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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 2  |  Page : 587-592

Correlation between brain-derived neurotrophic factor and executive function in cannabinoid addiction


1 Department of Neuropsychiatry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Neuropsychiatry, Ministry of Health, Kafr Elsheikh General Hospital, Kafr Elsheikh Governorate, Egypt

Date of Submission14-Sep-2019
Date of Decision02-Oct-2019
Date of Acceptance07-Oct-2019
Date of Web Publication30-Jun-2021

Correspondence Address:
Shereen M Ibrahim
Department of Neuropsychiatry, Ministry of Health, Kafr Elsheikh General Hospital, Kafr Elsheikh Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_294_19

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  Abstract 


Objectives
To measure relation between brain-derived neurotrophic factor (BDNF) and executive function in cannabinoid addiction.
Background
In the United States, marijuana (Cannabis sativa) was the most commonly used illicit substance, the use of which usually started in the adolescence period.
Patients and methods
A case–controlled study was conducted on 40 addicts and 40 healthy individuals from 18 to 60 years who were recruited from both community (street) and hospital-based sampling in three Egyptian governorates from the October 1, 2017 to the end of March 2018. The control group comprised 40 healthy individuals who were selected after being age and sex matched with addicts. Patients were subjected to proper history taking, general medical and neurological examination to exclude medical and neurological complications, detection of severity of addiction according to addiction severity index, level of serum BDNF in both groups, and also executive function in both groups before and after treatment.
Results
There was no significant difference between cases and control regarding their age (P = 0.338). A total of 16 (40%) male addict patients were studied and 24 (60%) female addict patients. There was no significant difference between cases and controls regarding their sex (P = 0.644). The addict patients' BDNF 1 mean value was 231.12 ± 286.86 s, whereas BDNF 2 was 248.91 ± 55.01 s. There was a highly significant difference between cases and controls regarding their BDNF 1 and BDNF 2 (P < 0.001 and 0.007, respectively). There was a highly significant difference between cases and controls regarding their executive function 1 and executive function 2 (P < 0.001 for both).
Conclusion
Cannabinoid drugs are associated with impairment in executive function regardless of the level of BDNF.

Keywords: addiction, cannabis, Egyptian, marijuana


How to cite this article:
Elhamrawy LG, Hamoudah MA, Ibrahim SM. Correlation between brain-derived neurotrophic factor and executive function in cannabinoid addiction. Menoufia Med J 2021;34:587-92

How to cite this URL:
Elhamrawy LG, Hamoudah MA, Ibrahim SM. Correlation between brain-derived neurotrophic factor and executive function in cannabinoid addiction. Menoufia Med J [serial online] 2021 [cited 2022 Nov 29];34:587-92. Available from: http://www.mmj.eg.net/text.asp?2021/34/2/587/319688




  Introduction Top


Drug addiction is a worldwide common disorder. Problems of substance abuse lead to dramatic costs to all societies in terms of low productivity, transmission of infectious diseases, family and social troubles, as well as crimes.

Addiction process usually starts by social substance taking in most cases, which become aggravated to compulsive and then complete dependence, followed by withdrawal [1].

Cannabis use was associated with impaired cognitive functions affecting motor coordination; complex executive function such as the ability to plan, solve problems, organize, decision making ability, and remember ability, and emotions and behavior control [2]. Brain-derived neurotrophic factor (BDNF) is known to modulate neuroplasticity and adaptive processes underlying learning and memory. BDNF binds to TrkB receptors, which are transactivated by endocannabinoids. Furthermore, cannabinoids may alter BDNF expression via actions on the extracellular signal-regulated kinase signaling pathway. Accordingly, the acute and chronic exposure to cannabinoids would alter serum BDNF levels in humans, and light users of cannabis had lower basal BDNF levels [3].

We conducted this study to measure relation between executive function and BDNF in a sample of Egyptian people.


  Patients and methods Top


A case–control study was conducted on 40 addict individuals from 18 to 60 years recruited from both community (street) and hospital-based sampling in three Egyptian governorates from the October 1, 2017 to the end of March 2018. The control group comprised 40 healthy individuals who were selected after being age and sex matched with the addicts. The patients were diagnosed with cannabinoid use disorder according to Diagnostic and statistical manual of mental disorders, 5th ed., criteria [4] with history of abused cannabinoids for at least 6 months and naïve detoxification. Inclusion criteria included patients fulfilling the criteria of dependence according to Diagnostic and statistical manual of mental disorders, 5th ed.

  1. Persons who abused cannabinoids for at least 6 months.
  2. Persons aged from 18 to 60 years.
  3. Persons with naïve detoxification.
  4. Patients fulfilling the criteria which were developed by the American Society of Addiction Medicine to be considered in the treatment of dependence, which is as follows:


    1. Patients with acute intoxication and/or withdrawal potential.
    2. Patients with biomedical conditions and complications.
    3. Patients with emotional, behavioral, or cognitive conditions and complications.
    4. Patients ready to change.
    5. Relapse, continued use, or continued problem potential. (f) Recovery/living environment.


