1,
Álvaro Astasio-Picado
2,*,
Jesús Jurado-Palomo
2 and
María del Carmen Zabala-Baños
2
1
Toledo University Hospital, 45007 Toledo, Spain
2
Physiotherapy, Nursing and Physiology Department, Faculty of Health Sciences, University of Castilla-La Mancha, 45600 Toledo, Spain
*
Author to whom correspondence should be addressed.
Appl. Sci. 2022, 12(20), 10464; https://doi.org/10.3390/app122010464
Submission received: 30 August 2022 / Revised: 6 October 2022 / Accepted: 13 October 2022 / Published: 17 October 2022
(This article belongs to the Section Computing and Artificial Intelligence)
Review Reports Versions Notes

Abstract

:
Introduction: Psychotic disorders are a mental illness that affect 3% of the world’s population. The external (cannabis) and internal vulnerability factors (polymorphisms of the AKT1 gene, the COMT gene and the DAT1 gene) acquire special relevance in the appearance of psychosis; this is known as the vulnerability–stress model. Objective: To analyze the scientific evidence that reflects the relationship between the polymorphism of the AKT1 gene and the consumption of cannabis in the appearance of psychosis. Material and Methods: The bibliographic search was made using databases such as Scopus, WoS, Cochrane Library, TRIP Database, PubPsych and PubMed. The criteria of the “MeSH” terminology and the inclusion and exclusion criteria were followed, obtaining a total of 22 articles that comprises this narrative review. Results: The presence of genetic variation in the locus rs2494732 of the AKT1 gene in a cannabis user raises the risk of the appearance of psychosis, especially if homozygous with the C allele. Likewise, consumption entails a slowdown in the functionality of the AKT1 gene, releasing a greater amount of dopamine in the striatum through the involvement of indirect mechanisms. Similarly, the COMT gene and the interaction of the AKT1 gene with the DAT1 gene raise the risk of developing psychotic disorder. Conclusion: The genetic polymorphism rs2494732 of AKT1 is the main factor responsible for the appearance of psychosis, although polymorphisms of the COMT and DAT1 gene are also implicated. Regarding the AKT1 gene, subjects with two copies of the C allele have a higher risk of developing psychosis compared to subjects with two copies of the T allele. It should also be noted that the muscarinic receptors rs115455482 and rx74722579 are related to a greater vulnerability to psychosis and the development of psychotic disorders.

