Drug Use and Schizophrenia

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Cannabis is a popular street drug in the youth population

The relationship between recreational drug and psychosis is one that has been long investigated. Of this, the similarities and correlations between recreational drugs and symptoms resembling Schizophrenia have garnered attention and research. Of the associations studied, the one between Cannabis use and Schizophrenia has accumulated the most amount of research and publications but relatively recent studies have explored the association between the well-known anesthetic drug Ketamine and the presence of schizophrenic like symptoms[1]. While there are inherent differences in the demographic and numbers of the population using Cannabis compared to Ketamine, an important similarity is that both are known to produce symptoms similar to some of the ones characteristic to schizophrenia and both having negative effects on individuals function as well as society in term of productivity, resources, and healthcare/therapy costs. Much of the currently existing research has examined the types of schizotypal symptoms that recreational use of these drugs produces[1], the pathways these drugs target which gives rise to these symptoms, as well as the effects these drugs have in terms of onset and prognosis for these disorders[2].

Cannabis use and schizophrenia

Your Brain on Drugs: Marijuana
A brief intro to marijuana interacting with the brain by AsapSCIENCE

Neural mechanisms behind the risk of psychosis

Psychosis is one of the most definitive symptoms of schizophrenia, and cannabis use has been long associated with producing psychotic effects. Studies have hypothesized that the relationship between cannabis use and psychotic symptoms most likely involves the signature constituent of cannabis tetrahydrocannabinol (THC) as well as other cannabinoids and parts of the cannabinoid and dopaminergic systems[7]. Although not entirely clear,current lines of evidence suggest that the psychotic symptoms most likely arise from pathways involving the neurotransmission of dopamine, glutamate, andGABA [7]. This is an important finding as hyperactivity of the dopaminergic systems has been attributed to the psychotic symptoms characteristic of schizophrenia[4]. Positive schizophrenic like symptoms caused by cannabis includes grandiose thinking, paranoia, hallucinations, delusion of passivity while negative symptoms included social and emotional withdrawal and psychomotor retardation[7]. One of the proposed mechanisms by which Cannabis works at the neural level is that THC has an effect on CB1 receptors which have associations with voltage gated calcium channels as well as potassium channels. One line of evidence that supports this claim is that brain regions involved in the psychotic symptoms, including the cingulate cortex, frontal cortex, and basal ganglia, all have large amounts of these CB1 receptors. The effects of THC on CB1 receptors is also hypothesized to increase dopaminergic firing in the brain which relates to the increased dopamine activity seen in patients with schizophrenia[7]. Patients with schizophrenia have shown decreased GABA activity and findings that THC can decrease GABAergic activity is further evidence for mechanisms of cannabis in producing psychotic symptoms. Related to this, cannabis has also shown to decrease the activity of glutamate which is responsible for normal functioning[7].

Prognosis, and relapse among heavy users

Cannabis use is not only common with normal adolescents and young adults but is also widely used amongst those who have a clinical diagnosis of schizophrenia. This is often due to cannabis being used a way to deal with the symptoms of schizophrenia as well a way of coping with the social, physical, and emotional problems individuals with schizophrenia face. One studying examining this phenomenon in a group of 24 cannabis using patients and 69 patients who did not use cannabis found that the cannabis use group not only had more relapses but relapses that were earlier than the control group[4]. They found that the heavier the cannabis use, the more the symptoms were exacerbated and the earlier the relapse. Of the 24 patients who were using cannabis, 14 reported increases in psychotic symptoms immediately following use[4]. This line of evidence illustrates the fact that cannabis not only increases the risk for psychotic symptoms in non-schizophrenic users but also increases symptoms and earlier relapses in schizophrenic patients, including those in remission.

Risk for youth/adolescent users

One study showed that individuals who qualified as cannabis dependent at the age of 18 showed a 3.7 times increase in risk for psychosis compared to those were not dependent and this study also showed that adolescent cannabis users aged 15-18 had a higher change of developing psychotic symptoms compared to controls[6]. This was true even after controlling for factors including socioeconomic status, ethnicity, IQ, abuse, education, as well as any existing psychotic symptoms. This study also concluded that there is a temporal relationship between duration of cannabis use and the development of symptoms as well as severity of those symptoms so that cannabis use staring at the age of 15 has a higher risk entailed than starting cannabis use at the age of 18[6]. Another group found similar evidence and showed that the development of psychotic symptoms related to cannabis use is of a temporal nature and that individuals with chronic cannabis use over a long period of time are at greater risk of developing psychotic symptoms compared than those who experience acute bouts of psychosis due to short term cannabis exposure[5]. In addition, this group also added that chronic use will not necessarily lead to the most severe psychotic symptoms possible and that severity will most likely be dependent of usage. They also go on to state that pre-existing vulnerabilities to the development of psychosis paired with chronic cannabis exposure entails the highest risk for psychotic symptoms than either of them alone[5].

