The impact of cannabis use on neurological soft signs in schizophrenia patients

Introduction

Cannabis and schizophrenia

Tetrahydrocannabinol (THC), which is included in the most used illegal narcotic in the world, Cannabis sativa, with studies suggesting that individuals exposed to cannabis might have a pooled chances ratio of 1/4 for developing psychosis, also mimics schizophrenia by causing psychotic symptoms and cognitive impairment. It is also misused by patients with schizophrenia, and long-term usage has been associated with aggravating symptomatology, relapsing and deterioration of the patients’ overall functionality⁽¹⁾. THC is a partial agonist at the CB1R receptor, increasing dopamine and glutamate levels, and decreasing GABA concentrations in the prefrontal cortex. Psychotomimetic effects include paranoia, grandiosity, thought disorganization, and perception changes, euphoria, anxiety, along with impairments in attention and working memory⁽²⁾. It seems that anti­psychotic treatment does not fully protect individuals with schizophrenia from symptom exacerbation after THC exposure^(3,4), even though psychosis associated with cannabis usage cannot be fully explained by dopamine abnormalities alone. Retrograde transmission in the cortical, hippocampus and midbrain areas is mediated by CB1 receptor activation, which inhibits glutamate and aminobutyric acid (GABA)⁽⁵⁾. Little research has been done to ascertain whether glutamatergic/GABA-ergic disorders are connected to cannabis usage in psychosis⁽⁶⁾.

Cannabis also contains cannabidiol (CBD), a crucial component with low affinity for CB1/ CB2 receptors, and potential partial agonist at the CB1 receptor⁽⁷⁾. CBD inhibits the reuptake and degradation of anandamide, increasing anandamide levels in the central nervous system⁽⁸⁾. CBD has been widely studied for its therapeutic potential and has been shown to counteract effects of THC and other CB1R agonists in healthy subjects, including anxiety, euphoria and psychosis. It has also been suggested to attenuate THC-induced memory impairment. Nonetheless, the metabolism of THC is hindered by CBD, resulting in a heightened enhancement of its behavioral effects when CBD is administered beforehand⁽⁹⁾. Some authors suggest that a higher CBD/THC ratio is associated with a lower risk of psychotic disorders, subthreshold psychotic symptoms and cognitive changes related to psychosis^(10,11). Several MRI investigations demonstrated changed glutamatergic metabolites in psychosis patients compared to controls, thus providing evidence that points to glutamatergic dysfunction in psychotic episodes, independent of the cannabis intake⁽¹²⁾.

Nonetheless, chronic cannabis use may result in a fundamentally distinct adaptation process in the brain that promotes rather than inhibits motor performance. As a result, several cannabis compounds have been investigated for the therapy of various motor dysfunctions such as dyskinesia and Parkinson’s disease. Oral administration of a cannabis extract, on the other hand, had no effect on parkinsonism or dyskinesias in Parkinson’s disease patients^(13,14).

Cannabis can affect the sensorimotor system both acute and on the long term, by stimulating cannabinoid receptors. Moreover, 9-tetrahydrocannabinol (9-THC) usage can have an immediate effect on sensorimotor functioning by alterating dopamine transmission in limbic/associative and sensorimotor cortical circuits⁽¹⁵⁾.

Neurological soft signs and schizophrenia

It has long been established that motor dysfunction is a characteristic of both schizophrenia and other conditions in the spectrum of this pathology⁽¹⁶⁾. Subtle neurological signs, commonly known as neurological soft signs (NSS), include impairments in sensory integration, motor coordination and sequencing of complex motor acts, as well as abnormalities of eyeball movements, but also the presence of certain pathological reflexes⁽¹⁷⁾. These neurological abnormalities are not caused by a clear neurological pathology, such as the presence of brain or spinal cord lesions, with the presence of irregular movements, resembling tardive dyskinesia, and cannot be attributed to the side effects of the use of neuroleptic drugs, but rather a feature of the disease itself⁽¹⁸⁾. It is also recognized that NSS is more frequent in patients with schizophrenia compared to healthy individuals. Moreover, NSS is more prevalent in patients with schizophrenia compared to their first-degree relatives, and they are more prevalent in first-degree relatives compared to healthy individuals⁽¹⁹⁾. Current literature acknowledges that NSS scores tend to decrease in patients who respond well to treatment, while they persist or increase in individuals with a partial therapeutic response⁽²⁰⁾. These have been regularly observed in treatment-naive first-episode psychotic patients, thus supporting the hypothesis that NSS is an intrinsic component of schizophrenia⁽²¹⁾.