1. Introduction

The World Health Organization (WHO) defines health as “a state of complete physical, mental and social well-being, and not merely the absence of disease or infirmity” [1]. In 1987, the United States National Institute of Mental Health (NIHM) defined serious mental illness as “a mental, behavioral, or emotional disorder that results in serious functional impairment that substantially interferes with or limits one or more major life activities” [2].
Mental health problems can debut at any evolutionary stage of life, both in childhood and in adolescence and adulthood, being a chronic disease [3,4]. In Spain, in 2018, it was estimated that 21% of the population had some type of mental illness, with a prevalence in people aged between 45–55 years, reaching a percentage of 21% with respect to the total [5].
Regarding the classification of these diseases, there are currently two international systems: the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). belonging to the WHO, which allows classifying diagnoses and other health problems based on morbidity and mortality statistics in different countries or demographic areas and at different times, and the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), belonging to the American Psychiatric Association (APA), which offers a diagnostic classification of various mental disorders to facilitate diagnosis and treatment for professionals [6]. The APA organizes severe mental illness (SMI) into 18 disorder groups, one of them being the spectrum of schizophrenia and other psychotic disorders [6].
Psychotic disorders comprise several mental illnesses whose characteristics are listed in Table 1 [3,5]:
Psychosis can be functional and organic; despite the fact that in both there is a loss of contact with reality, they differ in that in the first category there is no objectifiable organic cause, while in the second there is [7].
From the first manifestations that make up the first episode of psychosis (PEP), it is possible to act early [8]. Some factors that confer greater vulnerability favoring its appearance are shown in Table 2:
As psychosis has a multifactorial etiology, it requires an interaction between various causal factors to precipitate its appearance, which is known as the vulnerability–stress model [8,9,10]. This model indicates that there are people who are more vulnerable to acquire certain conditions, due to the presence of internal causal factors such as genetic predisposition or damage to brain structures, which, when interacting with external causal factors such as social changes, responses to stressful situations or drug abuse, cause it to manifest the said condition [9]. Genetic–environmental interaction can occur passively (genetic factors and the person’s development environment), evocatively (the person’s actions in social situations will evoke the response of others) and actively (behaviors and personal attitudes will interfere in a greater or lesser exposure to external causal factors) [10].
Cannabis use and smoking contribute to the onset of schizophrenia in 8.6% of cases. Similarly, prenatal maternal infections with toxoplasma gondii, herpes simplex virus, cytomegalovirus and rubella increase the risk of developing schizophrenia. This is because fetal neurodevelopment is interrupted as a consequence of the infection, as well as maternal immune activation [11,12].
The existing genetic risk factor for acquiring certain mental illnesses is due to the presence of polymorphisms in genes, that is, “the simultaneous existence in a population of genomes with different alleles for a given locus” [10]. There are various genetic alterations that could be involved in the pathogenesis of psychosis, as occurs with the AKT kinase in the first of the three serine/threonine-protein kinases (AKT1), the polymorphism of the catechol-O-methyltransferase (COMT) enzyme and alterations in the gene that encodes for the dopamine transporter (DAT1) [10,13,14].
The AKT1 gene is located on chromosome 14 at position 32.33 [13]. It is a gene responsible for encoding the protein kinase AKT1, which is found performing various functions such as participation in important cellular processes including cell division, apoptosis, the size and metabolism of glucose and cell survival [13]. The correct functionality of the AKT1 kinase is vital since it acquires an important role in the intercellular communication of neurons, their survival and the formation of memories, while it is also essential for the correct development of the nervous system [10,13]. This gene belongs to a class of genes known as oncogenes, which when mutated have the potential to cause normal cells to become cancerous [10,13,15].
The name AKT stands for AK strain transformation. Its origin dates back to 1928 when experimental studies in mice showed that they developed spontaneous thymic lymphomas. Strains A, R, S and T were studied, and it was concluded that strain A caused many cancers and strain T represented transformation. The oncogene in transforming retroviruses from these mice is designated AKT8. Subsequently, analyzing the clones of the dividing transforming cells called v-akt, AKT1 and AKT2 were identified in humans. In addition, in 2011, an AKT1 mutation was associated with Proteus syndrome, the disease that affected the Elephant Man [15].
Tetrahydrocannabinol (THC), also known as delta-9-tetrahydrocannabinol (Δ9-THC), is a psychoactive component of cannabis that activates AKT1 and alters a person’s perception and mood. It has various therapeutic properties such as analgesic, anti-inflammatory, neuroprotective, antioxidant, muscle relaxant, antiemetic, antitumor, orexigenic and reduces appetite for drug use. Likewise, it can produce common adverse effects such as tiredness, drowsiness, headache, dizziness, imbalance and dry mouth [14]. In addition, it is part of the herbal cannabinoids or phytocannabinoids, although there are also synthetic and endogenous cannabinoids [10,14]. The action of cannabinoids is performed thanks to the endocannabinoid system, which allows the union of cannabinoids with cannabinoid B-1 (CB1) and cannabinoid B-2 (CB2) receptors located in the brain, nervous system, tissues and organs [14].
It is important to consider cannabis use in relation to the AKT1 gene, since it is the most widespread illegal drug in the world [14]. In Europe, approximately one in five people are cannabis users, starting at an age of approximately 18 years [16]. The consumer profile is usually a man between 15 and 34 years old who consumes an average of 2.5 joints per day [14]. Cannabis consumption can occur through inhalation and can be smoked alone or mixed with tobacco, taken orally or ingested by cakes and candies, percutaneously through patches and creams, sublingually through sprays and tinctures, and rectally via the use of suppositories [16]. In order to reduce its consumption among the population, it is essential to keep in mind the influencing factors, including a lack of good communication and intra-family relationships, consumer friendships, availability of drugs, history of consumption or criminal behavior by two or more family members and age, all of which increase the risk of consumption [16]. The effects of consumption begin 10 min later when the route of administration is inhalation or smoking, while if it is ingested, the effects appear between 20 and 60 min after the intake. These effects can be psychic, producing euphoria in the person including laughter, losing track of time and appearing flight of ideas, memory alterations, sharpening of the senses (sight and hearing), depersonalization and, if the consumption is very high, panic states, hallucinations and psychosis [17].
Based on this information, it can be stated that cannabis use is very common among the world’s population, and its action on a healthy psychopathological structure is not the same as on a vulnerable or sick one [10,14]. The presence of a genetic alteration (polymorphism of the AKT1 gene) can lead to a higher risk of developing adverse effects in the mental sphere, compared to healthy people who do not present genetic alterations [10]. Therefore, a review of the literature is necessary to shed light on the possible causal link between both factors.
The objective of this study is to analyze the scientific evidence that reflects the relationship between the AKT1 gene polymorphism and cannabis use in the onset of psychosis.
To meet this objective, a study design based on a narrative review has been undertaken.

2. Methodology

In this narrative review work, it is proposed as a starting point to research if there is a relationship between the polymorphism of the AKT1 gene and the consumption of cannabis in the appearance of psychosis.
The bibliographic search to undertake this review was performed from November 2021 to March 2022 in different databases and scientific journals. The last search was completed on 21 March 2022.