Ketamine use and schizotypal symptoms

Role of the NMDA receptor

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Figure 1: Ketamine pathways to positve schizotypal symptoms

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has long been used for the purposes of inducing as well maintaining general anesthesia in both humans and animals[10]. Despite not currently being the method most often used in medical practice for anesthetic purposes in the developed nations, it is still a valuable tool for emergency medical procedures in the third world countries where the latest medical equipment and medication is not available. It is effective for the above mentioned circumstances due to the fact that as an NMDA receptor antagonist it disrupts the activity of glutamate by binding to the phencyclidine site within the NMDA receptor complex[10]. Due to the high density of NMDA receptors in frontal love regions as well as hippocampus, ketamine has been known to interfere with executive functioning as well as memory[10]. This is similar to the type of experience a patient awakening from anesthesia might experience which may be characterized by short term memory loss and temporary confusion. However, ketamine has also been associated with producing behavioral symptoms similar to those seen in schizophrenia, especially dissociative symptoms[1]. It is the dissociative states that ketamine can give rise to which has increased the popularity of its use as a street drug. One study aimed to use a rat model to study the effects the neural mechanisms behind the chronic administration of ketamine. The result of the endeavor was a model which showed the pathways proceeding chronic ketamine use which either lead to positive or negative psychotic symptoms[10]. The group found data that suggests that as a result of an almost 3 fold increase in the amount of 5HT being produced in the cortex and striatum there is increased activity of the serotonergic system which may explain the negative symptoms[10]. Furthermore, the finding that there were decreased amounts of glycine in the cortex and striatum as a result of chronic presence of ketamine is relevant, as decreased concentration of glycine is also seen in schizophrenia resulting in negative symptoms. Further evidence shows hyperactivity of the dopaminergic which is also found in schizophrenia. In addition to blocking glutamate activity ad NMDA receptors, ketamine was also found to inhibit NMDA activity within GABA neurons which further allows for the activity of dopamine and serotonin[10].

The Dangers of Ketamine Abuse
A brief discussion by the Doctors TV Show

Delusional ideation and difficulties in associative learning

Some schizophrenic patients have shown difficulties with prediction and responding to appropriate cues, much like abnormal salience and spurious associations that are often associated with schizophrenia. One studying looking at learning through a task involving cues and blocking in ketamine users versus controls found that ketamine users had difficulty with selective attention and blocked unassociated cues which was evident by their high accuracy in responding to cues that should have been blocked[13]. Furthermore, the ketamine users showed increase levels of delusional ideations, all of which the researchers conducting the experiment suggest is the result of decreased glutamate activity leading to interference with learning. Another study exploring the implications of delusions on predicting error in 15 healthy participants injected either with a low dose of ketamine (100ng/mL plasma), high dose of ketamine (200ng/mL plasma) or placebo, found that while low doses resulted in interference with right frontal cortex, affecting learning, high doses resulted perceptual disturbances as well as delusional beliefs[9]. This demonstrates that certain doses of ketamine can produce schizotypal symptoms such as prediction error and delusions providing further evidence for relationship between ketamine use and psychotic symptoms.

Emotional Recognition Impairments

One study sought to look at the effects of subanaesthetic doses of ketamine on social cognitions, specifically emotion recognition[1], a disability that is seen in some cases of schizophrenia. This group hypothesized that the role of ketamine as an NMDA receptor antagonist would cause reduction of function and their study involved eighteen male subjects who were tested on two different occasions, of which one was after ketamine administration[1]. The participants were tested on the Ekman's face test, the Psychometric States Inventory (PSI), and theContinuous Performance Test (CPT)[1]. This group found that the administration of ketamine resulted in the reduction of the ability to recognize facial emotions. Due to the fact that past studies have shown a relationship between the loss of the ability to recognize facial emotions and emotional flattening, a negative symptom, this provides evidence that even subanaestheitc doses of ketamine can cause schizotypal symptoms[1]. Further evidence by more recent studies also support this hypothesis as they showed that disabilities in the recognition of emotions such as fear and sadness have been displayed in individuals who are a high risk for psychosis[15]. This suggests, although further study is needed to identify neural processes, that the induction of psychosis symptoms by ketamine may alter the neural mechanisms that are affected by ketamine and put individual users at a higher risk of developing schizotypal symptoms and associated disorders.

For similar topics of interest

Brain Morphology of Schizophrenia
Addiction Treatments
Reward Pathway and Behavior in Addiction
Addiction Comorbidity
Natural, Synthetic, and Endogenous Psychedelic Compounds
Genetics of Addiction

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