Aim and method

The purpose of this review was to better understand the impact of cannabis use on NSS in patients with schizophrenia, thus aiming to draw the boundaries of research in the field up to this point. At the same time, by conducting this review, we wanted to observe the extent of research interest in this regard, thus evaluating the opportunity of conducting a future meta-analysis. We therefore used the PubMed database to identify relevant articles using the following keywords: “((cannabis) AND (schizophrenia)) OR (neurological soft signs)” and “(cannabis) AND (neurological soft signs)”. We excluded the following publications: articles that included children and adolescents, studies including subjects with severe neurological or genetic diseases, intellectual disabilities or other comorbidities, articles published in languages other than English, meta-analysis or systematic reviews, and articles that were not open access.

Results

The initial search conducted in the Pub Med database revealed a total of 144 publications. By using automation tools, 137 records were removed, and seven remaining studies were further reviewed in full-text.

The research carried out by Wolf et al.⁽¹⁵⁾ on 66 participants was based on two assumptions. Their first hypothesis stated that individuals with heavy cannabis use (HCU) will exhibit higher levels of NSS compared to the control group, especially in sensorimotor subdomains related to complex motor tasks and integrative sensorimotor processes. The second hypothesis was that the differences in NSS among individuals with HCU will have a significant correlation with regional homogeneity alterations in brain areas that are involved in sensorimotor execution and control. The study examined the associations between NSS and increased neuronal activation in individuals with HCU compared to healthy control participants. The authors concluded that participants with HCU had significantly higher scores on all sensorimotor subdomains of the Heidelberg⁽²²⁾ NSS scale compared to controls. Three subdomains of NSS (motor coordination, sensory integration, and complex motor acts) were associated with use-dependent variables, such as THC use onset and current cannabis use. Complex motor task in HCU participants was significantly correlated with increased neuronal activation in specific brain regions, including the postcentral, inferior frontal and occipital cortices as identified using brain MRI evaluation. The author’s findings support the prediction that individuals with HCU would have higher total NSS scores compared to healthy control subjects. Furthermore, the results of the study also support the assumption that cannabis, particularly through the stimulation of cannabinoid receptors, can impair the functioning of the sensorimotor system in the short and long term. Moreover, it was suggested that acute and long-term effects of THC use can directly influence sensorimotor functioning by modulating dopamine transmission in the limbic/associative and sensorimotor cortical circuits.

The aim of the research conducted by Bersani
et al.⁽²³⁾ was to assess the impact of chronic cannabis use or abuse on the occurrence and severity of NSS in 50 male subjects diagnosed with chronic schizophrenia. Additionally, the study aimed to explore potential differences in positive and negative symptoms between patients with schizophrenia and cannabis use and those who do not use cannabis. Thus, the participants were divided into three groups: (1) non-consumers of any illegal drugs, (2) cannabis users without significant dysfunction, and (3) cannabis abusers with social or occupational dysfunction. Data were collected through self-reports, as toxicology screening tests were not feasible in the author’s point of view. The patients’ ages ranged from 20.94 to 29.94 years old, and they had been on stable neuroleptic treatment for at least three years. The authors concluded that the prevalence and intensity of NSS are higher in non-consuming schizophrenia subjects compared to consumers, suggesting that cannabis is not a factor that induces or worsens these abnormalities as there is no clear evidence of irreversible and definitively demonstrated cerebral alterations caused by cannabis use. The correlation analysis of the research indicated a direct relationship between NSS and negative symptoms of schizophrenia, which are higher in non-consuming subjects, suggesting that chronic cannabis use may alter the clinical course of schizophrenia. On the other hand, the authors pointed out that cannabis use was associated with a worsening of positive symptoms, particularly delusions and hallucinations.

Similar conclusions were drawn from the research of Ruiz-Veguilla et al.⁽²⁴⁾ The study included 92 patients, with 64% males. The mean age of the patients at the time of the study was 26.9 years old, and most of them (87%) had non-affective psychosis. Among the patients, 62% reported a lifetime history of illegal drug use, with cannabis being the most used drug. Of those who used cannabis, 89% reported daily or near-daily use. Cocaine use was reported by 37% of the patients, with most of them classified as heavy cocaine users. In summary, the study found a high prevalence of illegal drug use, particularly cannabis and cocaine, among patients diagnosed with psychosis. Furthermore, the statistical analysis of the research showed an inverse relationship between heavy cannabis use and the presence of NSS in patients with first-episode psychosis. The study found that first-episode psychosis patients who smoked cannabis daily or almost every day before the onset of their psychotic symptoms had a lower frequency of high NSS compared to those who did not use cannabis heavily.

