Structural brain changes in heroin users: a literature review

Introduction

Heroin, also known as diacetylmorphine, is obtained by acetylation of morphine and was first synthesized on a commercial scale in 1898 (Florek and Piekoszewski 2020).
The effects of heroin stem from activating the opioid receptors μ, δ and κ, which are located in the central nervous system, but also in other tissues. Natural ligands for these receptors are endorphin and enkephalin (Piekoszewski and Florek 2020). Heroin, similarly to other opioids, causes analgesia, euphoria, sedation and sleepiness.
Heroin can be typically administered intravenously, intranasally, by vaporization after heating on an aluminum foil (called “chasing the dragon”) or smoked (Adamowicz 2023). Using heroin can lead to addiction and increasing tolerance when the same amount of the drug does not cause the same effect. Withdrawal symptoms include craving for the heroin, but also physical symptoms (Piekoszewski and Florek 2020).
Drug addiction and behavioral changes are commonly known, but structural brain changes in heroin users are still not widely examined. In this paper we found publications in which authors described structural changes in brains of heroin users, mostly gray matter reduction in different parts of the brain, including the nucleus accumbens (NAc) and prefrontal cortex (PFC). The nucleus accumbens (with the pallidum and striatum) is a part of brain reward system that is involved in drug-seeking behaviors. In a study that examined electric stimulation of the nucleus accumbens in heroin addicts, the stimulation of especially the left NAc induced euphoria similar to heroin-induced euphoria (Seifert et al. 2015). The prefrontal cortex (among other regions) has an important role in cognitive control, coordinating thoughts and actions in line with internal objectives (Liu et al. 2009). The ventromedial prefrontal cortex (vmPFC) is considered to be critical for functions such as reward decision-making (Hiser and Koenigs 2018). There are data indicating that reduced gray matter volumes in, for example, the prefrontal cortex are observed in males with substance use disorder (Nowak and Nowak 2023).

Methods

A PubMed search was conducted using the keywords “brain changes heroin” (498 results), “heroin and structural brain damage” (11 results), “heroin nucleus accumbens” (393 results), “heroin PFC” (36 results), “heroin dependence brain structure” (1,008 results) and “heroin and gray matter volume reduction” (3 results); some of the results overlapped. Papers about brain structure changes and substance abuse or opiate dependence without particularly indicated heroin addiction were excluded.

Eligibility criteria

Most of the results did not cover the chosen topic of structural brain changes in heroin addicts, but focused, for example, on functional changes or gene expression levels. From all the results, only 10 papers directly covered the subject, and all of them were analyzed by the authors. For the purpose of this review, 7 papers were selected based on relevance. Publications that were not available in English were excluded.

