Impact of At Least 2 Years of Synthetic Cannabinoid Use on Cognitive and Psychomotor Functions Among Treatment-Seeking Male Outpatients

Abstract

Introduction: Synthetic cannabinoid (SC) use, an important public health problem, is becoming increasingly widespread and leads to many medical and psychiatric problems. This study aimed to evaluate the impact of SC use on cognitive and psychomotor functions of patients.

Materials and Methods: The participants (30 outpatients with SC use disorder and 33 healthy controls) were administered the Montreal Cognitive Assessment (MOCA) test, the Edinburgh Handedness Inventory (EHI), the Finger-Tapping Test (FTT), and the Adult Memory and Information Processing Battery-B form (AMIPB-B).

Results: The SC users scored lower in AMIPB-B, MOCA. and FTT compared to the healthy controls.

Conclusion: These findings suggest that SC might impair both cognitive and psychomotor functions. Therefore, outpatients with SC use disorder should be carefully evaluated for cognitive and psychomotor functions since neurological examinations and interventions may also be required in treatment programs for these cases.

Introduction

According to World Health Organization (WHO), cannabis is the most commonly used illicit drug worldwide.¹ However, this information seems to have changed over time. According to our clinical practice, previous cannabis users have started to use synthetic cannabinoids (SCs), and the number of cases who use SC as a first substance is increasing.² Another probable reason for this change is that SCs are easier to produce than cannabis since they can be produced in clandestine laboratories.³ Similar to cannabis, SCs are psychoactive substances affecting both cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors.⁴

SC products acutely cause adverse effects such as tachycardia, vomiting, seizures, and psychiatric symptoms, including psychosis, irritation, and anxiety.⁵ However, human-trial data related to their effects on cognitive functions and locomotor activity are limited. It is suggested that SCs cause impairment in memory, attention, concentration, and motor skills similar to tetrahydrocannabinol, which is the main cannabinoid found in cannabis.⁶ It has been reported that cognitive impairment might be seen as a result of chronic daily use of SCs.⁷ JWH-081, a SC, has been found to cause impairment in learning and memory in mice.⁸

SCs such as AM-411 and U-144 have been shown to cause reductions in locomotion, or suppression of locomotor activity as one of the consequences of CB1 receptor agonism in mice.^9,10 The other molecule that confirms the relationship between CB1 receptor and locomotor activity is rimonabant, a CB1 receptor antagonist. It has been shown that rimonabant stimulates locomotor activity in mice.¹¹ The Finger-Tapping Test (FTT) is used to assess muscle control and motor ability in the upper extremities.¹² It is also used for psychomotor evaluations.^13,14 In studies where the FTT is used, psychomotor function has been shown to be impaired in cannabis users,¹⁵ bipolar patients,¹⁶ and patients with mild cognitive impairment.¹⁷

Information processing is also described briefly as the fundamental aspect of concentration and attention, and is also the building stone of higher cognitive functions.¹⁸ The Stage Theory Model is a model of information processing based on the work of Atkinson and Shiffrin.¹⁹ Transient and multistaged learning and memory are the building blocks of this model. Sensory memory, short-term or working memory, and long-term memory have been defined as the three stages of the model. It is considered that new information is taken in and processed before it is stored.²⁰ Previously, the Adult Memory and Information Processing Battery-B form (AMIPB-B) was used among cannabis users,¹⁵ bipolar disorder patients,¹⁶ and multiple sclerosis patients²¹ to examine information processing; we believe that this is the first study to use this form in patients with SC use disorder.

In this study, we aimed to examine the impacts of SC use on cognitive and psychomotor functions in treatment-seeking outpatients with SC use disorder.

