Fibroblast Growth Factor-2 (FGF-2) and Fibroblast Growth Factor-9 (FGF-9) Levels in Patients With Opioid Use Disorder in Remission: Implications for Neuroplasticity

Abstract

Fibroblast growth factors are a family of proteins that have recently been implicated in neuroplasticity, and their association with psychiatric disorders has attracted growing interest. We aimed to compare Fibroblast Growth Factor-2 (FGF-2) and FGF-9 levels in opioid use disorder (OUD) patients in remission with healthy controls. This cross-sectional study included 45 patients with OUD in remission receiving buprenorphine/naloxone (B/N) maintenance therapy and 45 healthy controls. Peripheral blood samples were collected from all participants. FGF-2 and FGF-9 serum levels were similar in the OUD group and healthy controls (p = 0.665, p = 0.090, respectively). A positive correlation was also found between FGF-2 and FGF-9 (r = 0.496, p = 0.001). Neuroplasticity in OUD patients in remission receiving B/N treatment appears to be comparable to that of healthy controls. These findings underscore the importance of long-term treatment strategies in OUD.

Keywords

fibroblast growth factor FGF-2 FGF-9 opioid use disorder substance use disorder

Introduction

Substance use disorder (SUD) is a significant public health problem that is rapidly increasing worldwide. According to the United Nations 2025 World Drug Report, 316 million people (excluding alcohol and tobacco) reported using drugs in 2023, representing 6% of the population aged 15-64. Cannabis remains the most commonly used drug, with 244 million users. This is followed by opioids with 61 million users, amphetamines with 30.7 million users, cocaine with 25 million users, and ecstasy with 21 million users. This period of global instability has been described in the report as marking one of the highest levels of drug use in history. Opioids, the second most commonly used substances after cannabis, continue to represent a major global concern (United Nations Office on Drugs and Crime, 2025). Opioid-related deaths in the United States have been increasing rapidly in recent years, with approximately 100,000 people dying each year from opioid overdoses (Spencer et al., 2024). Opioid use is a significant problem in our country, and almost half of patients receiving addiction treatment seek treatment for opioid use disorder (OUD) (Erdoğan et al., 2022).

OUD is a chronic disorder associated with structural and functional changes in the brain. Neuroimaging studies show significant reductions in gray matter volume and cortical thickness in OUD patients compared to healthy controls, particularly in the prefrontal and temporal cortices. These findings suggest that OUD has a detrimental effect on neuroplasticity (Li et al., 2014; Wollman et al., 2017). Neuroplasticity is also regulated by various proteins collectively known as neurotrophins. Among them, fibroblast growth factors (FGFs) constitute a large family of polypeptides. In adults, FGFs play essential homeostatic roles in tissue repair and cell proliferation. FGF-2, one of the most prominent neurotrophins, is abundantly expressed in the central nervous system and has critical functions in early brain development, neuroprotection, adult neurogenesis, and neuroplasticity. Another key member of this family, FGF-9, is highly expressed in regions such as the cortex, hippocampus, cerebellum, and thalamus, where it contributes to neuronal development and glial cell maturation (Reuss & von Bohlen und Halbach, 2003; Kanda et al., 2000).

In recent years, the role of the FGF system in brain-related disorders has attracted great interest (Turner et al., 2016). In particular, several studies have demonstrated associations between FGF-2 and FGF-9 and psychiatric disorders such as depression and schizophrenia (Li et al., 2022; Wang et al., 2023). However, research exploring this issue within the field of addiction is still insufficient. One review reported that FGF-2 acts as a positive regulator of alcohol- and drug-related behaviors, suggesting that reducing FGF-2 activity may represent a potential treatment strategy for SUD. Nevertheless, most of the studies included in this review were conducted in animal models (Even-Chen & Barak, 2019). No studies on FGF-9 and addiction have been found in the literature. Neuroplastic changes are also reported with treatment in psychiatric disorders. Studies have shown changes in FGF-2 and FGF-9 levels with treatment in patients with depression (Elsayed et al., 2012; Xia et al., 2021).