Results

There are limited papers where the researchers examined structural changes in the brains of heroin addicts. It is particularly difficult to exclude the influence of other substances on structure of the brains when subjects were using or abusing other illicit drugs, alcohol or nicotine. Therefore, confounding factors must be taken into consideration when interpreting the results. Also, it is hard to compare outcomes of respective studies, because almost all of them had different criteria when selecting the groups. Not all papers mention, for example, the duration of use of heroin by the addicts or the dose (groups selected for studies are shown in Table 1).
Liu et al. (2009) examined 15 heroin-dependent people and 15 matched healthy controls. The heroin dependency was confirmed using the Structured Clinical Interview for DSM-IV. Addicted individuals were taking heroin intravenously or inhaling. One of the exclusion criteria for the examination was history of polysubstance abuse, other than nicotine – subjects were smokers, while the healthy controls were non-smokers (comparison of number of cigarettes smoked per day shown in Table 2). When magnetic resonance imaging (MRI) was conducted, the heroin dependents had been receiving methadone maintenance treatment (MMT) for 2-6 days. The study showed reduced gray matter volume (GMV) in the right prefrontal cortex, left supplementary motor cortex, and bilateral cingulate cortex. The authors stated that nicotine use can be a confounding factor when interpreting the results, as existing data show that nicotine-dependent people have lower gray matter density in some brain regions in comparison to non-smokers (Liu et al. 2009).
In other study, Qiu et al. examined 24 heroin-dependent people and 24 matched healthy controls (Qiu et al. 2013). The subjects’ diagnosis of opiate dependence was confirmed using DSM-IV criteria, and it was determined that patients never used other illicit drugs. Both addicted individuals and controls were smokers. During the examination, the heroin dependents were receiving MMT. Conducted MRI showed that heroin dependents have significantly decreased gray matter volume in the bilateral medial prefrontal cortex, bilateral dorsolateral prefrontal cortex, and right fusiform cortex. There were also negative correlations between duration of heroin use and the ratios left medial PFC GMV/total GM volume, right medial PFC GMV/total GM volume, left dorsolateral PFC GMV/total GM volume, and right dorsolateral PFC GMV/total GM volume (Qiu et al. 2013). In this study, in contrast to one previously described, also healthy controls were smokers, and this was also included as a covariate when performing statistical analysis.
Another study focused on duration of heroin use and gray matter density (not GM volume) and was performed by Yuan et al. DSM-IV was used to confirm the diagnosis of opiate dependence of 30 individuals, and they were matched with 34 healthy controls (Yuan et al. 2009). The subjects were smokers, and healthy controls were non-smokers. Other illicit drug use was excluded. Both subjects and healthy controls drank a small amount of alcohol during social occasions. During the research the heroin addicts were receiving treatment for about 5 months, but it was not MMT. The MRI showed that heroin users have significantly decreased gray matter density in the prefrontal, anterior cingulate, and temporal regions as well as the insular, anterior cingulate cortex, and temporal cortex. Duration of heroin use was negatively correlated with gray matter density in most brain areas except the cerebellum and BA13 (insular cortex), but the researchers did not find a correlation between gray matter density and abstinence time (Yuan et al. 2009).
In another study Seifert et al. recruited 30 heroin dependents and 20 healthy controls (Seifert et al. 2015). Opiate dependence was confirmed using DSM-IV criteria. The way of administration included intravenous. 30% of subjects and 25% of controls used cannabinoids, while 53% of subjects and none of the controls used cocaine, but they were instructed not to use illicit drugs for duration of the study. All the participants were smokers. The patients were receiving heroin-assisted treatment for at least 6 months, which means they received prescribed diacetylmorphine or diacetylmorphine with methadone or oral morphine. Analysis of MRI scans showed a significant decrease of the volume of the left nucleus accumbens, but no changes of amygdala volume. Although the authors stated that the FSL-FIRST analysis that was used to obtain the results is statistically weak, according to them, other studies support their results (Seifert et al. 2015).
On the other hand, Müller et al. analyzed the volume of the nucleus accumbens in brains obtained postmortem from heroin addicts who had died of a heroin overdose (Müller et al. 2015). The subject group comprised 14 males, and healthy controls were 12 males who died of causes other than drug overdose. The matching of age and postmortem delay of groups was as close as possible; however, the subjects were younger, and the mean duration of autolysis was longer, and the influence of these factors cannot be completely ruled out. The analysis of the brains showed that the total brain volume was larger in heroin dependents, but the mean volume of the nucleus accumbens was smaller – the left NAc volume was 15% lower in the subject group, and the volume of the right NAc also differed significantly (Müller et al. 2015). The particular limitation of the postmortem study is the lack of data on duration of heroin abuse, taken dose, and way of administration of the drug. Some of the above-mentioned researchers also examined hypothalamus volume in postmortem brains, which led to the conclusion that the hypothalamus volume in heroin addicts is reduced (left side about 20% reduction and right side about 27% reduction) (Müller et al. 2018).
Another study by Ceceli et al. (2023) examined addicts of heroin and cocaine, but in this paper only heroin dependents were taken into consideration. The subject group comprised 32 people compared to 32 healthy controls. All heroin addicts were cigarette smokers. The subjects met the criteria for substance use disorder with heroin, but some of them also for alcohol and other substance use disorders, such as marijuana. Addicts undergoing treatment tested positive for methadone, buprenorphine, or both, in urine toxicology. MRI scan analysis showed significantly lower GMV in the left ventromedial prefrontal cortex and left nucleus accumbens with non-significant differences in the right orbitofrontal cortex and right caudate (Ceceli et al. 2023).

