Exploring the diversity of cannabis cannabinoid and non-cannabinoid compounds and their roles in Alzheimer’s disease: A review

Article type: Review Article

Keywords: Cannabis sativa, Alzheimer’s disease, Neuroprotection, Cannabinoids, Multi-target therapy

Authors: Hanane Doumar, Hicham El Mostafi, Aboubaker Elhessni, Mohamed Ebn Touhami, Abdelhalem Mesfioui

Affiliations: Laboratory of Biology and Health, Department of Biology, Faculty of Sciences, Ibn Tofail University, Kenitra, Morocco; Laboratory of Materials Engineering and Environment: Modeling and Application, Department of Chemistry, Faculty of Sciences, Ibn Tofail University, Kenitra, Morocco

License: © 2025 The Authors CC BY 4.0 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Article links: DOI: 10.1016/j.ibneur.2024.12.011  |  PubMed: 39866750  |  PMC: PMC11763173

Relevance: Moderate: mentioned 3+ times in text

Full text: PDF (1.5 MB)

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, representing a progressive and irreversible neurological disorder characterized by declining memory, cognition, and behavior (ref. WHO, 2023). It affects over 55 million people worldwide, with a significant prevalence in low- and middle-income countries. The World Health Organization (WHO) estimates that the number of individuals living with dementia could rise to 139 million by 2050, alongside a doubling of the financial burden, from $1.3 trillion in 2019 to $2.8 trillion by 2030. AD profoundly impacts individuals, families, and society as a whole (ref. Alzheimer’s Disease International, 2023).

(ref. Zhang and Gordon, 2018; ref. Birks and Grimley Evans, 2015)The scientific and pharmaceutical research community has faced significant challenges in developing effective treatments for AD due to the complexity of the human brain (ref. Abubakar et al., 2022). After nearly two decades of intensive pharmacologic research, current treatments include cholinesterase inhibitors like tacrine (ref. Sameem et al., 2017), donepezil (ref. Zhang and Gordon, 2018), rivastigmine (ref. Birks and Grimley Evans, 2015) and galantamine (ref. Nakayama et al., 2017), which temporarily improve memory and cognitive function, along with memantine for moderate to severe cases. However, these therapies primarily address symptoms rather than the underlying disease mechanisms (ref. Husna Ibrahim et al., 2020).

The reasons for the high failure rate in AD treatment trials are complex and cannot be attributed to a single cause. For example, in 2018, more than 50 % of drugs in Phase III trials focused on targeting beta-amyloid (Aβ), but by 2024, this focus had diminished to only 22 %, highlighting the challenges associated with amyloid-targeted therapies (ref. Cummings et al., 2018, ref. Cummings et al., 2024). Among the notable therapeutic strategies are monoclonal antibodies aimed at reducing amyloid burden, which are considered disease-modifying, even though they are not etiological treatments (ref. Budd Haeberlein et al., 2022). Recent approvals include aducanumab and lecanemab, with donanemab currently under review (CH et al., 2023; ref. Budd Haeberlein et al., 2022; ref. Sims et al., 2023; ref. FDA, 2024). Despite their promise, these treatments are effective mainly in the early stages of the disease and may have side effects such as swelling or microhemorrhages, in addition to high treatment costs (ref. Reardon, 2023, ref. Wu et al., 2023).

Indeed, complex neurological pathologies like Alzheimer’s are unlikely to be effectively addressed with a single-target solution. A more holistic approach may prove more efficient. In this context, it may be beneficial to return to nature, which has consistently offered effective treatments for numerous human diseases. This is evidenced by the fact that over 60 % of drugs approved between 1981 and 2019 are derived from or inspired by natural compounds. Natural products play a critical role in drug discovery, with 64.9 % of small molecule drugs approved for cancer treatment since 1981 being based on natural product structures (ref. Newman and Cragg, 2020).