Materials and Methods

The study was designed to include 30 outpatients with SC use disorder admitted to AMATEM Clinic (Alcohol and Drug Research, Treatment and Training Center), Bakirkoy Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, and 33 healthy controls. The control group consisted of volunteers who were relatives of the patients admitted to the neurology outpatient clinic. They were asked to participate in the study, and those who accepted were included in the control group. The SC users were diagnosed with substance use disorder (abuse or dependence) according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revised (DSM-IV-TR).²²

The patients who had been admitted to AMATEM were invited, and volunteers who were using SC on a daily basis for at least 2 years were included in the study. The study was conducted according to the WMA Declaration of Helsinki—Ethical Principles for Medical Research Involving Human Subjects. All participants gave their verbal and written informed consent to the anonymous use of their clinical data. They were assured that this procedure would not lead to any positive or negative change in their treatment programs.

Exclusion criteria were presence of morphological deformity or functional disability in one extremity (trophic weakness, innervation problems, etc.), asymmetrical vision defect and amblyopia, alcohol or substance use disorder other than SCs, significant impairment of cognitive functions verified by Montreal Cognitive Assessment (MOCA) (score less than 21), significant impairment of sleep duration and quality, and heavy drug use that may affect cognitive and psychomotor functions. Among 36 outpatients with SC use disorder, who were evaluated with MOCA, 6 patients were excluded from the study due to scoring less than 21, which is recommended as the cutoff value. A study conducted in Turkey has shown that MOCA scores under 21 predict cognitive impairment.²³ It was thought that the patients who had MOCA scores lower than 21 would have difficulty in understanding the instructions of other tests.

None of the participants reported that they had a neurological and physical disease that would affect their motor and cognitive functions, and none of them used opioids as a painkiller. In addition, none of the participants reported that they were hungry or had any sleep-related disorder. Cases with substance withdrawal or intoxication symptoms were not included to the study.

According to the study protocol, the MOCA test and Edinburgh Handedness Inventory (EHI), which determines the dominant hand, were administered to the participants. Afterward, the AMIPB-B form and FTT were administered to the participants who had scored 21 or higher in MOCA. The study was approved by the ethical committee of the institution.

A standard form containing questions related to information such as age, gender, educational status, family, and profession was used to collect sociodemographic data from the participants. Another questionnaire containing items related to SC information such as time, amount, and frequency of substance use, and age of onset was administered to the participants. Diagnoses were evaluated by a structured interview according to DSM-IV (SCID)^24,25 and all participants underwent cognitive evaluation. The tests used for cognitive evaluation are described below. The tests were administered by an experienced and certificated clinical neuropsychologist (C.K.), who had the necessary competence to perform and assess such cognitive and psychomotor tests.

The SC users and healthy controls underwent a urine screening test by CEDIA (cloned enzyme donor immunoassay) method in our toxicology laboratory. The metabolites screened were SC, cannabinoid, opiate, heroin, cocaine, amphetamine, ecstasy, benzodiazepine, and ethyl glucuronide. Semiquantitative measurement was performed in our toxicology laboratory and the threshold value of 20 ng/mL was accepted positive for SC. The urine screening test was performed within 2 days of using SC. All of the SC users included in the study were found SC positive and none of the substance metabolites was detected in any of the healthy controls.

The MOCA test

MOCA assesses visuospatial functions, executive function, attention, memory, working memory, speaking, and abstract thinking. It is a sensitive tool in diagnosis of mild cognitive impairment and mild cognitive insufficiency.^23,26 Sensitivity and specificity of MOCA were found to be better than the Mini Mental State.²⁶ It may be used in various clinical settings in neurology and psychiatry. According to the ROC analysis, the cutoff value for the MOCA total score was 21 points.²³ Individuals with a MOCA score lower than 21 were excluded from the study.

Edinburgh Handedness Inventory

EHI is a Likert-type scale used to determine hand preference.²⁷ It includes items regarding hand preference when using scissors, knife, or spoon, as well as catching a ball and hand writing. To increase its reliability, assumptions (cutting with scissor and, cutting bread with a knife) may be useful.