Discussion

Substance abuse is a public health problem (Esteban et al. 2023), and when talking about this topic we should bear in mind that heroin abusers can also be polysubstance abusers. Using illicit drugs as well as alcohol and nicotine can also cause structural brain changes, which probably influences the interpretation of results written above. It is worth noting that out of five analyzed papers that involved living people, only in two of them were both groups – addicts and healthy control – smokers. Studies have shown that smokers have a lower gray matter volume in brain regions such as the right insular cortex, left and right amygdala, and left thalamus. Lowering of the GMV applies to established smokers as well as younger smokers compared to non-smokers (Hanlon et al. 2016). As mentioned above, there is also reduced gray matter density in the left PFC in smokers, which is negatively corelated with pack-years (Zhang et al. 2011). Another important aspect to consider is whether substance use or abuse causes brain morphology changes or people with a particular brain structure are predisposed to start using drugs. For example, Xiang et al. stated that reduced gray matter volume in the left vmPFC was a risk factor for the initiation of smoking in the future (Xiang et al. 2023). Consecutive analysis (longitudinal and Mendelian randomization) suggested that reduced gray matter volume in the left vmPFC is involved in rule-breaking behavior, which may be connected to substance abuse (Xiang et al. 2023)
Alcohol use also can cause brain structure changes. Alcohol dependents showed lower GMV of, for example, the left nucleus accumbens, both amygdalae and both putamina. When examining the non-dependent adults with low-to-moderate alcohol consumption, the studies showed that greater alcohol intake was correlated with smaller volume in, for example, the amygdala, insula and nucleus accumbens (Karoly et al. 2024). Mackey et al. performed a study comparing dependent participants who used one of several substances – alcohol, nicotine, cocaine, methamphetamine, and cannabis – to healthy controls. This comparison showed lower subcortical volume of the right nucleus accumbens, both amygdalae and lower cortical thickness of, for example, the left and right insula and right medial orbitofrontal cortex in dependent individuals (Mackey et al. 2019). It is worth noting that this huge analysis did not involve heroin addicts or opioid addicts in general. As we mentioned above, data for relating brain structure changes to heroin abuse are limited.
When compared to other opioids (not heroin), a study showed reduced volume of the left and right amygdala in opioid-dependent participants compared to controls, without other changes in subcortical structures (Upadhyay et al. 2010). This result shows that examining a particular substance (such as heroin) as opposed to examining the whole group (opioids) is important to learn about the effects of a specific drug.

Conclusions

There is significant gray matter volume reduction in heroin addicts in different brain regions, including the nucleus accumbens, which is part of the reward system. Structural brain changes can be related to changes in behavior in heroin addicts. Duration of heroin use is negatively correlated with gray matter density in most brain parts and the prefrontal cortex GM volume/total GM volume ratio. Different dosage, duration of use, and way of administration of the drug should be taken into consideration when planning other research.
There is a need for further studies that include heroin as well as other opioids and its effect on the brain morphology. It is important to take into consideration whether heroin causes brain changes or if there are brain changes that can predispose people to become heroin dependent. Use of substances other than heroin, including nicotine, can influence the results of research as well as receiving methadone or buprenorphine maintenance treatment. It is necessary to undertake research that takes into consideration and also examines the effect of the latter substances on the brain structure.

Disclosures

This research received no external funding.
Institutional review board statement: Not applicable.
The authors declare no conflict of interest.

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