Cannabis is a natural plant with a long history of human use, particularly in therapeutics. Historically, cannabis was regarded as a neurotoxic and addictive natural product with significant risks. However, recent research has sparked renewed interest in its medicinal benefits (ref. Crocq, 2020). This shift in perception is largely due to the discovery of phytocannabinoids, which interact with cannabinoid receptors to modulate biological responses such as inflammation and pain (ref. Crocq, 2020). Studies are now focusing on the therapeutic properties of various chemical compounds extracted from cannabis, emphasizing the importance of appropriate extraction methods and dosages. Cannabis is notable for its remarkable chemical diversity, containing over 550 bioactive compounds with promising therapeutic potential (ref. Rock and Parker, 2021). This is further supported by research highlighting not only cannabinoids like CBD and THC but also non-cannabinoid compounds, including terpenes and flavonoids, which have shown potential in treating neurodegenerative disorders (ref. Laaboudi et al., 2024; ref. Yadav et al., 2023). ref. Laaboudi et al. (2024), further emphasize the role of secondary metabolites, such as terpenes and phenolic compounds, in enhancing the therapeutic effects of cannabinoids through the "entourage effect." These non-cannabinoid compounds play a vital role in modulating inflammation, oxidative stress, and other key pathological processes, which are crucial in the treatment of Alzheimer’s disease. ref. Yadav et al. (2023), expand on this, noting that cannabis contains a wide array of compounds beyond cannabinoids, including over 150 terpenes and 42 phenolic compounds, each with distinct pharmacological activities such as anti-inflammatory, anti-cancer, and neuroprotective effects.

In addition, Tyrakis et al. (ref. Tyrakis et al., 2024) extensively review the endocannabinoid system, focusing on its role in Alzheimer’s disease. The article examines the modulation of the system’s pathways and how various cannabinoids, including non-selective cannabinoid agonists, impact key pathological features of Alzheimer’s, such as neurodegeneration and inflammation. Their synthesis of studies from 2014 to 2024 identifies significant mechanisms through which cannabinoids improve memory, cognition, and behavioral symptoms in Alzheimer’s disease models. Although the role of phytocannabinoids is only briefly addressed in the article, the findings align with growing evidence that modulating the endocannabinoid system can provide therapeutic benefits for Alzheimer’s patients.

While the referenced studies provide valuable insights into the broader pharmacological properties of cannabis, our review not only catalogs over 323 cannabis-derived chemical compounds, emphasizing both well-studied cannabinoids and often-overlooked non-cannabinoid compounds, but also specifically examines their effects on AD-related pathological features. We highlight the synergistic effects of cannabis extracts, including flavonoids and terpenes, through the entourage effect, offering a more comprehensive understanding of cannabis’s therapeutic potential in Alzheimer’s treatment. Additionally, this review underscores the growing body of clinical and preclinical studies, aiming to fill gaps in knowledge regarding the most effective extraction methods, dosages, and synergistic effects of cannabis compounds in Alzheimer’s treatment, an area not fully explored in the existing literature.

Classification of Cannabis components

As previously mentioned, cannabis is a chemically diverse plant with over 550 identified compounds, including more than 100 phytocannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) (ref. Rock and Parker, 2021). This diversity has significantly expanded due to advances in extraction and separation technologies, and the rapidly growing cannabis industry underscoring the importance of product development and extraction methods (ref. Alves et al., 2021, ref. Brighenti et al., 2024).

To classify cannabis compounds, several criteria can be used, including chemical structure, biosynthetic pathway, pharmacological activity, functional groups, plant part origin, extraction method, and therapeutic potential. In this review, we categorize cannabis compounds into two main groups based on their chemical structure and biological activity: cannabinoids and non-cannabinoids. Each category, sub-categories and its compounds types are detailed in Table 1, Table 2, following a previous study (ref. Radwan et al., 2021).

Cannabinoids (11 subcategory) (Fig. 1)

The term "cannabinoid" broadly refers to a group of compounds with a characteristic C21 terpenophenolic backbone, including synthetic cannabinoids, endocannabinoids, and phytocannabinoids that interact with cannabinoid receptors (ref. Pertwee, 2005). Initially, the term was used to describe a set of oxygenated aromatic hydrocarbon metabolites from marijuana, now known as phytocannabinoids. Cannabinoids are molecules that interact with the endocannabinoid system (ECS) in the body. The discovery of phytocannabinoids began in 1964 when Raphael Mechoulam and Yechiel Gaoni isolated THC, identifying it as the primary psychoactive compound in cannabis (ref. Mechoulam and Gaoni, 1965, ref. Pertwee, 2006). This discovery led to the identification of the ECS, named for its interaction with cannabinoids. In 1988, Devane et al. identified the first cannabinoid receptor (CB1) in the brain (ref. Devane et al., 1988), followed by the isolation of the first endocannabinoid, anandamide, in 1992 (ref. Devane et al., 1992). Named after the Sanskrit word for "bliss," anandamide revealed the natural production of cannabinoids in the human brain, distinct from those in cannabis (ref. Crocq, 2020).