Finger-Tapping Test

This test measures tapping rate of the index finger (manual motor speed). Participants are asked to touch a button as quickly as possible using the index finger of their dominant and nondominant hand for 10 sec. The procedure involves five consequent trials with each hand to eliminate the effect of outliers on score.²⁸ The test allows for a maximum of 10 trials and the trial is cancelled if the difference between the said trial and the previous trials is more than 5 points. There are various finger tapper devices, which may lead to variations in results. In this study, we used a device manufactured by PARINC^® and it was adjusted specifically for counting.

Adult Memory and Information Processing Battery-B form

AMIPB-B aims to measure information processing speed by assessing motor speed. Run speed may determine the reaction time. According to the instructions recommended by Coughlan and Hollows,²⁹ the participant is asked to find the redundant number on the right side among two different groups of numbers separated by a line. A 4-min time limitation is recommended for the battery. Participants first need to memorize the numbers on the left side of the task and remember them while comparing with those on the right side. Giving an example that we frequently do, when we want to cross the street, we control the left way first and then control the right way. When checking the right way, we need to remember the left way to pass the street safely. This process is performed by our working memory.

Statistical analysis

The data were analyzed using SPSS version 20.0 package for Mac OSX. In addition to descriptive statistics (mean, standard deviation, median, minimum and maximum) and frequencies, we also performed chi-square test to investigate the relationship between categorical variables, and Mann–Whitney U test for continuous variables of independent groups as they were not normally distributed according to Kolmogorov–Smirnov test. When normality of distribution is satisfied, independent sample t-test (two-sided) was used for identifying differences between two independent groups. The statistical significance level was accepted to be p<0.05/5=p<0.01 for independent sample t-test and Mann–Whitney U test based on the Bonferroni correction. In other cases, p<0.05 was accepted as statistically significant.

Results

Outpatients (n=30) with SC use disorder and healthy controls (n=33) were included in this study. Both of the groups consisted of males only to ensure data homogeneity since outpatients with SC use disorder admitted to the AMATEM during the study period were all male. Table 1 shows the comparison between the outpatients with SC use disorder (n=30) and healthy controls (n=33) in terms of sociodemographic characteristics. The mean age of the outpatients with SC use disorder (24.03±5.25) was lower than the control group (33.45±7.79, p<0.001). The mean duration of education was 8.50±2.55 for the outpatients and 9.50±2.88 for the healthy controls, and the difference was not significant. An important finding was that 16 outpatients with SC use disorder (53.3%) were unemployed and 13 of them (13/16; 81%) believed that this was due to SC use.

Table 1.

Comparison of the Two Groups in Terms of Sociodemographic Characteristics

	Outpatients with SC use disorder		Healthy controls
	n=30	%	n=33	%	χ2	df	p
Marital status					10.69	1	0.001*
Single	24	80.0	13	39.4
Married	6	20.0	20	60.6
Employment					5.88	1	0.015*
Employed	14	46.7	27	81.8
Unemployed	16	53.3	6	18.2
	Mean	SD	Mean	SD	ta
Age, years	24.03	5.25	33.60	7.79	5.56		<0.001*
Education, years	8.93	2.04	10.12	3.12	−1.76		0.082

^aIndependent sample t-test.

^*p<0.05.

χ², chi-square test; SC, synthetic cannabinoid; SD, standard deviation.