Another study⁽²⁵⁾ included 61 patients with the diagnosis of schizophrenia according to DSM-IV-TR, between 18 and 50 years old, who were in a stable course of illness and without medication or symptom changes for at least four weeks before the cognitive evaluation, and had a minimum duration of psychosis of one year. The authors further divided the patients into two groups, patients with and without cannabis use. The study found three significant differences: the group without cannabis use disorder exhibited fewer neurological soft signs, better cognitive functioning, and fewer negative symptoms. These findings suggest that patients with schizophrenia without cannabis use disorder may have experienced more significant and earlier neurodevelopmental alterations. The study also revealed a higher prevalence of familial first-degree psychosis among participants reporting cannabis use disorder before the onset of psychosis. Based on these results, the authors suggested that cannabis may have a role as a late environmental factor in patients who experienced less early neurodevelopmental impairment but still exhibited sensitivity to its pharmacological effects. Additionally, patients with schizophrenia who used cannabis before the psychosis onset showed fewer neurological soft signs, indicating better motor coordination, sensory integration, and sequencing of complex motor acts compared to non-users.

A cross-sectional study⁽²⁶⁾ conducted in Tunisia over a period of 14 months aimed to assess patients hospitalized for first-episode psychosis according to DSM-IV criteria. Patients with various psychotic disorders were included (schizophrenia, schizophreniform disorder, brief psychotic disorder, cannabis-induced psychosis, delusional psychosis, psychotic disorder not otherwise specified), while those with specific criteria, such as age over 55 years old, prior psychiatric hospitalization, psychotic disorder due to a medical condition, mental retardation or major neurological disorders, were excluded. In their study, the authors used several assessment tools to collect data. Premorbid functioning was evaluated using the Premorbid Adjustment Scale (PAS), while the duration of untreated psychosis was estimated through interviews with caregivers/family and patients. Psychometric assessment was conducted using the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning scale (GAF). Neurological evaluations were performed using the neurological soft signs scale (NSS) and extrapyramidal side effects of antipsychotics were evaluated using the Simpson Angus (SA) scale. Cannabis use was ascertained using the cannabis subsection of the Composite International Diagnostic Interview (CIDI) which identified patients who had used cannabis on five or more occasions. Patients who reported daily or near-daily cannabis use were categorized as “heavy cannabis users”.  The study concluded that cannabis users among first-episode psychosis patients had significantly fewer NSS compared to patients without a history of cannabis use. These findings are consistent with previous studies of the present review, that also reported a negative association between cannabis use and NSS in first-episode psychosis patients.

The study of Simonienko et al.⁽²⁷⁾ involved 25 individuals diagnosed with schizophrenia, divided into two groups. The first group consisted of individuals who had a history cannabis usage, specifically marijuana, synthetic cannabinoids and hashish. The second group included individuals who not only used marijuana but also other substances such as amphetamine, methamphetamine or MDMA. Participants were excluded if they had a history of major somatic diseases that could influence the course of schizophrenia. The study collected data through questionnaires on the effects of drug use and symptoms that had the greatest impact on the well-being of the participants. However, it should be noted that the questionnaires used in the study were not scientifically validated. The study found no significant differences in the age of schizophrenia onset between the two groups, with the average age of onset being around 21-22 years old. However, subjects who also used stimulants started using psychoactive substances at an earlier age, around 16 years old, on average, while the cannabis group started at almost 18 years old. Curiosity (up to 92%) and the need to relax (up to 96%) were the most common overall reasons to abuse illicit substances. Other reasons included overcoming stigma, achieving an altered state of consciousness, mood regulation, and filling feelings of emptiness. The author’s statement was that cannabis was used by the patients included in their study to alleviate productive symptoms and help tolerate treatment side effects. Furthermore, it was concluded that patients treated with second-generation neuroleptics used fewer substances compared to those following a treatment with first-class neuroleptics.