2.1. Keywords

To perform this search, following the criteria of the “MeSH” terminology, the following keywords were used: “psychosis”, “psychotic disordered”, “schizophrenia”, “severely mental disorder”, “AKT1”, “cannabis”, “THC”, “cannabinoid” and “marijuana”. These words were appended, returning the following definitive search string: (psychosis or “psychotic disorder*” or schizophrenia or “sever* mental disorder”) AND AKT1 AND (cannabinoid or cannabis or THC or marijuana).
Based on this search string, the Boolean operators AND and OR were used to append the keywords. On the one hand, the Boolean AND operator was used to join the various parts that make up the search string. On the other hand, the Boolean operator OR was used to link the keywords that have an equivalent meaning.
Similarly, asterisks, quotation marks and parentheses were used. Firstly, the use of asterisks as truncations made it possible to cover a greater number of words related to psychotic disorders and serious mental illnesses in the search. Secondly, the use of quotation marks made it possible to join two or three words so that when performing the search, results were obtained that had both words associated. Thirdly, the use of parentheses made it possible to collect words that have similar meanings.

2.2. Criteria for Inclusion and Exclusion of Articles

The inclusion and exclusion criteria are shown in Table 3:

2.3. Databases Consulted

The search for articles was performed with various databases, obtaining the results that are shown in Table 4:
The main databases were consulted, including Scopus, WoS, Cochrane Library, TRIP Database, PubPsych and PubMed.
Likewise, clinical practice guidelines and databases were consulted that, after being explored with the same search string, did not yield results; these include CMA Infobase, Guía Salud, CUIDEN, ISOC, CINAHL, EMBASE, Sociedad Española de Psiquiatría, PsicINFO, PsyeBITE, Psicodoc, Dialnet, National Guideline Clearinghouse and Virtual Health Library Spain.
Finally, a total of 45 articles make up this work.
The critical reading sheet of the selected articles comprising this review is attached in Appendix A (Table A1).

3. Results

The main objective of this work is to gather scientific evidence about the “Relationship between the polymorphism of the AKT gene and the consumption of cannabis in the appearance of psychosis”. The scientific evidence reveals that in the appearance of pathologies such as psychosis, cannabis is a trigger factor [14], but the existence of genetic vulnerability is decisive. Thus, several genotypes, involved in dopaminergic function such as the AKT kinase in the first of the three serine/threonine-protein kinases (AKT1), are especially involved in making possible the onset of mental illness, considering genetic counseling as a source that can help reduce exposure to cannabis among genetically sensitive people [17,18,19,20].
Likewise, in carrying out this work, the findings also lead to taking into account other genetic variations such as the polymorphism of the enzyme catechol-O-methyltransferase (COMT) and alterations in the gene that codes for the dopamine transporter (DAT1) that could contribute to an increased risk of developing psychosis after interaction with cannabis. Therefore, in this section of the results, we present data succinctly regarding whether or not they confer said vulnerability, constituting a very interesting aspect to investigate, since Chandni Hindocha (2020) found that AKT1, COMT or FAAH did not modulate the specific psychotomimetic response to cannabis, contrary to previous research [13,14,19,21,22].

3.1. Locus and Genotype of the AKT1 Gene and Psychosis

The presence of specific molecular genetic variants may, together with environmental risk factors such as cannabis use, contribute to the onset of mental illnesses such as psychosis (schizophrenia), depression and anxiety to a greater extent. There are other conditions such as the age of onset of consumption and the amount consumed that influence the risk of developing a psychotic disorder [10,14,22].
Various studies identify the rs1130233 locus of the AKT1 gene as a modulator of sensitivity to the psychotomimetic effects of cannabis, increasing in people carrying the AKT1 rs1130233 G/G genotype, and producing greater striatal activation affecting cognition after consumption [16,17,18,19]. Likewise, there is a single nucleotide polymorphism (SNP) in the AKT1 gene (rs2494732), which, by interacting with cannabis, moderates the risk of psychosis and short-term psychotomimetic effects, thus simulating prodromes, namely, symptoms before the onset of the disease [20,21,22,23,24,25,26,27].
Regarding the risk of onset of psychotic disorder, studies show the presence of the genetic polymorphism of AKT1 rs2494732: homozygotes T/T, heterozygotes C/T and homozygotes C/C [23,28]. Subjects carrying both alleles without “risk”, that is, T/T homozygotes of the rs2494732 polymorphism of the AKT1 gene, despite consuming marijuana daily or on weekends, do not increase the probability of onset of psychosis [10,29,30,31]. Likewise, subjects carrying one of the “risk” alleles, that is, C/T heterozygotes of the rs2494732 polymorphism of the AKT1 gene, do not present an increased risk of acquiring the psychotic disorder after consumption [18,32]. In contrast, based on results obtained, subjects carrying both “risk” alleles”, that is, homozygotes C/C of the genetic polymorphism rs2494732 in AKT1, have more than twice the risk of developing psychosis if they are daily users of cannabis as opposed to consumers on weekends, in which the risk is not high [19,31,32,33].
Similarly, the data show that subjects with two copies of the C allele have a seven-fold increased risk of psychosis compared to subjects with two copies of the T allele, despite considering all subjects’ daily cannabis use [27,34]. In addition, research reveals that selective alterations that lead to sustained attention deficit occur in homozygotes C/C. This increased susceptibility also appears with the muscarinic receptor represented by rs115455482 and rs74722579, which until relatively recently were not identified [20,33,34,35,36].
Because cannabis use is a modifiable risk factor, it has been identified that in young people aged between 12 and 21 years old with the rs2494732 polymorphism, and who also have a high family risk of psychotic disorders, genetic counseling is especially useful to enhance the improvement of these individuals’ mental health [33,37,38].