As the significant potential of the ECS continues to emerge, interest in these molecules has grown, leading to extensive research. Cannabis phytocannabinoids, a key group within this category, can be categorized into 11 (Fig. 1) distinct sub-categories: cannabichromene (CBC), CBD, cannabielsoin (CBE), cannabigerol (CBG), cannabicyclol (CBL), cannabinol (CBN), cannabinodiol (CBND), cannabitriol (CBT), (−)-Δ8-trans-tetrahydrocannabinol (Δ8-THC), Δ9-THC, and miscellaneous-type cannabinoids (ref. Radwan et al., 2021) (Fig. 1). Among these 11 sub-categories, the most extensively studied are the psychotropic cannabinoids, with THC (Δ9-THC) being the most notable, followed by CBN and Δ8-THC. Non-psychotropic cannabinoids such as CBD, CBC, and CBG are also of significant interest due to their therapeutic potential. These six compounds: THC, CBD, CBN, CBC, CBG, and Δ8-THC, are often referred to as "the major cannabinoids" or "the big four" due to their prevalence and importance in cannabis research (ref. Atakan, 2012, ref. Lewis et al., 2017).

The Table 1 will detail these cannabinoids: with sub-categories, including the compounds types within each category and the methods used for their extraction.

Non cannabinoids (Fig. 2)

In addition to cannabinoids, over 400 non-cannabinoid constituents have been isolated and identified from the cannabis plant. These non-cannabinoid compounds belong to various chemical sub-categories (Fig. 2), including phenols, flavonoids, terpenes, and alkaloids (ref. ElSohly and Slade, 2005; ref. Turner et al., 1980). The non-cannabinoid components of cannabis were first identified during the early chemical analyses of the plant in the mid-20th century, but they were initially overshadowed by the more psychoactive and widely studied cannabinoids (ref. Radwan et al., 2021). Terpenes, which contribute to cannabis’s distinctive aroma, were among the first non-cannabinoid compounds to be characterized. Despite this, these compounds were largely considered secondary to the cannabinoids and were not deeply investigated for their therapeutic potential (ref. Sommano et al., 2020).

Non-cannabinoid molecules belong to a broad spectrum of secondary metabolites extracted from plants. Several criteria are used to classify these molecules, including chemical structure (such as the presence of rings or sugars), composition (whether they contain nitrogen), solubility in organic solvents or water, and biosynthetic pathways (ref. Lowe et al., 2021). Among these, the biosynthetic pathway is the most commonly used criterion for grouping secondary metabolites in plants. Based on this approach, non-cannabinoid compounds are divided into four major groups: terpenes, phenolic compounds, flavonoids, and alkaloids (ref. Satish et al., 2020). For example, phenolic compounds are natural metabolites primarily derived from the shikimate/phenylpropanoid pathway, which produces phenylpropanoids. These compounds are characterized by an aromatic ring with one or more hydroxyl groups (ref. Santos-Sánchez et al., 2019).

With further subdivisions based on chemical structure and functional groups. Phenols are divided into subgroups such as spiro-indans, which feature a distinctive spiro-linked ring system, and dihydrostilbenes, characterized by two phenyl rings connected by an ethylene bridge, as detailed by (ref. Bercht et al., 1973; ref. Turner et al., 1973). Flavonoids include cannabis-specific cannflavins, known for their anti-inflammatory properties, and more common plant flavonoids like quercetin, recognized for antioxidant activity, as outlined by (ref. Guo et al., 2018). Terpenes are categorized into monoterpenes, smaller molecules like myrcene, and sesquiterpenes, larger molecules such as β-caryophyllene, both distinguished by the number of isoprene units they contain, as reported by (ref. ElSohly and Slade, 2005). Alkaloids are divided into simple and complex types based on the presence of nitrogen atoms and the complexity of their ring structures, as described in studies like those of (ref. Radwan et al., 2008).

