We present a progressive case of early-onset frontotemporal dementia without significant past medical history except for Marijuana use for two years before the onset of symptoms. The diagnosis was made according to the typical presentation of almost all core features of the probable bvFTD, including behavioural disinhibition, apathy, loss of empathy, compulsive behaviours, hyperorality, and the inevitability of quitting his job due to deficit in executive functions. Our patient also showed significant insensitivity to pain [1]. Brain imaging studies indicated bilateral significant frontotemporal lobar atrophy inappropriate for his age.

Intuitive attitude and a common misconception about the early-onset presentation of dementia bring up genetic inheritance as the cardinal etiology. Nevertheless, plenty of observational studies show that only a minority of early-onset dementia, including both Alzheimer’s disease (AD) and FTD, have autosomal dominant patterns or can be accredited to known gene mutations [11–13]. When multiple relatives experience FTD or a comparable illness through successive generations, it is considered to be familial FTD. As an example, a grandparent, parent, and adult child are all closely related to one another and all belong to one side of the family, not both. When only one member of a family develops FTD, it is considered to be sporadic FTD. Hence, there are deliberate endeavors to identify the environmental and lifestyle risk factors contributing to the disease presentation; Regarding early-onset FTD, occupational exposure to heavy metals, metalloids, dyes, pesticides, along with smoking, heavy alcohol consumption, traumatic brain injuries, and traumatic professional sports, obesity, and particularly cumulative exposure to risk factors are among the known environmental and modifiable risk factors [13–15]. Air pollutants, occupational exposures, cardiovascular risk factors, and dietary consumption of cereal, dairy, dry cake, and ice cream are shown to be associated with an increase in the odd ratio of disease presentation [12, 16].

Considering our presenting case, the lack of significant familial history, the insufficiency of possible attributable risk factors, and the significant history of Marijuana consumption before symptom onset suggest us impute the connection between cannabis and early-onset FTD. A likely hypothesis is that as an illicit drug in the country without standardized preparation and processing, cannabis users are at high risk of receiving cannabis contaminants and toxins in unsafe quantities. Common cannabis contaminants are heavy metals, pesticides, and microbes [17] that can increase the risk of FTD [13, 14].

A large number of previous studies on the usage of cannabis indicate its promising effects on symptom control of behavioural and psychological symptoms of dementia (BPSD). Anti-oxidant, anti-neuroinflammatory effects, increase in the neurogenesis activation, and pro-survival factors including Brain-Derived Neurotrophic Factor (BDNF) and inhibition of tau hyperphosphorylation are among the contributing mechanisms [18, 19].

Most studies examining the effect of cannabis on controlling BPSD involve AD patients or did not specify the type of dementia; in our literature review, only a few studies specifically present the effect of cannabis on FTD patients, and together they introduced nine FTD patients. Gopalakrishna et al. [6], in a case series including three FTD cases showed that cannabinoids could improve behavioural symptoms and ameliorate caregiver burden [6]. Another case series of 17 cases encompassed three FTD patients; two reported significant improvements in behaviour and mood 18. Amanullah et al. [20], Pia-Escudero et al. [21], and Zajac et al. [22] each present a case of FTD (or mixed FTD and vascular dementia) with positive results, including improvement in agitation, behavioural disinhibition, bruxism, and increased sociability.

Almost all the studies investigating the effect of cannabis and cannabinoid on BPSD were not contesting the long-term efficacy or the adverse effects of chronic marijuana use in dementia. They were conclusive based on the promising short-term results [18]. However, looking into the brain of chronic cannabis users would illustrate its deleterious effects. As in a study by Amen et al., persistent hypoperfusion in multiple brain regions, including the hippocampus, parahippocampal gyrus, precuneus, posterior cingulate, and medial temporal lobe, was significantly shown [23]. The orbitofrontal cortex and hippocampus are the most affected brain regions through studies [24]. The large cohort of the IMAGEN study demonstrates the negative association between adolescent marijuana abuse and cortical thickness in the prefrontal cortex [25]. Cannabis consumption is related to reduced gray matter volume in the medial temporal cortex, insula, temporal pole, orbitofrontal cortex, and parahippocampal gyrus; Regions rich in cannabinoid CB1 receptors and functionally related to emotional, motivational, and affective processing [26]. Another impaired process in the brain of chronic marijuana users is the dopamine deficit, which can also make the picture of FTD pathology [27, 28].

Cannabinoid use would impair the regulation of endocannabinoid system in its critical stage of development, Renard et al. showed that the chronic cannabinoid exposure during adolescence has been shown to induce long-term changes in the PFC, such as reduced dendritic arborization of pyramidal neurons, impaired synaptic plasticity, altered expression of synaptic markers, decreased gray matter volume, and abnormal connectivity. These changes may impair the communication between the PFC and other brain regions, such as the hippocampus, which is essential for learning and memory. As a result, chronic cannabinoid exposure during adolescence may increase the risk of developing frontotemporal dementia later in life [29].

The duration of cannabis use that can cause neurocognitive problems is not clearly determined in the literature. However, some studies have suggested that chronic cannabis use, defined as regular consumption for at least one year with a minimum frequency of once per week, is associated with significant impairments in cognitive impulsivity, cognitive flexibility, attention and short-term memory [30], and verbal learning and memory [31]. Furthermore, the age of onset of cannabis use and the quantity and potency of cannabis consumed may also influence the neurocognitive effects, [30, 31]. Therefore, it is likely that the longer, earlier and more frequently someone uses cannabis, especially high-potency strains, the more severe and persistent the neurocognitive problems will be.

Since cannabis has a complex pharmacology, medical use demands extensive formulary studies. The two most prominent constituents of cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have several paradoxical and sometimes confronting effects. THC, as the main psychoactive factor of cannabis, is shown to cause cognitive dysfunction, psychosis, and alteration in cortical structure and function in adolescents [32, 33]. CBD has a lower risk profile and is accounted to alleviate THC’s harmful effects. It is regarded to act as an antipsychotic, anxiolytic, and immune modulator. However, due to the limitation of evidence, CBD prescription for psychiatric disorders is still an open debate [33]. It has been shown that there is no information on the CBD content for more than 58% of cannabinoid products, and the amount of side effects of these products increases with the ratio of THC to CBD [34]. Recreational and illegal use of cannabis, as in our patient, are at risk of adverse effects due to formulary reasons.

These severe effects on the brain structure and brain chemistry of chronic cannabis users may potentially contribute to the development of neurodegenerative disorders like FTD in genetically vulnerable individuals. While the warning about cannabis consumption’s impact on brain structure is valid, the scarcity of reported FTD cases in patients with chronic cannabis use suggests the need for more nuanced conclusions. Therefore, the recommendation of cannabis as medical management for BPSD should be approached with additional caution, particularly for early-onset patients who are more likely to engage in long-term use and dependence, increasing their vulnerability to neurodevelopmental abnormalities.