3.2. Pathophysiology of Psychosis

The pathophysiology of psychosis remains an enigma, so studies have described a biologically plausible mechanism that makes it possible to detect the increased risk of people developing a psychotic disorder when exposed to cannabis, due to the presence of THC, which is responsible for psychotomimetic effects [21,30].
As has been described, the AKT1 gene inactivates the enzyme glycogen synthase kinase 3 (GSK-3) by phosphorylation, which acts as a serine/threonine kinase that participates in signaling downstream of the dopamine D2 receptor (DRD2) [18]. In this way, cannabinoids activate the AKT1/GSK3 pathway by acting on CB-1 and CB-2 receptors thanks to the endocannabinoid system [18,39,40]. Likewise, CB-1 receptors are coupled to G proteins and are abundantly distributed in the limbic system (hippocampus and amygdala), cerebellum, prefrontal cortex (PFC) and basal ganglia, thus mediating the release of glutamate and gamma-aminobutyric acid (GABA) in the PFC, while in the cortical area, there is a subtype of GABAergic interneurons and CB-2 receptors, the latter being similar to CB-1 receptors, despite the fact that they are present in smaller quantities in the central nervous system (CNS) [27,31,36,39].
Regarding THC, the data reveal that it induces a decrease in the functionality of the AKT1 gene, producing an alteration in the inhibitory and excitatory balance that reaches the dopaminergic cells, which causes a greater response to the stimulation of DRD2 and a greater release of dopamine in the striatum, compared to that released in response to natural stimuli [40]. Therefore, studies indicate that dopamine release may be affected by the biological vulnerability of the psychotic disorder, showing that cannabis use leads to a decrease in the synthesis of dopamine. In healthy people, an increase in dopamine is found in those who had first-degree relatives with a psychotic disorder [28,31,41]. In the same way, the findings show that this greater release in the striatum can produce alterations in cognitive functions such as attention and working memory [42].
Similarly, studies show that CB-1 and DRD2 receptors are jointly expressed in several brain regions and are involved in signal transduction [31]. In addition, they show that CB-1 receptors are absent in dopamine neurons, but they are expressed in glutamate and GABAergic neurons that are associated with dopaminergic neurons [31]. This leads to the results showing that dopaminergic neurotransmission by cannabinoid agonists is achieved involving indirect mechanisms through GABAergic signaling and glutamatergic [31,34,43].
The mechanisms of action that indirectly increase dopamine levels in the striatum are shown below [34].

3.2.1. Interactions between Cannabinoids and GABA

Regarding these interactions, studies confirm that CB1 receptors are present in the axon terminals of cholecystokinin (CCK) cells that present GABAergic interneurons, directed at pyramidal cells (PC) [31,41]. Activation of CB1 receptors in GABAergic neurons exert an inhibitory effect on the activation of dopamine neurons which project towards the nucleus accumbens, so the agonism of CB1 receptors due to THC facilitates a lower reuptake of dopamine, meaning that there is an overabundance of it with a longer lifespan [27,28]. When the activation of CB1 receptors occurs, a prior deficit of GABA can be found, as well as that of ionotropic N-methyl-D-aspartate receptors (NMDA), also known as “slow”, as occurs in schizophrenia [34,44].

3.2.2. Interactions between Cannabinoids and Glutamate

Regarding the relationship between cannabinoids and glutamate, glutamate is an excitatory neurotransmitter in the CNS. It is synthesized by glutamatergic neurons and inhibited by presynaptic activation of CB1 receptors, which, according to research, also inhibits postsynaptic currents that are available to the NMDA receptor, located in GABAergic interneurons, and the entry of Ca2+ [29]. CB1 receptors, by inducing endocytosis of NMDA receptors, reduce the activation of pyramidal cells, thus producing a failure in the activity of dopaminergic neurons contributing to THC-induced psychotic symptoms [31,32].
Various studies have shown that there are other genetic alterations that can confer vulnerability to the onset of psychosis, in addition to the polymorphism of the AKT1 gene. The following section reviews which genes are involved and their model of action.