The exclusion criteria included the patients experiencing any general medical diseases not related to addiction and patients experiencing any neurological diseases not related to addiction. Patients were subjected to proper history taking, general medical and neurological examination to exclude medical and neurological complications, and detection of severity of addiction according to addiction severity index [5].

Blood BDNF sample was collected from both groups before the start of treatment. It was named BDNF 1 before treatment and then BDNF 2 after 6 months of treatment. During the 6 months, the patient group was divided into three groups. The first group comprised 14 patients and received acetylcysteine 1200 mg twice per day through 6 weeks, the second group comprised 13 patients and received gabapentin 400 mg started gradually up to 1200 mg per day through 6 weeks, and the third group number comprised 13 individuals and received baclofen 15 mg starts 15 mg twice per day for 2 weeks then 15 mg three times per day through 6 weeks, to study the effect of this medicine on relapse rate. During the 6-month treatment, eight patients relapsed and did not complete their treatment. Both groups used executive function questionnaire before treatment and again after 6 months of treatment. The control group is a group of healthy people who were not subjected to any psychological or physical stress at that time.

Statistical analysis

Data were fed to the computer and analyzed using IBM SPSS software package, version 20.0. (IBM Corp., Armonk, New York, USA).

Randomized control trail sample size was calculated using open Epiinfo two-sided confidence level 95%. Power of the study was 90. Ratio of exposed to unexposed was 1: 1. Percent of exposed with outcome was 55.1%. Percent of unexposed with outcome was 20%.

Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, SD, and median. The used tests were c2 test for categorical variables, to compare between different groups and Student t test for normally distributed quantitative variables to compare between two studied groups. Significance of the obtained results was judged at the 5% level. P value was significant if less than 0.05.

Ethical consideration: the study was conducted after obtaining approval of the ethics committee of the Faculty of Medicine and of the ethics committee of Menoufia University Hospital. An informed consent was signed by all studied cases.

All studied cases consented to participate in the study.


  Results Top


The addict patients' age ranged from 18.0 to 45.0 years (mean age, 29.03 ± 7.66 years). The controls' age ranged from 19.0 to 55.0 years (mean age, 30.95 ± 10.03 years). There was no significant difference between cases and controls (P = 0.338). A total of 16 (40%) male addict patients were studied and 24 (60%) female addict patients, in comparison with 14 (35%) normal male controls and 26 (65%) normal female controls. There was no significant difference between cases and controls regarding their sex (P = 0.644) [Table 1].
Table 1: Comparison between the two studied groups according to demographic data

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Twenty (62.5%) patients had duration of addiction less than or equal to 10 years and 12 (37.5%) had duration of addiction more than or equal to 10 years. The range of addiction duration was 2.0–22.0 years (mean duration, 9.50 ± 6.02 years). One (2.5%) patients had mild degree, 15 (37.5%) had moderate, and 24 (60%) had severe degree [Table 2].
Table 2: Distribution of the studied cases according to addiction severity index and duration of addiction in patients group (n=60)

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The addict patients' BDNF 1 ranged from 124.40 to 1985.0 (mean, 231.12 ± 286.86 s), whereas BDNF 2 ranged from 31.01 to 335.10 (mean, 248.91 ± 55.01). The control BDNF 1 ranged from 255.10 to 2858.10 (mean, 409.59 ± 568.98), whereas BDNF 2 ranged from 31.01 to 335.10 (mean, 281.28 ± 10.79). There was a highly significant difference between cases and controls regarding their BDNF 1 and BDNF 2 (P < 0.001 and 0.007, respectively) [Table 3].
Table 3: Comparison between the two studied groups according to brain-derived neurotrophic factor

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Regarding executive function 1 in addict group, 11 (27.5%) had attention deficit, 10 (25%) had working memory deficit, eight (20%) had emotional deregulation, six (15%) had making of decision deficit, and five (12.5%) had verbal fluency deficit. In control group, 24 (60%) had attention deficit and 16 (40%) had working memory deficit. Regarding executive function 2 in addict group, the executive function was resolved in 18 (54.5%) and worsened in 15 (45.5%). In control group, 24 (60%) of them were normal and 16 (40%) had attention deficit. There was a highly significant difference between cases and controls regarding their executive function 1 and executive function 2 (P < 0.001 for both) [Table 4].
Table 4: Comparison between the two studied groups according to executive function

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  Discussion Top


Cannabis use is frequently associated with negative long-term outcomes especially in adolescence as reduced intelligence quotient (IQ) and working memory and increased risk for schizophrenia [6]. In Egypt, the cannabis was on the top list of the addiction substances according to statistics of Fund for Drug Control and Treatment of Addiction. Half of the 129 850 cases who attending the drug rehabilitation were addicted to cannabis. The majority of them were between 15 and 25 years of age. In agreement with our study, among the 100 patients who were included in the study by Taha et al. [7], the patients' age ranged from 18 to 55 years with mean value of 28.8 ± 8.3, and the majority (64) were male patients versus 36 females [7].