The mean age of first SC use was 21.68±5.39 and the duration of regular use was 23.70±14.55 months (Table 2) among the patients. The mean daily consumption and duration of use were 2.83±1.98 g and 28.33.85±6.28 months, respectively (Table 2). The rate of SC cessation attempt was found to be 76.7% (n=23) (Table 2). The time that the outpatients could spend without using SC varied between 4 h and 4 days. In the outpatient group, 18 (60%) had used cannabis and 2 (6.7%) had used heroin before using SC, while 10 patients (33.33%) had begun directly with SC. The distribution of SC use methods was as follows: 30% (n=9) smoking, 20% (n=6) inhalation (using a pet bottle), and 50% both smoking and inhalation (Table 2). Ninety percent (n=27) of the outpatients were found to experience withdrawal symptoms (Table 3). The most reported withdrawal symptom was restlessness (66.7%; n=20) followed by sleeplessness (53.3%; n=16) (Table 3). Among the outpatients with SC use disorder, 28 (93.3%) reported that the reason behind their SC use was the sense of relief. All the outpatients with SC use disorder had experienced negative effects, and palpitation was the most frequent negative effect (n=21; 70%). In addition, 20 SC users (66.7%) reported that they had experienced petulance. Surprisingly, half of the outpatients with SC use disorder (n=15; 50%) reported that they had heard and/or witnessed an SC use-related death in their social circle.

Table 2.

The Pattern of Synthetic Cannabinoid Use

	Mean	SD
Age of onset of SC use	21.68	5.39
SC amount, gr/day	2.83	1.98
Duration of use, months	28.33	11.38
Duration of regular use, months	23.70	14.55
	N	%
Type of consumption
Smoking	9	30
Pet bottle	6	20
Pet bottle and smoking	15	50
Environment of SC use
Alone	18	60
Group	4	13.3
Both alone and group	8	26.7
Cessation attempts	23	76.7

Table 3.

Withdrawal Symptoms and Undesirable Effects

	N	%
Withdrawal symptoms positive	27	90
Withdrawal symptoms
Restlessness/anxiety	20	66.7
Sleeplessness	16	53.3
Nausea	9	30
Loss of appetite	13	43.3
Irritability	3	10
Others	4	13.3
Undesirable effects of SCs
Hallucinations	13	43.3
Delusion	8	26.7
Petulance	20	66.7
Irritability	12	40
Palpitation	21	70
Dermatitis	14	46.7
Alopecia	3	10
Thirst/hunger	18	60
Others	2	6.7

Twenty-eight outpatients with SC use disorder (93.3%) had started to use SC through their friends, while two SC users (6.6%) had been introduced to SC by a drug dealer. Independent sample t-test revealed that the healthy controls had higher AMIPB-B scores than the outpatients with SC use disorder, and difference was statistically significant (t=−2.980, p=0.004). The healthy controls had higher total MOCA scores than the SC users, and the difference was statistically significant (t=−6.200, p<0.001) (Table 4). Considering the subtests of MOCA, the healthy controls had higher visuospatial/executive, language, and abstraction scores compared to outpatients with SC use disorder (Z=−4278, p<0.001; Z=−4075, p<0.001; and Z=−6397, p<0.001, respectively), whereas there was no statistically significant difference in terms of naming, memory, and attention scores (Z=−1638; p=0.101; t=−1.692, p=0.096; and Z=−0.474, p=0.636, respectively) (Table 4). The comparison between the FTT scores of the groups showed that the healthy controls scored higher than the SC users in terms of both dominant and nondominant hand (t=−4.739, p<0.001; and t=−3.792, p=<0.001, respectively) (Table 4).

Table 4.

Comparison of Cognitive Performance Tests and Psychomotor Speed Between the Outpatients with Synthetic Cannabinoid Use Disorder and Healthy Control Groups

	SC users		Controls
Tests	Mean	SD	Mean	SD	ta	p
AMIPB-B	56.96	19.67	71.27	18.42	−2.980	0.004*
FTT, dominant hand	50.18	6.87	57.48	5.31	−4.739	<0.001*
FTT, nondominant hand	46.57	4.81	51.36	5.18	−3.792	<0.001*
MOCA total score	24.20	2.12	27.18	1.68	−6.200	<0.001*
MOCA subtests
Memory	3.10	1.47	3.63	1.02	−1.692	0.096

	Median (25–75% values)	Median (25–75% values)	zb
Visuospatial/executive	4 (4–4)	5 (4–5)	−4.278	<0.001*
Naming	3 (2–3)	3 (3–3)	−1.638	0.101
Attention	6 (5–6)	6 (5–6)	−0.474	0.636
Language	2 (1–2.25)	3 (2–3)	−4.075	<0.001*
Abstraction	1 (1–1)	2 (2–2)	−6.397	<0.001*

^aIndependent sample t-test.