Discussion

Psychoactive substances are commonly used by individuals with mental illness, including schizophrenia, to relieve symptoms, counteract medication side effects, achieve balance and reduce dysphoria⁽²⁸⁾. Patients may use psychoactive substances as a form of self-medication, unaware of the potential negative consequences and the potential to worsen their illness. Fear and discomfort associated with psychotic processes contribute to the desire to relax and unwind through substance use⁽²⁹⁾.

Neurological soft signs are minor abnormalities in motor coordination, sensory integration, and other neurological functions. The impact of cannabis on NSS is a topic of scientific investigation. Nevertheless, it is worth noting that the exact mechanisms by which cannabis may influence NSS are not yet fully understood. However, it is important to consider that individual responses to cannabis can vary, and not everyone who uses cannabis will experience neurological abnormalities or NSS. Additionally, other factors, such as the frequency and duration of cannabis use, dosage, genetic predisposition and co-occurring conditions, may also influence the impact of cannabis on NSS. Furthermore, NSS are considered trait variables of schizophrenia and are stable over time, potentially correlated with a specific structural brain alterations⁽¹⁷⁾.

Cannabis use can be considered a significant environmental risk factor that plays a role in the development of psychosis, even in individuals who may have a lower inherent vulnerability to the condition based on biological and genetic factors⁽³⁰⁾. The lower NSS scores indicate a lesser degree of neurodevelopmental impairment in these individuals. Therefore, despite having less pronounced biological and genetic susceptibility, the use of cannabis could still contribute to the manifestation of psychosis. This implies that cannabis may have a powerful influence on the development of psychosis, independent of an individual’s inherent predisposition to the disorder⁽³¹⁾.

Some researchers suggest that certain components of cannabis, particularly cannabidiol (CBD), may have antipsychotic and neuroprotective properties, which could potentially alleviate symptoms and improve neurological functioning, including NSS, in individuals with schizophrenia⁽³²⁾. Based on the articles included in the present review, cannabis use is inversely related to the presence of NSS in patients with first-episode psychosis, indicating better motor coordination and sensory integration. However, cannabis use might be related to a worsening of positive symptoms, particularly delusions and hallucinations, in individuals with schizophrenia.

Overall, patients with schizophrenia without cannabis use included in the articles exhibit fewer neurological soft signs and better cognitive functioning, compared to those with cannabis use disorder.

Even though, according to the included studies, cannabis use was not a factor that induced or worsened NSS, cannabis use in patients with schizophrenia may have a role as a late environmental factor, inducing neurodevelopmental alterations and sensitivity to pharmacological effects.

It is worth mentioning that studies investigating the potential benefits of cannabis in schizophrenia have numerous limitations in the research methodology, mostly regarding the follow-up of patients who used cannabis. Furthermore, these studies have generally examined other symptoms of schizophrenia, such as psychosis or cognitive impairments, rather than specifically targeting NSS.

Conclusions

The relationship between cannabis use, NSS and schizophrenia remains a complex and evolving area of research. While the impact of cannabis on NSS and its potential benefits in schizophrenia are still being explored, it is crucial to approach this topic with caution. Even though some studies included in the present review have explored potential therapeutic effects of cannabis, the overall evidence is limited and inconclusive. Additionally, the use of cannabis in schizophrenia is a complex issue, as it involves weighing clear benefits against potential risks. Given the limited number of articles available and the diverse methodologies used, which often yield conflicting results, we believe that conducting a meta-analysis at this time may not be the most appropriate course of action.

To develop effective strategies for addressing substance use in schizophrenia, further research is necessary. Specifically, more comprehensive studies are needed to better understand the complex relationship between cannabis use and NSS, which are indicators of neurological dysfunction in individuals with schizophrenia. Research should focus on elucidating the potential implications of cannabis use on cognitive and functional outcomes, especially among vulnerable populations such as individuals with psychiatric disorders. Psychoeducation and social support are necessary to address the use of psychoactive substances by individuals with schizophrenia.

Institutional review board statement: not ­applicable.

Informed consent statement: not applicable.

Data availability statement: not applicable.

All authors have read and agreed to the published version of the manuscript. This scientific material is part of a larger study of a PhD thesis currently under development by the main author, Cristian Petrescu, from the Faculty of Medicine of the “Carol Davila” University of Medicine and Pharmacy, Bucharest, with Prof. Adela Magdalena Ciobanu as the thesis coordinator. We would like to thank Prof. Doina Cozman for the involvement in the publication process of the present manuscript.

 

Conflict of interest: none declared

Financial support: none declared

This work is permanently accessible online free of charge and published under the CC-BY.