3.3. Other Genetic Alterations and Psychosis

Genetic alterations confer vulnerability to the appearance of psychotic symptoms after exposure to cannabis by producing gene–environment interaction (GxE) [15]. Apart from genetic variation in AKT1, COMT and DAT1 gene polymorphisms could contribute to the increased risk of development of psychosis after interaction with cannabis, so the following sections analyze whether the COMT and DAT1 genes confer said vulnerability [21].

3.3.1. COMT Gene

The COMT gene is located on chromosome 22 in the q11.2 region and encodes the enzyme that degrades dopamine in the PFC [26]. The COMT rs4680 genetic polymorphism involves replacing guanine with adenine, which leads to valine (Val) being replaced by methionine (Met) at position 158 associated with the membrane, or at position 108 of the soluble form of gene [31,33,39,40].
The interaction established between the COMT Val 158 Met genotypes with the use of cannabis leads to an increase in the production of psychotic symptoms. This is because the Val enzymes increase the degradation activity, that is, they are associated with sensitivity to cannabis, while Met enzymes decrease activity, that is, they are associated with protection as they are less efficient [28,34,39]. Thus, people who are homozygous for the Val allele have lower levels of dopamine in the PFC, increasing the risk of psychosis tenfold and presenting poorer cognitive performance [31]. In contrast, people homozygous for the Met allele have higher dopamine levels and people heterozygous for the Val/Met allele have intermediate levels of dopamine in the PFC [30,33,40,45].
Therefore, the COMT gene polymorphism interferes not only with cognitive performance, but also with structural brain abnormalities when cannabis is consumed [29]. In addition, the association with a history of childhood abuse increases the chances of positive psychotic symptoms appearing along with negative, especially in those with Val alleles [31,45].

3.3.2. DAT1 Gene

The research indicates that the DAT1 gene is responsible for eliminating dopamine from central synapses, so the polymorphism causes a lower activity of the dopamine transporter and, therefore, higher levels of dopamine in the striatum [32,41,42]. This gene presents 40 base pairs (bp) of tandem repeats (VNTR) in the 3′ untranslated region (UTR), with alleles presenting from 3 to 11 copies of the 40 bp repeats, with the most common repeats being 9 (frequency of 71.9%) and 10 (frequency of 23.4%) [31,32,44]. In this way, the data reveal that individuals who carry the allele of 9 VNTR 3′ UTR in the DAT1 gene present an increase in psychotic symptoms and, therefore, higher levels of synaptic dopamine than the 10-repeat allele [34,40].
Subjects homozygous for the G allele of AKT1 and carriers of the 9 VNTR 3′ UTR allele in the DAT1 gene have a higher risk of developing psychotic disorder after consuming cannabis, compared to those who only present one of the two variants [25,40,45].

4. Discussion

Research performed in recent years has allowed a better understanding of the etiology of psychosis, which is based on the vulnerability–stress model [10]. This model postulates a combination of molecular genetic variants together with environmental factors such as etiological factors of psychosis [14,23].
Regarding the risk of acquiring the psychotic disorder, the authors all agree that cannabis is a trigger factor in the onset of psychosis [12]. Therefore, they argue that without the genetic variations of genes such as AKT1, COMT and DAT1, the debut of mental illness would be possible [18].
On the other hand, all studies agree that the AKT1 gene has various loci involved in the development of psychosis, such as rs11300233 and rs2494732 [18].
Likewise, the authors disagree about the alterations in the rs2494732 polymorphism of the AKT1 gene and its relationship with the appearance of the mental disorder [26,27]. Based on this, the authors all affirm that in the presence of the rs2494732 locus, being homozygous T/T does not increase the risk of acquiring the disorder, while being homozygous C/C does increase the risk [10,21,24,28,29,30,31,32]. In addition, all the investigations converge that carriers of one C and one T allele do not increase the probability of debut of the disease. This is unlike others who say yes, although not exponentially such as those with the two C alleles, which shows that this allele is the main one involved in the appearance of the mental disorder in terms of the gene that AKT1 refers. This finding is very revealing since it can shed light on treatments aimed at the intervention of this pathology, which currently does not have a curative treatment [25,27,29,30,31,32].
Likewise, it is worth asking what is the minimum dose of cannabis necessary for schizophrenia to develop, since studies show that this disease can appear in very low percentages [34]. For this reason, it is important to make the population aware that low doses can cause the disease and intervening in the early stages of psychosis is essential to be able to stop the disease’s progression. In addition, the nurse’s work in this area is vital, carrying out primary prevention.
A strongly emphasized fact in all the studies, and in which the various authors converge, is to focus on the biological plausibility of psychosis due to cannabis use in the presence of genetic variations [29,31]. For this reason, the investigations coincide in the idea that the greater amount of dopamine released in the striatum is responsible for the appearance of mental illness [33]. Despite this, the direct mechanisms that cause the onset of the said illness are not shown exactly, with all the authors suggesting that the indirect mechanisms of GABAergic and glutamatergic signaling play a fundamental role [30,33].
In another aspect, it is difficult to know exactly the action of the COMT gene with respect to the development of psychotic disorder [31]. Because of this, the authors begin to postulate that the COMT gene, in the presence of the amino acid Val in a specific position, increases the risk of acquiring the psychotic disorder, although others also suggest that the substitution for methionine contributes to its reduction, which reveals the importance that the presence of the amino acid Val has for the appearance of psychotic symptoms [27,29,30,32,33,34]. Likewise, traumatic experiences such as child abuse contribute to the development of mental pathology, increasing the risk of the onset of psychotic disorder. This condition converges with consumption [21,33].
Likewise, the exponential increase in the probability of acquiring the psychotic disorder is conditioned by the interaction of the G allele of AKT1 and being carried by allele 9 of tandem repeats in the 3′ untranslated region, due to the greater amount of free dopamine in the striatum [23,30,42,43,44,45].
Finally, it is shown that the AKT1 gene influences acute psychotic responses derived from cannabis use regardless of the size of the population sample. Unlike the COMT gene, which fails to replicate these findings unless the sample size is reduced, thus seeing that the ATK1 gene plays a fundamental role in the development of psychosis symptoms. Based on this, it is essential to undertake more in-depth studies since gene–environment associations have less statistical power than gene–disorder associations [42,45].
This work is not without its limitations. Most existing studies are cross-sectional and do not allow follow-up over time. For this reason, it is necessary to carry out longitudinal studies that allow corroborating long-term results and their maintenance over time.