In this study, there was no significant difference between cases and control. The addict patients' mean age was 29.03 ± 7.66 years, which was slightly lower than mean age of the controls (30.95 ± 10.03 years). However, Miguez et al. [8] found that on average cannabis users were slightly older than noncannabis users [8].

Moreover, the same was proved by the observation recorded by an Egyptian community-based study conducted in Egypt by Hamdi et al. [9]. They found the adult age category was the more presented group among drug abusers, and 67.5% of the whole sample comprised males. This may be explained by the upper hand of males in Arabian countries where they can go to the work and earn money more than females, and this allow them to easily buy the drugs [9].

Against our results, a higher age was reported in study by Elfving et al. [10], which was 46.5 ± 9.6 versus 45.7 ± 10.4 years in the control group, and the majority of case group was females (135) versus 27 males [10].

Moreover, Mageid [11] found there was a significant difference in mean age between addict and healthy individuals (P = 0.003), as they found the control group members were older (36.52 ± 9.4) than cases (42.45 ± 16.3), and they reported that most cannabis consumers (47.16%) were 25 to less than 35 years. In contrast to our study, Mageid [11] noticed that males were significantly higher than females in both groups (86.5% in cases and 68.1% of the control group, P < 0.001).

In addition, a previous study on drivers reported that most of cannabis user were in the younger age group, ranging from 18 to 25 years old [12], and the same was observed in an American study where the rates of marijuana use was ~30% among young adult age group [13]. This discrepancy between the results may be explained by the difference in cultural environment, as some countries have wide availability of the drug in the younger age environment.

We found no significant difference between cases and controls regarding sex. Men are more likely to be coerced into treatment [14]. Several studies have shown that interpersonal relationships may have contradictory effects for women who are addicts as they may be either the source of support or the contributor to ongoing addict and possibly increased the incidence of relapse [15]. Women with cannabis use problems are less likely than men to participate in the treatment program over the lifetime [16]. Few studies have noted specific sex differences. A notable exception is the study by Hanninen and Koski-Jannes [17], which identified five stories among those recovering from addiction: the alcoholics anonymous story, the love story, the growth story, the codependence story, and the mastery story. The authors reported sex differences among the stories, as the alcoholics anonymous story was commonly used by men, whereas women commonly preferred the growth story.

There was a highly significant difference between cases and controls regarding their executive function 1 and executive function 2 (P < 0.001 for both). Regarding executive function 1 in the addict group, 11 (27.5%) had attention deficit, 10 (25%) had working memory deficit, eight (20%) had emotional dysregulation, six (15%) had making of decision deficit, and five (12.5%) had verbal fluency deficit, whereas in control group, 24 (60%) had attention deficit and 16 (40%) had working memory. Regarding executive function 2 in the addict group, the executive function was resolved in 18 (54.5%) and worsen in 15 (45.5%), whereas in the control group, 24 (60%) of them were normal and 16 (40%) had attention deficit.

In agreement with our study was the study by Schoeler and Bhattacharyya [18]. Many studies in humans have shown that chronic cannabis consumption, especially when initiated early in life, correlates with a range of cognitive impairments in adulthood, including learning and memory deficits. Meanwhile, the evidence remained equivocal, partly owing to the myriad of confounding factors, characteristic of human studies, as well as different methodology employed by the distinct studies, some unveiling clear effects, whereas others found marginal or no effects [18]. Our results were supported by Arguello and Jentsch [19], who reported that the cannabinoids agonist induced deficits in attention measured on the executive task. In addition, treatment with antagonist reversed the induced attention impairment, although, when administered alone, this compound did not produce any effects on attention [19]. Chronic heavy marijuana use is also associated with impairments in verbal fluency, learning and memory, sustained attention, and executive functioning [20].

In contrast to these studies, Bolla KI et al. [20] reported minimal or no lasting effects of chronic cannabis use on overall IQ, attention, working memory, and abstract reasoning [20]. Fried et al. [21], prominently, noted that cannabis-induced cognitive impairments may be dependent on the age of onset of cannabis use; in particular, those starting before the age of 17 years have greater impairment. Thus, age of onset and other baseline variables, like IQ, may explain the conflicting findings regarding long-term marijuana use on cognitive outcomes [21].