Despite growing interest in the fibroblast growth factor family, to our knowledge no studies have investigated FGF-2 and FGF-9 levels in patients with OUD. The aim of this study was to investigate and compare serum FGF-2 and FGF-9 levels in patients with OUD in remission and healthy controls, in order to better understand their potential role in neuroplasticity.

Method

Sample

Our study is a cross-sectional case-control study. To determine the sample size, power analysis was conducted using G*Power 3.1.9.4 software using data from the reference study (Li et al., 2022). Assuming a medium-to-high effect size (d = 0.60), a 5% significance level (α = 0.05), and 80% statistical power (1–β = 0.80), a total of 90 participants were required, with a minimum of 45 participants per group. This study was conducted at the Akdeniz University Alcohol and Substance Addiction Research and Treatment Center (AMBAUM). Forty-five patients diagnosed with OUD according to DSM-5 diagnostic criteria and 45 age- and sex-matched healthy controls were included in the study.

Inclusion criteria for the OUD group:

- Meeting the diagnostic criteria for OUD according to DSM-5

- Being between 18 and 65 years of age

- Being in remission for at least one month under buprenorphine/naloxone (B/N) treatment

Exclusion criteria for the OUD group:

- Presence of psychiatric comorbidity (e.g., psychotic disorders, bipolar disorder, schizoaffective disorder, alcohol use disorder)

- Presence of a significant physical illness

- History of neurological disease

- Pregnancy or breastfeeding in female patients

- Diagnosis of intellectual disability

Inclusion criteria for the healthy control group:

- Being 18–65 years of age

- No current or past psychiatric disorder or major physical illness

- No history of alcohol or substance use

Procedure

Written informed consent was obtained from participants who volunteered to participate in the study. All participants were assessed using the Structured Clinical Interview Form for DSM-5 (SCID-5-CV) (First, 2014). A sociodemographic data form and the Substance Craving Scale (SCS) (Evren et al., 2011) were administered. Biochemical analyses were carried out at the Medical Biochemistry Unit of the Central Laboratory, XXXXXXX University Hospital.

Blood Sample Collection

Ten mL of venous blood was collected from the subjects in the morning after at least 8-12 hours of fasting. Following clotting, the blood samples were centrifuged at 4000 rpm for 10 minutes at 4°C within 1 hour, to separate the serum. The separated sera were transferred to Eppendorf tubes and stored at −80°C until analysis. On the day of analysis, the serum samples were thawed at room temperature and vortexed prior to analysis using the ELISA method.

FGF-2 and FGF-9 Analyses

Serum FGF-2 and FGF-9 levels were measured using the ELISA method. For FGF-2, an ELK Biotechnology kit (Cat. No: ELK1258) with a sensitivity of 5.16 pg/mL and a measurement range of 15.63–1000 pg/mL was used. For FGF-9, an ELK Biotechnology kit (Cat. No: ELK1418) with a sensitivity of 5.5 pg/mL and a measurement range of 15.63–1000 pg/mL was used. Both assays were performed using the sandwich ELISA technique, and similar procedural steps were applied for each parameter. During the analysis, 96-well microplates pre-coated with antibodies specific for FGF-2 and FGF-9 were used. Standards and serum samples, prepared according to the manufacturer’s instructions, were added to the wells. The plates were incubated for 80 minutes at 37°C to allow binding of the analytes to the antibodies. Following incubation, unbound components were removed by washing. In the next step, biotin-labeled secondary antibodies were added to the wells and incubated for 50 minutes at 37°C, followed by a washing step. Subsequently, streptavidin–horseradish peroxidase (HRP) conjugate was added and incubated for another 50 minutes at 37°C. After washing to remove unbound enzyme, substrate solution was added. Following a 20-min incubation at 37°C, the color intensity was measured at 450 nm using a BIO-TEK ELx800 microplate reader. Serum FGF-2 and FGF-9 concentrations (pg/mL) were calculated from a standard curve generated by plotting absorbance values against known standard concentrations.

Research Ethics

Ethical approval for the study was obtained from the Clinical Research Ethics Committee of the XXXXXXX University Faculty of Medicine on April 24, 2025 (decision no: TBAEK-389). Written informed consent was obtained from all participants. The study was conducted in accordance with the Declaration of Helsinki.