5. Conclusions

Based on the results obtained after the review, we can conclude that the genetic polymorphism rs2494732 of the AKT1 gene is, to date, the most promising genetic variation for the appearance of the psychotic disorder, with the subjects carrying both risk alleles having more than double the risk of developing psychosis if they are daily cannabis users as opposed to weekend users, when the risk is not high. In the same way, the data show that subjects with two copies of the C allele have seven times more risk of psychosis, unlike subjects with two copies of the T allele, despite all being considered daily cannabis users. Furthermore, research reveals that selective alterations leading to sustained attention deficits occur in homozygotes C/C. The muscarinic receptors rs115455482 and rx74722579 are related to a greater vulnerability for the development of psychotic disorders. Knowing specific biomarkers and genetic profiles of psychosis have also been established, which will help identify people at higher risk and establish prevention measures and strategies. Using genetic counseling in patients at high risk due to their personal genotype increases their mental health improvement.

Author Contributions

Conceptualization, M.d.C.Z.-B.; Data curation, M.d.C.Z.-B., Á.A.-P. and M.L.-M.; Formal analysis, Á.A.-P. and M.L.-M.; Methodology, M.d.C.Z.-B. and M.L.-M.; Project administration, M.L.-M.; Resources, J.J.-P.; Software, J.J.-P.; Supervision, M.d.C.Z.-B. and Á.A.-P.; Writing—review and editing, Á.A.-P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Critical Reading Sheet of the Articles