Interest in non-cannabinoid compounds began to increase in the late 20th and early 21st centuries, driven by the discovery of the "entourage effect." This concept suggests that the therapeutic effects of cannabis are not solely due to individual cannabinoids but also to the synergistic interactions between cannabinoids and non-cannabinoid compounds. Researchers began to explore how terpenes and flavonoids might modulate the effects of cannabinoids, enhance bioavailability, and exert their own therapeutic properties (ref. Ferber et al., 2020).

Advances in extraction technologies, such as supercritical CO₂ extraction, have allowed for the more precise isolation of non-cannabinoid compounds from cannabis. These methods have enabled researchers to study these compounds more rigorously, leading to discoveries about their anti-inflammatory, neuroprotective, and antioxidant properties. For example, terpenes like β-caryophyllene have been found to activate cannabinoid receptors independently of THC, offering potential anti-inflammatory and neuroprotective effects (ref. Cheng et al., 2014a). Flavonoids, including cannflavins, have demonstrated strong anti-inflammatory actions, surpassing even aspirin in some models (ref. Abdel-Kader et al., 2023)

Table 2 provides an overview of these chemical sub-categories in cannabis, including their compounds types and the methods used for their extraction.

Studies exploring the effects of cannabis extracts on AD

Cannabis (Cannabis sativa L.) is renowned for its rich chemical diversity across various biogenetic categories. While the plant contains unique phytochemicals, many of these compounds belong to chemical categories shared with other plants. The therapeutic potential of cannabis, particularly in the context of neurodegenerative diseases like Alzheimer’s, has garnered significant attention (ref. Abate et al., 2021).

Two main research approaches have emerged in the study of cannabis compounds for AD: one focusing on isolated, highly purified molecules, and the other utilizing complex extracts with multiple known or unknown compounds. The latter approach often emphasizes the entourage effect mentioned earlier (ref. Ferber et al., 2020). For instance, the combination of THC and CBD has demonstrated enhanced therapeutic outcomes compared to either compound alone (ref. Christensen et al., 2023).

Much of the therapeutic interest in cannabis centers around its modulation of the ECS through phytocannabinoids, as it has become increasingly clear that the ECS is a crucial regulator of various biological responses (ref. Lu and Mackie, 2016). Phytocannabinoids can increase the levels of endocannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which bind to endocannabinoid receptors (CB1Rs) in the nervous system, particularly at GABAergic nerve terminals. This interaction enhances dopamine concentration and transmission, contributing to antipsychotic and antidepressive effects observed in animal models (ref. Bloomfield et al., 2016, ref. Bloomfield et al., 2019). These effects are likely mediated by interactions with TRPV1 and serotoninergic receptors (5-HT1A), which play essential roles in emotional regulation, stress response, and neuroprotection (ref. Sales et al., 2018).

Moreover, cannabinoids have been shown to activate Peroxisome Proliferator-Activated Receptor Gamma (PPARγ), leading to microglial activation and reduced expression of inflammatory genes, further exerting neuroprotective effects (ref. Nadal et al., 2017). This broad interaction with multiple therapeutic targets underscores the potential of cannabinoids in modulating the pathogenesis of neurodegenerative diseases (ref. Dos Reis Rosa Franco et al., 2021).

With the growing understanding of the ECS, a wide array of molecules has emerged, capable of modulating ECS activity and showing potential therapeutic benefits in AD (ref. Karl et al., 2012). These compounds include endocannabinoid reuptake inhibitors, which extend the action of naturally occurring endocannabinoids, and enzyme inhibitors that prevent their breakdown, thereby enhancing their effects. Furthermore, synthetic molecules that selectively target ECS receptors, either by activating or blocking them, have been developed to fine-tune the system’s activity. These ECS modulators are particularly promising in Alzheimer’s research, as they can impact key processes such as neuroinflammation, synaptic plasticity, and neuronal survival, which are crucial in the disease’s progression. Although these compounds are still under investigation, they hold significant potential for alleviating symptoms or slowing the advancement of Alzheimer’s by harnessing the body’s endogenous cannabinoid system (ref. Karl et al., 2012).