^bMann–Whitney U test.

^*p<0.05/5=p<0.01 by using Bonferroni correction for independent sample t-test and Mann–Whitney U test.

AMIPB-B, Adult Memory and Information Processing Battery-B form; FTT, Finger-Tapping Test; MOCA, The Montreal Cognitive Assessment test.

Discussion

The main finding of this study is that the outpatients with SC use disorder scored lower than the healthy controls in AMIPB-B, MOCA, and FTT, which may suggest that SCs impair cognitive and psychomotor functions. Six subjects were also excluded from the study due to scoring lower than 21 in MOCA, which may suggest that these subjects had severe cognitive and psychomotor impairment. Due to the cross-sectional design of the study, we could not directly associate this impairment with SC use. Nevertheless, we consider this result as an important finding in terms of the potential damage of SCs on brain. Similar results were reported for cannabis use in human studies,^15,30–35 but to the best of our knowledge, cognitive functions (especially information processing) and psychomotor functions were not studied previously among SC users. Thus, we believe that the findings of this study may pave the way for prospective studies.

The outpatients with SC use disorder had a lower total MOCA score than the healthy controls. Regarding the subtests of MOCA, the outpatients had significantly lower visuospatial/executive, language, and abstraction scores. Our findings are consistent with the animal studies and human case series that found a relationship between cognitive functions and use of SC.^6,11 High levels of CB1 receptors are present in the cortex, basal ganglia, hippocampus, cerebellum, and thalamus.³⁶ Thus, the mentioned regions may be affected in SC users. The results from the study conducted by Tomiyama and Funada³⁷ indicate that the cytotoxicity of SC toward primary neuronal cells is mediated by the CB1 receptor, and SC may induce the apoptosis due to neuronal damage or deficits in the brain.

In one neuroimaging study, Tl-weighted magnetic resonance images revealed that adolescents with cannabis use disorder showed an attenuated loss of cortical thickness—normally required reduction of cortical thickness for neuronal pruning in the developing brain, in various regions of the brain, compared to healthy controls. In addition, this study indicated that greater cumulative cannabis exposure predicted greater cortical thickness in both the left and superior frontal gyri.³⁸ These findings suggest that cannabis, which is a partial agonist, causes harm to the brain and affects cognitive functions by CB1 receptor agonism. In one animal study, acute administration of JWH-081, a full agonist more potent than cannabis, was observed to impair short-term memory, but not long-term memory, in the Object Recognition Task.⁸ SC users have lower performance in cognitive tasks compared to both natural cannabis users and healthy controls.^39,40

Both pre-clinical and clinical studies revealed a relationship between SC and impairment of cognitive functions regardless of acute or repeated consumption, and the severity of this impairment depends on several factors such as the type of drug, dose of use, quantity, age of onset, and duration of use.⁴¹ We found that information-processing scores of the outpatients with SC use disorder were lower compared to the control group. This study seems to be compatible with those that revealed a relationship between CB1 agonism and cognitive functions, especially information processing.