Statistical Analysis

Analyses were conducted using IBM SPSS (Statistical Package for Social Sciences) version 23.0 (IBM Corporation, Armonk, NY, USA). Continuous variables are presented as mean ± standard deviation, median (Q1-Q3) and Mean Rank, while categorical data are presented as numbers and percentages. The Kolmogorov-Smirnov Goodness of Fit Test was used for normality analyses of continuous variables. The Mann Whitney U Test was used in the analysis of data that did not conform to a normal distribution. The Chi-square Test was used for comparison of categorical data. Spearman Correlation Analysis was used in correlation analyses. Statistical significance was accepted as p < 0.05.

Results

The mean age of OUD patients was 34.73 ± 7.27 years, while the mean age of healthy controls was 34.71 ± 10.62 years (p = 0.991). Other sociodemographic data are summarized in Table 1.

Table 1.

Comparison of Sociodemographic Characteristics Between the Opioid Use Disorder Group and the Healthy Control Group

		Opioid use disorder (n = 45)		Healthy control (n = 45)		p
		n	%	n	%	p
Gender	Male	40	88.9	40	88.9	1.000
Gender	Female	5	11.1	5	11.1	1.000
Marital status	Single	22	48.9	24	53.3	0.384
	Married	19	42.2	20	44.4
	Divorced	4	8.9	1	2.2
Education	Primary Education	25	55.5	3	6.7	<0.001
	High School	15	33.3	7	16.6
	University	5	11.1	35	77.8
Forensic history	Yes	20	44.4	0	0.0	<0.001
Forensic history	No	25	55.6	45	100.0	<0.001
History of imprisonment	Yes	10	22.2	0	0.0	<0.001
History of imprisonment	No	35	77.8	45	100.0	<0.001
History of suicide attempt	Yes	4	8.9	0	0.0	<0.001
History of suicide attempt	No	41	91.1	45	100.0	<0.001
Self-mutilation	Yes	5	11.1	0	0.0	<0.001
Self-mutilation	No	40	89.9	45	100.0	<0.001
Smoking	Yes	45	100.0	12	26.7	<0.001
Smoking	No	0	0.0	33	73.3	<0.001
Family history of substance use	Yes	5	11.1	0	0.0	<0.001
Family history of substance use	No	40	89.9	45	100.0	<0.001
Age (median) (Q1-Q3)		34.00 (29.50-39.50)		30.00 (27.00-41.00)		0.431

When the clinical characteristics of OUD patients were examined, the rate of patients using other substances in addition to opioids (polysubstance use) was found to be 60%. Intravenous use was identified in 15.6% of patients, with cannabis being the most frequently used additional substance (37.8%). The median SCS (Q1-Q3) score was 1.00 (0.00-7.00), the median total duration of opioid use (Q1-Q3) was 7.00 (3.00-10.00) years, the median remission duration (Q1-Q3) was 24.00 (12.00-72.00) months, and the median B/N (Q1-Q3) dose was 8.00 (8.00-14.00) mg/day.

Comparison of FGF-2 and FGF-9 levels between OUD patients and healthy controls is summarized in Table 2.

Table 2.

Comparison of FGF-2 and FGF-9 Levels Between the Opioid Use Disorder Group and Healthy Controls

	Opioid use disorder (n = 45)	Healthy control (n = 45)	p
FGF-2* (median) (Q1-Q3) Mean Rank	46.36 (22.22-60.76) 46.69	43.15 (19.39-64.24) 44.31	0.665
FGF-9* (median) (Q1-Q3) Mean Rank	93.00 (15.81-157.32) 40.86	177.28 (19.84-217.50) 50.14	0.090

*FGF-2: Fibroblast Growth Factor-2, FGF-9: Fibroblast Growth Factor-9.

Correlation analyses were performed in the OUD group. As remission duration increased, SCS scores decreased (r = −0.386, p = 0.009). There was a positive correlation between FGF-2 and FGF-9 (r = 0.496, p = 0.001). No correlation was found between remission duration and FGF-2 and FGF-9 levels, between SCS scores and FGF-2 and FGF-9 levels, or between B/N dose and FGF-2 and FGF-9 levels (p > 0.05 for all).