In addition to cannabinoids, non-cannabinoid phytochemicals have also demonstrated therapeutic potential. Notable among these are flavonoids such as cannflavin A-C, the stilbenoid canniprene, and a range of terpenes (ref. Andre et al., 2016). Cannflavins, which can constitute up to 1 % of cannabis leaf material, possess strong anti-inflammatory profiles, while canniprene targets 5-lipoxygenase, a key enzyme involved in neuroprotection (ref. Izzo et al., 2020; ref. Yelanchezian et al., 2022). Although these minor compounds are less studied compared to conventional flavonoids, recent evidence suggests that they also exhibit neuroprotective effects, such as inhibiting Aβ aggregation (ref. Hole and Williams, 2021).

Terpenes, another significant sub-category of cannabis phytochemicals. Common terpenes like limonene, α-pinene, and β-caryophyllene have demonstrated neuroprotective properties, including the ability to stimulate antioxidant defenses, limit ROS-induced apoptosis, and inhibit Aβ aggregation (ref. Porres-Martínez et al., 2016). Additionally, some terpenes like β-caryophyllene and α-bisabolol have shown promise in reducing neurodegenerative effects via cannabinoid receptor-independent pathways (ref. Porres-Martínez et al., 2016).

Given the significant scientific interest in cannabis, numerous studies have explored the effects of its compounds on AD. Recognizing the abundance of references in this area, we deemed it essential to classify these studies using a suitable categorization system. In the first part of our research, we categorized cannabis-related compounds into cannabinoids and non-cannabinoids.

Cannabinoids effect on AD

We first focused on cannabinoid compounds, distinguishing between natural and synthetic ones or ECS modulators.

Natural compounds: include all cannabinoids that affect the ECS, whether they are derived from cannabis plants or produced endogenously within the body (endocanabinoids). Importantly, we considered the chemical structure of these compounds to be natural, regardless of whether they were isolated from natural sources or chemically synthesized.

On the other hand, synthetic compounds or ECS modulators: are chemically designed to mimic, enhance, or inhibit the effects of natural cannabinoids. These compounds may replicate the effects of their natural counterparts, amplify them, or act as inhibitors.

In this section, we will present this sub-category of compounds and their effects within the context of AD (Table 3).

Both natural and synthetic cannabinoids exhibit significant therapeutic potential in addressing AD, with effects on neuroinflammation, cognitive function, and neuroprotection.

Natural cannabinoids, such as CBD, CBG, and Δ9-THC, have been shown to reduce neuroinflammation and oxidative stress, enhance cognitive functions, and improve synaptic plasticity. They exert anti-apoptotic effects and modulate the ECS, thereby protecting neuronal cells and mitigating Aβ toxicity. Chronic low-dose Δ9-THC administration has been linked to cognitive improvement in preclinical studies, while CBD demonstrates anxiolytic properties and reduces behavioral comorbidities associated with Alzheimer’s. These findings highlight the broad therapeutic potential of natural cannabinoids in targeting various aspects of Alzheimer’s pathology.

Synthetic cannabinoids, including compounds like MDA7, JWH-133, ACEA, and WIN55,212–2, also show substantial promise. They have been reported to improve memory, reduce Aβ levels, normalize neuroinflammatory markers, and offer neuroprotection. Clinical studies with nabilone and dronabinol reveal their effectiveness in alleviating behavioral symptoms such as agitation and disturbed behavior, alongside their anti-inflammatory benefits. In vitro studies further support their role in protecting against Aβ-induced toxicity and microglial activation. Overall, synthetic cannabinoids are emerging as effective agents for managing Alzheimer’s, with significant benefits in neuroprotection and inflammation control.

Non-Cannabinoids effect on AD

In the second part of our classification, we shifted our focus to non-cannabinoid compounds derived from cannabis. These compounds have historically remained in the background, overshadowed by the attention given to the ECS. However, their potential therapeutic roles are gaining recognition (Table 4).