Table
Table A1. Critical reading record of articles.
Table A1. Critical reading record of articles.
TitleType of Study/SampleConclusions
Gene–environment interaction in the etiology of psychosis. [10]NarrativeThe vulnerability of a person suffering from psychosis increases when they are a cannabis user and have the C/C genotype at rs2494732 in AKT1.
The effect of interactions between genetics and cannabis use on neurocognition. A review. [14]NarrativeThe rs1130233 locus of the AKT1 gene increases sensitivity to the symptomatic and neural effects of cannabis compared to the rs2494732 locus, which moderates the risk of psychosis in users. In contrast, the polymorphism of the COMT Val/Met gene does not mediate the psychotic response to the effect of THC, although it interferes with various cognitive functions such as memory and work.
Clarifying the link between cannabis use and risk of psychosis. [23]NarrativeThe onset of psychotic disorder is higher in cannabis users. Gene variations such as AKT1 increase the risk of developing psychosis.
The AKT1 genotype moderates the acute psychotomimetic effects of naturally smoked cannabis in young cannabis smokers. [34]Descriptive/N = 442Psychotic symptoms were increased in cannabis-intoxicated individuals who had the variation in the rs2494732 locus of the AKT1 gene increasing with the dose of the C allele. In addition, these symptoms may be exacerbated because THC increases dopamine, the main neuromediator involved in the positive symptoms of psychosis. Unlike the AKT1 locus he rs2494732, the COMT Val/ Met genotypes do not mediate the acute psychotic response to cannabis from cannabis use.
Laboratory study in humans on cannabinoids and psychosis. [29]NarrativeThe probability of risk of psychotic disorder is greater in cannabis users with genetic polymorphism of AKT1 rs2494732 carriers of the C/C genotype. The presence of the polymorphism in the AKT1 gene and the consumption of THC cause a greater release of dopamine with a greater activation of the CB-1 receptors, inhibiting the release of GABA; constant use of cannabis is associated with reduced levels of glutamate. There is a controversy of opinions regarding the influence on the risk of psychosis in people exposed to cannabis who present the genetic polymorphism of COMT. In addition, the polymorphism of the DAT1 gene leads to an increase in dopamine in the striatum.
Genetic influences on cannabis use disorder and psychosis: dopamine and beyond. [33]NarrativeGenetic polymorphism in AKT1 rs2494732 with the C allele is associated with schizophrenia in cannabis users. In addition, cannabis produces an increased risk of psychotic disorder when the Val allele is present in the COMT gene.
Cannabis and psychosis: How much proof do we require? [42]NarrativeThere is a significant association between cannabis use and psychotic experiences in carriers of variants in the AKT1 gene. In addition, a variation of DRD2 increases the risk of psychosis in cannabis users.
GABA deficiencies increase the psychotomimetic effects of Δ9-THC. [44]Cases and controls/N = 27The variation in the AKT1 gene increases the risk of psychosis in cannabis users since it interacts with the neurophysiological response to THC.
Interaction between genetic variations of DRD2 and AKT1 in the risk of psychosis in cannabis users: a case-control study. [18]Cases and controls/N = 459Cannabis users who are carriers of the AKT1 gene with the rs2494732 locus have a higher probability of psychosis; however, the risk is higher in those with the C/C genotype. High mesolimbic dopamine levels make a person with the AKT1 gene polymorphism more vulnerable to the psychotic effects of THC use.
A review of the association between cannabis and psychosis. [31]NarrativeCannabis users with the C/C allele in AKT1 are at increased risk of psychosis. The interaction of variations in the AKT1 and DAT1 genes produces greater sensitivity to the psychotomimetic effects of THC. There is no interaction between the COMT genetic polymorphism and cannabis use for schizophrenia. There is a greater release of dopamine mediated by CB-1 receptors due to THC in people with a first-degree family history.
Genotype-based prevention of the onset of psychosis and schizophrenia: a personalized approach in a target population. [26]NarrativeThe AKT1 rs2494732 SNP confers greater vulnerability to psychosis in cannabis users. There is an increased risk of psychosis in people with the C/C genotype at AKT1 rs2494732 compared to those with the T/T genotype.
Gene–environment interactions in severe mental illness. [35]NarrativeThe rs2494732 polymorphism of the AKT1 gene together with cannabis use increases the risk of psychosis; carriers of the C/C genotype in rs2494732 are more likely to develop psychotic disorders when smoking cannabis. The COMT gene together with cannabis leads to psychotic symptoms, although the Val allele is associated with cannabis sensitivity while the Met allele is protective.
Different dopaminergic abnormalities underlie cannabis dependence and cannabis-induced psychosis. [41]SystematicVariation in the AKT1 gene makes some people more vulnerable to developing psychosis when using cannabis. In cannabis-induced schizophrenia, low dopamine synthesis occurs with high sensitivity to D2/D3 receptors.
Molecular and environmental genetic gene studies using candidate genes in schizophrenia: a systematic review. [21]NarrativeCannabis users with the rs2495732 genotype who are homozygous C have a higher probability of psychotic disorder compared to homozygotes T. In the AKT1 genotype rs1130233, those who are homozygous G together with the DAT1 gene variation have an increase in psychotic symptoms. The risk of psychotic experiences is also increased by the interaction of the COMT gene and cannabis use.
Cannabinoids, monoamines, COMT and schizophrenia: pathobiological mechanisms in psychosis. [38]NarrativeThe AKT1 gene polymorphism modulates dopaminergic function, influencing the onset of psychosis. The COMT genotype influences cognition, while the DAT1 genotype increases sensitivity to the psychotomimetic effects of cannabis use together with the genetic polymorphism in AKT1 (rs130233).
Cannabis and psychosis: a systematic review of genetic studies. [28]SystematicVariations of the genetic polymorphism in AKT1 are more sensitive to the psychotomimetic effects of THC being mediated by dopamine. In addition, alterations in the neural response to THC occur in dopamine-rich regions of the striatum and brain. The interaction between the DAT1 and AKT1 genotypes together with THC produces greater psychotic effects in people who present AKT1 G homozygotes in rs1130233 and carry the 9 VNTR 3′ UTR allele.
Preliminary report of the biological basis of sensitivity to the effects of cannabis in psychosis: AKT1 and DAT1 genotypes modulate the effects of delta-9-tetrahydroca-nnabinol in midbrain and striatal function. [45]Descriptive/N = 35Variations of the genetic polymorphism in AKT1 are more sensitive to the psychotomimetic effects of THC being mediated by dopamine. In addition, alterations in the neural response to THC occur in dopamine-rich regions of the striatum and brain. The interaction between the DAT1 and AKT1 genotypes together with THC produces greater psychotic effects in people who present AKT1 G homozygotes in rs1130233 and carry the 9 VNTR 3′ UTR allele.
Confirmation that the AKT1 genotype (rs2494732) influences the risk of psychosis in cannabis users. [24]Narrative The variation in the rs2494732 locus of the AKT1 gene, especially in those with the C/C genotype, contributes to the increased risk of mental disorder in cannabis users; the variation in the locus rs1130233 of AKT1 also influences the appearance of psychosis due to cannabis use. Carriers of the DAT1 gene variation and the AKT1 rs130233 gene polymorphism have a greater psychotic response to THC use. The AKT1 gene together with the DRD2 genes are involved in the regulation of dopamine signaling and in psychotic disorders.
Genetic variation underlying cannabis psychosis-induced effects: critical review and future directions. [25]Narrative Cannabis users with the AKT1 rs2494732 gene with the C/C genotype are more likely to develop psychotic disorder compared to those with the T/T genotype. The genetic polymorphism of AKT1 rs1130233 increases the effects of psychotic symptoms when consuming cannabis. These effects increase if it interacts with a specific variation of the DAT1 gene.
Genetic and environmental interactions underlying the effect of cannabis on first-episode psychosis. [30]Narrative The AKT1 RS2495732 genotype together with cannabis use shows that people with the C/C genotype have a higher risk of psychosis, unlike those with the T/T genotype. In contrast, the polymorphism of the COMT Val gene is questioned as a candidate gene for schizophrenia.
AKT1 moderation of cannabis-induced cognitive impairments in psychotic disorder. [27]Cases and controls/N = 1120Cannabis users with the AKT1 rs2494732 C/C genotype are twice as likely to develop a psychotic disorder. A lower functionality of AKT1 due to THC leads to dopaminergic hyperactivity, stimulating DRD2 to a greater extent.
Own elaboration.