FGF-2 and FGF-9 levels were found to be similar in groups with and without a history of polysubstance use (p = 0.584, p = 0.762). FGF-2 and FGF-9 levels were found to be similar in groups with and without a history of intravenous use (p = 0.257, p = 0.313).

Discussion

In our study, FGF-2 and FGF-9 levels were found to be similar in OUD patients in remission and healthy controls. In the OUD group, a positive correlation was found between FGF-2 and FGF-9 levels, and a negative correlation was found between remission duration and SCS scores. No correlation was found between B/N dose and FGF-2 and FGF-9 levels.

The concept of neuroplasticity has attracted considerable attention in psychiatry in recent years. Broadly, neuroplasticity refers to the capacity of the nervous system to adapt to internal and external stimuli and to respond adaptively to future challenges. Although the processes of neuroplasticity are complex and not yet fully elucidated, it is widely recognized that they involve both morphological and functional adaptations (Wolpaw, 2012; Liu et al., 2017). The role of the FGF system in neuropsychiatric disorders has attracted considerable attention in recent years. To clarify its involvement in neurological and psychiatric conditions, it is essential to identify which FGF family members are implicated, their sites of expression, and the mechanisms regulating their activity. Each disorder appears to affect distinct molecular pathways in specific anatomical regions, and these may represent potential therapeutic targets (Turner et al., 2016). FGF-2 and FGF-9 can be considered as two important members of the FGF family that are thought to be associated with neuroplasticity (Reuss & von Bohlen und Halbach, 2003; Kanda et al., 2000). Significant alterations in serum levels of growth factors, including fibroblast growth factors, have been reported in psychiatric disorders (Galvez-Contreras et al., 2016). In a study comparing 70 patients with bipolar disorder manic episode who were not receiving treatment and 50 healthy controls, FGF-2 serum levels were found to be significantly higher in patients than in healthy controls. It has been proposed that this elevation may be attributable to compensatory processes, including neuroprotection and angiogenesis (Liu et al., 2014). In a meta-analysis of eight studies including 310 patients with depression and 268 healthy controls, FGF-2 levels were compared between the two groups. Random-effects meta-analysis showed no difference in peripheral blood FGF-2 levels between patients with depression and healthy controls. However, high heterogeneity in the results was reported (Wang et al., 2023). In a study including 40 patients with schizophrenia and 40 healthy controls, serum FGF-2 levels were significantly lower in patients with schizophrenia compared to controls. A positive correlation was reported between serum FGF-2 levels and disease severity in schizophrenia patients (Shamseldin et al., 2025). One review suggested that FGF-2 functions as a common sensitivity gene for nicotine, amphetamine, cocaine, and alcohol. Short-term exposure to addictive substances was associated with generalized increases in FGF-2 expression, whereas longer-term exposure produced more region- and substance-specific effects, including downregulation in certain brain areas. However, these findings are derived exclusively from animal studies and lack direct human evidence (Even-Chen & Barak, 2019). This study demonstrated that FGF-2 and FGF-9 levels in remitted OUD patients under B/N maintenance therapy did not differ from those of healthy controls. Given the absence of prior research on this topic, our results may be considered in light of findings from other psychiatric disorders. For example, a study of 130 patients with schizophrenia and 111 healthy controls reported significantly reduced serum FGF-9 levels in first-episode, medication-free patients, but not in chronically medicated patients. Further analyses showed that treatment of first-episode, medication-free patients with antipsychotics for eight weeks significantly increased serum FGF-9 levels. FGF-9 showed good performance in differentiating between medication-naïve schizophrenia patients and those receiving chronic medication (Li et al., 2022). In our study, the similarity of FGF-2 and FGF-9 levels between treated patients and healthy controls provides valuable insight into the potential effects of treatment on neuroplasticity in this population. However, the absence of data on FGF-2 and FGF-9 levels in actively using opioid patients limits the interpretation of our findings.