There was a highly significant difference between cases and controls regarding their BDNF 1 and BDNF 2 (P < 0.001 and 0.007, respectively). The addict patients' BDNF 1 mean value was 231.12 ± 286.86 s and BDNF 2 mean value was 248.91 ± 55.01, which was lower than the controls' BDNF 1 mean value (409.59 ± 568.98) and BDNF 2 mean value (281.28 ± 10.79). In agreement with our study, D'Souza et al. [3] found the light users of cannabis had lower basal BDNF levels than healthy controls. In the study by Lisano et al. [22], BDNF was significantly lower in cannabis users compared with nonusers (P = 0.02), and BDNF was significantly lower in physically active cannabis users compared to nonusers [22]. In contrast to our study, according to Miguez et al. [23], high BDNF levels were evident among marijuana users compared with nonusers (3731.1 ± 903.4 vs. 2046.2 ± 262.5, P = 0.02).

In contrast to our study, Luan et al. [24] found serum BDNF levels were markedly higher in patients than in controls (1692.94±707.71 vs. 1194.46±230.98 pg/ml, P<0.001).

Angelucci et al. [25], in their study, measured the serum NGF and BDNF levels using enzyme-linked immunosorbent assay in two groups of patients: cannabis-dependent patients and healthy participants. We found that NGF serum levels were significantly reduced in cannabis abusers as compared with healthy participants. However, serum BDNF was higher in patients than controls (5984.23±335.9 vs. 5683.62±237.65 pg/ml, P = 0.499) [25].

Addiction is associated with alteration in endogenous BDNF, according to Barker et al. [26]. Many abused drugs lead to changes in endogenous BDNF expression in neural circuits responsible for addictive behaviors. BDNF is a known molecular mediator of memory consolidation processes, evident at both behavioral and neurophysiological levels. Specific neural circuits are responsible for storing and executing drug-procuring motor programs, whereas other neural circuits are responsible for the active suppression of these 'seeking' systems. These seeking circuits are established as associations are formed between drug-associated cues and the conditioned responses they elicit. Such conditioned responses (e.g. drug seeking) can be diminished either through a passive weakening of seeking circuits or an active suppression of those circuits through extinction [26].

The explanation for these results may be as follows: self-report data have been identified as a valid method for assessing historical patterns of substance use, which is a concern, as in the interview settings, participants may underreport behaviors; the small sample size is a limitation; and also BDNF levels were measured in plasma and not in the CNS. However, in both humans and animals, peripheral levels highly correlated with changes observed in the brain, which may be the main reason that the results were negative. Moreover, a possible disadvantage of measuring BDNF in serum may be a decline in BDNF levels after long-term storage of serum, which may not occur for BDNF stored in platelets. In addition, psychological factors such as social environment stress could also affect the determination of BDNF levels and cognitive functions must be explored. Moreover, BDNF regulates drug-induced behavior in a very complex manner that varies from one brain region to another, which needs more deep technology of brain imaging that we could not achieve. In the future, we will explore this field as much as possible. Although self-report data have been identified as a valid method for assessing historical patterns of substance use, it is also a concern that in interview settings participants may underreport behaviors.

Recommendation

We recommended larger and in-depth studies with special concern on social and cultural factors and to focus on examining risk factors for infectious complications associated with drug use. Moreover, we need more studies to investigate the behavioral and mood changes before and after the onset of cannabis use to determine whether variations in behavior and mood are either risk factors or consequence of cannabis addiction. Moreover, we needed to evaluate the effects of different content of cannabis on long-term changes. Meanwhile, increased BDNF may not be associated with attention deficit, working memory, emotional regulation, making of decision deficit, and verbal fluency. In addition, psychological factors such as social environment stress could also affect the determination of BDNF levels and cognitive function must explore.

Moreover, BDNF regulates drug-induced behavior in a very complex manner that varies from one brain region to another, which needs more deep technology of brain imaging that we could not achieve. In the future, we will explore this field as much as possible.


  Conclusion Top


We concluded that, the cannabinoid drugs have become increasingly popular despite the potential harms associated with their use. Taking together the recent finding of both animal and human studies, repeated consumption of cannabinoids is associated with EF impairments. Yet, there is still a gap of knowledge regarding the last of these impairments. Our data suggest that cannabis involve and affect cognitive functions, in EF specifically. Meanwhile, increased BDNF may not be associated with attention deficit, working memory, emotional regulation, making of decision deficit, and verbal fluency. Further study is necessary to elucidate the role of central BDNF in cannabis addiction and cognitive function. We will focus the future research on fundamental experiment study and translational research from basic to clinical. A series of complicated mechanism from cell and molecular level to protein expression of BDNF are not clear. To deeply understand the role of BDNF in addiction, we need to embark on mechanism research from genetics, molecule, and cell to entirety and association research from endophenotype to phenotypes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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