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Table
Table 1. Characteristics of psychotic disorders.
Table 1. Characteristics of psychotic disorders.
Distinctive Features of Psychotic Disorders.
  • Prevalence of 3% of the population;
  • Appearance normally between adolescence and 30 years, with debut decrease from age 40;
  • There are no distinctions regarding sex;
  • Alterations occur in perception and the presence of abnormal ideas that lead to a loss of contact with reality.
Adapted [3,5].
Table
Table 2. Vulnerability factors for the appearance of psychosis.
Table 2. Vulnerability factors for the appearance of psychosis.
Psychosis Vulnerability Factors.
  • Genetics;
  • First-degree family history of psychosis;
  • Biology;
  • Environment;
  • Personal experiences;
  • External circumstances such as traumatic accidents, family problems and consumption of toxic substances;
  • Stress.
Adapted from WHO.
Table
Table 3. Criteria for inclusion and exclusion of articles.
Table 3. Criteria for inclusion and exclusion of articles.
Inclusion CriteriaExclusion Criteria
  • ✓ Articles published from 2010 to the present.
  • ✓ Articles published in English or Spanish.
  • × Articles whose subjects had another mental disorder.
  • × Articles whose subjects had another mental disorder plus associated intellectual disability.
Own elaboration.
Table
Table 4. Article selection process.
Table 4. Article selection process.
SCOPUSWOSCOCHRANE LIBRARYTRIP DATABASEPUBPSYCHPUBMEDTOTAL
Without filters33477121824141
Duplicates0211592157
Other languages0000010
Title and abstract1015374039
TOTAL VALID2311405245
Own elaboration.
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López-Martín, M.; Astasio-Picado, Á.; Jurado-Palomo, J.; Zabala-Baños, M.d.C. Relationship between the Polymorphism of the AKT1 Gene and the Consumption of Cannabis in the Appearance of Psychosis. Appl. Sci. 2022, 12, 10464. https://doi.org/10.3390/app122010464

AMA Style

López-Martín M, Astasio-Picado Á, Jurado-Palomo J, Zabala-Baños MdC. Relationship between the Polymorphism of the AKT1 Gene and the Consumption of Cannabis in the Appearance of Psychosis. Applied Sciences. 2022; 12(20):10464. https://doi.org/10.3390/app122010464

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López-Martín, Mónica, Álvaro Astasio-Picado, Jesús Jurado-Palomo, and María del Carmen Zabala-Baños. 2022. "Relationship between the Polymorphism of the AKT1 Gene and the Consumption of Cannabis in the Appearance of Psychosis" Applied Sciences 12, no. 20: 10464. https://doi.org/10.3390/app122010464

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