Another important finding of our study is that craving scores decreased significantly as remission duration increased. This finding suggests that long-term treatment may have a significant impact on craving in individuals with OUD. Similarly, the literature reports a decrease in craving in later stages of remission (Balcı et al., 2022; Kakko et al., 2019). This result suggests that increasing the duration of treatment may reduce cravings and, consequently, relapses in patients. Therefore, we believe that B/N treatment should be continued for as long as possible in the OUD patient group.

This study has several limitations that should be considered when interpreting the findings. First, the cross-sectional design limits the ability to draw causal inferences regarding the relationship between FGF-2 and FGF-9 levels and opioid use disorder. Therefore, the findings should be interpreted with caution, particularly in relation to treatment and remission processes. Second, the absence of a comparison group consisting of individuals with active opioid use is another limitation. Without such a group, it is difficult to evaluate whether FGF-2 and FGF-9 levels differ across different stages of the disorder (i.e., active use vs. remission), which may limit the interpretation of the potential impact of remission and treatment on these biomarkers.

Despite these limitations, our study has several notable strengths. To the best of our knowledge, this is the first study to investigate FGF-2 and FGF-9 levels in patients with substance use disorders. In addition, the inclusion of a well-defined and relatively homogeneous patient group and the presence of a healthy control group strengthen the comparability of the findings. Furthermore, the study simultaneously evaluated both growth factors and examined their relationships with relevant clinical variables, providing a more comprehensive understanding of their potential role in OUD.

Conclusion

In conclusion, it can be said that FGF-2 and FGF-9 levels in OUD patients in remission with B/N are similar to those in healthy controls. It can be argued that FGF-2 and FGF-9 levels in OUD patients are not related to B/N dose, but there are positive correlations between FGF-2 and FGF-9 levels. Furthermore, it can be said that craving levels decrease as the duration of remission in OUD patients increases. Considering the gap in the literature, it is evident that numerous prospective studies, each evaluating individual substances separately, are needed to clarify the importance of fibroblast growth factors in the field of addiction.

Footnotes

Acknowledgments

We would like to thank the staff of the Akdeniz University Alcohol and Substance Addiction Research and Treatment Center (AMBAUM) for their support during the conduct of this study.

ORCID iDs

Betül Keskin

Burçin Özkaya

Ali Erdoğan

Mustafa Nogay Coşkun

Sercan Karabulut

Ethical Considerations

Ethical approval for the study was obtained from the Clinical Research Ethics Committee of the Akdeniz University Faculty of Medicine (Decision No: TBAEK-389, dated 24.04.2025). Written informed consent forms were obtained from all participants. Our study was conducted in accordance with the Helsinki Declaration.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.*

Declaration of Generative AI in Scientific Writing

Generative AI and AI-assisted Technologies (GPT-5) were used solely for the purpose of improving the clarity, readability, and linguistic quality of the English translation. No AI tools were used for data analysis, interpretation, or content generation.

Author Biographies

Betül Keskin is a research assistant in the Department of Psychiatry at Akdeniz University, with research interests in addiction and clinical psychiatry.

Burçin Özkaya is a research assistant in the Department of Psychiatry at Akdeniz University, focusing on substance use disorders and clinical research.

Ümmü Nur Kaya Tan is a research assistant in the Department of Psychiatry at Akdeniz University, with an interest in psychiatric disorders and neurobiology.

Ali Erdoğan is an associate professor of psychiatry at Akdeniz University, specializing in addiction psychiatry and neurobiological mechanisms of mental disorders.

İkbal Özen Küçükçetin is an assistant professor in the Department of Biochemistry at Akdeniz University, with research interests in molecular biomarkers.

Mustafa Nogay Coşkun is a psychiatrist at Antalya Atatürk State Hospital, working in clinical psychiatry and addiction treatment.

Sercan Karabulut is an associate professor of psychiatry at Akdeniz University, focusing on clinical psychiatry and neuropsychiatric research.

Burak Kulaksızoğlu is an associate professor of psychiatry at Akdeniz University, with interests in mood disorders and psychiatric research.

Buket Cinemre is an associate professor of psychiatry at Akdeniz University, specializing in clinical psychiatry and affective disorders.

Sadıka Halide Akbaş is a professor of biochemistry at Akdeniz University, with expertise in biochemical and molecular research.

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