Non-cannabinoid compounds, such as terpenes and flavonoids, show significant promise in addressing AD features, particularly in neuroprotection and reducing Aβ aggregation. Terpenes like α-pinene, β-pinene, and β-caryophyllene have demonstrated neuroprotective effects against Aβ-induced toxicity and oxidative stress, as well as the ability to reduce Aβ fibril formation. Flavonoids, such as cannflavin A, exhibit similar protective effects, particularly at lower concentrations, where they enhance cell viability and inhibit Aβ aggregation. Additionally, some terpenes modulate neuronal hypersensitivity and calcium influx, suggesting a broader mechanism of action that could be beneficial in neurodegenerative conditions. Overall, these natural compounds represent a potential multi-target approach for mitigating AD pathology.

Direct Cannabis extracts

In this section we highlight cannabis extracts that contain both cannabinoid and non-cannabinoid compounds. Although the number of studies on these extracts is relatively small, there is growing evidence of the unique effects of mixed compounds, underscoring the importance of the entourage effect (Table 5).

Cannabis extracts have demonstrated a range of significant effects on AD-related features and neuroinflammatory responses. In in vivo studies, marijuana improved cognitive function in 6-OHDA-induced rat models by enhancing spatial learning and memory while also modulating dopamine and cannabinoid receptor expression. Additionally, extracts with a combination of THC and CBD showed positive effects on memory and reduced Aβ plaque content in APP/PS1 transgenic mice, independent of CB2 receptor presence.

In vitro studies highlighted the potential of cannabis extracts in inhibiting cholinesterase activity without cytotoxicity, suggesting a protective role against AD. THC, in particular, exhibited strong antioxidant properties, whereas CBD showed limited efficacy in combating oxidative stress.

In studies involving LPS-stimulated murine macrophages, THCV and THCV-BDS demonstrated anti-inflammatory effects by inhibiting nitrite production and down-regulating pro-inflammatory enzymes and cytokines, primarily through CB2 receptor pathways. COE extracts further supported anti-inflammatory outcomes by suppressing TNF-α, inhibiting COX-2 and iNOS expression, and reducing paw edema and inflammation in rat models.

Overall, cannabis extracts show a multifaceted potential in addressing cognitive impairments, neuroprotection, and inflammation, making them promising candidates for AD therapy.

Conclusion

Cannabis, encompassing both natural cannabinoids, synthetic cannabinoids, and non-cannabinoid compounds, represents a multifaceted and promising avenue for therapeutic intervention in AD. The therapeutic potential of cannabinoids such as CBD, Δ9-THC, and synthetic counterparts like MDA7 and JWH-133 has been supported by evidence demonstrating their neuroprotective properties, ability to reduce neuroinflammation, enhance cognitive function, and alleviate behavioral symptoms.

Additionally, non-cannabinoid compounds derived from cannabis, including terpenes and flavonoids, contribute significantly to the overall therapeutic profile. These compounds may exert complementary effects and influence the efficacy of cannabinoid-based treatments, highlighting the importance of understanding the "entourage effect"—the synergistic interaction between cannabinoids and non-cannabinoid compounds.

However, while the therapeutic promise is substantial, caution is warranted. The complexity of cannabis chemistry and its interactions with the ECS necessitates careful consideration of preparation methods, dosage, and the specific molecular targets involved. Rigorous research and clinical trials are essential to elucidate how cannabinoids and non-cannabinoid compounds interact within the human body, ensuring that therapeutic applications are both effective and safe. Continued investigation into the diverse effects of cannabis extracts and isolated compounds, as well as their interactions, will be crucial for developing well-defined therapeutic strategies and optimizing their potential benefits in AD management.

CRediT authorship contribution statement

Abdelhalem Mesfioui: Writing – review and editing, Validation, Supervision, Conceptualization. Hanane Doumar: Writing – original draft, Methodology, Investigation, Conceptualization. Hicham El Mostafi: Writing – review & editing, Methodology, Formal analysis, Conceptualization. Aboubaker Elhessni: Writing – review & editing, Supervision, Conceptualization. Mohamed Ebn Touhami: Writing – review & editing, Project administration.

Declaration of Competing Interest

There are no conflicts of interest among all authors.

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