The study conducted by Bhattacharyya et al.⁴² demonstrated that vulnerability to acute psychomotor impairments induced by cannabis depends on variation in a gene that codes for a protein that influences central dopaminergic transmission. It was also reported that cannabis slowed down reaction time, impaired motor coordination, and had effects similar to that of alcohol and benzodiazepines,⁴³ and this hypomotility was mediated by CB1 receptors.⁴⁴ Chronic cannabis use was found to be related to impaired psychomotor speed even after 28 days of withdrawal.³⁵

Pharmacological activities of three SCs, including cannabicyclohexanol, CP-47,497, and JWH-018, were examined by analyzing electroencephalogram (EEG) power spectra and locomotor activity in rats, and the researchers found that the total amount of locomotor activity was significantly reduced.⁴⁵ In another animal study, it was demonstrated that each of the SC compounds, including JWH-203, JWH-250, and AM-2201, reduced locomotor activity for up to 90 min.⁴⁶ In addition, rimonabant, a CB1 receptor antagonist, blocked locomotor depressant effects of CP-47,497, which is an SC compound.⁴⁷ Motor speed was found to be reduced in the outpatients with SC use disorder in our study and this result was consistent with previous studies reporting negative impacts of cannabinoids on psychomotor functions.

One study suggested that structural changes of lower regional callosal fibers might be responsible for age-related bimanual motor deficits.⁴⁸ Given this suggestion, motor reduction in outpatients with SC use disorder may be due to reversible changes in lower regional callosal fibers induced by SC. This must be verified by studies using advanced imaging methods in patients with SC use disorder.

Symptoms such as auditory and visual perceptual distortions, paranoid thoughts, irritability, and anxiety are considered undesired effects of SC.⁴⁹ Winstock and Barratt⁵ also reported that SCs have adverse effects such as tachycardia, vomiting, seizures, and psychiatric symptoms, including psychosis, irritation, and anxiety. The features of undesired effects of SCs and withdrawal symptoms found in this study seem to be compatible with previous studies.^2,5,49

Limitations

This study has several limitations: one of the most significant limitations of this study is that the mean age of the healthy controls was higher than the outpatients with SC use disorder. However, it is suggested that the average age decrements in psychometric abilities could not be demonstrated before age 60.⁵⁰ In fact, age is taken into account when scoring AMIPB; thus AMIPB scores are already adjusted for age. Moreover, age was not correlated with AMIPB scores in this study. Due to the reasons mentioned above, we believe that the age difference may have not affected the results of the study. Second, our toxicology laboratory can only detect JWH-18, JWH-73, and AM-2201, and most of the other varieties of SC cannot be detected. Although the spectrum of SC compounds used may be much different today, Istanbul Narcotic Department of the Council of Forensic Medicine found that 99.4% of SC compounds contained JWH-018.⁵¹ Therefore, the SC variation detected in our toxicology laboratory was probably one of these three SC types or a combination of these. Third, the study was only conducted with males; therefore, the results cannot be generalized to female patients. Fourth, despite the fact that the participants did not suffer nicotine withdrawal, it should be kept in mind that nicotine withdrawal may also affect cognitive functions. Finally, the effects of SC on cognitive functions and psychomotor function, whether permanent or temporary, are unclear. Thus, follow-up studies on cognitive and psychomotor functions will provide useful data for this ambiguity.

Conclusion

These findings suggest that SCs might impair cognitive and psychomotor functions. Therefore, outpatients with SC use disorder admitted to clinics should be carefully evaluated for cognitive and psychomotor functions; neurological examinations and interventions may also be required. Since use of these drugs has increased over time, noticing the impairment of cognitive and psychomotor functions due to consumption of SC is very important.

Abbreviations Used

AMIPB-B

Adult Memory and Information Processing Battery-B form

CB1

cannabinoid type 1

CB2

cannabinoid type 2

DSM-IV-TR

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revised

EHI

Edinburgh Handedness Inventory

FTT

Finger-Tapping Test

MOCA

Montreal Cognitive Assessment

SC

synthetic cannabinoid

WHO

World Health Organization

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Cite this article as: Umut G, Evren C, Atagun MI, Hisim O, Yilmaz Cengel H, Bozkurt M, Keskinkilic C (2020) Impact of at least 2 years of synthetic cannabinoid use on cognitive and psychomotor functions among treatment-seeking male outpatients, Cannabis and Cannabinoid Research 5:2, 164–171, DOI: 10.1089/can.2019.0017.