Cannabis sativa, the plant from which cannabis products are derived, contains over 100 cannabinoids, with delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) emerging as the most prominent compounds.
The diverse methods of cannabis consumption, ranging from inhalation to topical application, have contributed to its widespread use.
Composition of Cannabis and Routes of Administration
Cannabis sativa’s complexity lies in its intricate chemical makeup, housing a spectrum of cannabinoids. The psychoactive Δ9-THC, isolated in 1964, and the nonpsychoactive CBD, isolated in 1940, are the most abundant components. Consumption methods include inhaled smoke, vaping of liquid extracts, topical applications such as lotions, and ingestible forms like edibles. Inhaled cannabinoids exhibit rapid absorption in the lungs, while other routes, such as dermal, oral, and rectal, show varying absorption rates.
Pharmacokinetics and Storage
The highly lipophilic nature of cannabinoids results in their storage in adipose tissue for extended periods, ranging from weeks to months. Moreover, these compounds concentrate in the breast milk of both rodents and humans, raising concerns about potential developmental implications in offspring.
Therapeutic Potential of CBD
CBD products have gained recognition for their potential health benefits, serving as therapeutic agents for conditions such as Parkinson’s disease, anxiety, and epilepsy. However, accumulating evidence also suggests neurotoxic and reproductive effects from CBD exposure, challenging the prevailing perception of its safety.
Changing Landscape: Δ9-THC:CBD Ratio
As cannabis legalization, social acceptance, and use increase, the ratio of Δ9-THC to CBD in cannabis has shifted. From 1995 to 2014, the Δ9-THC:CBD ratio increased significantly from 14:1 to 80:1, impacting the potency and potential risks associated with cannabis use.
Δ9-THC Exposure: Concerns for Developmental Health
With the escalating use of cannabis, particularly in pregnant and breastfeeding women, concerns arise regarding the impact of Δ9-THC exposure on the developing brain and neurodevelopment of offspring. The complexity of cannabis neurotoxicity is influenced by multiple factors, including exposure level, purity, route of administration, developmental age, health status, pregnancy and lactational status, and other variables.
Balancing Risks and Benefits
This comprehensive review explores both the risks and benefits associated with Δ9-THC and CBD exposure. While CBD is often deemed safe, concerns about its reproductive and developmental effects have surfaced, especially as it becomes increasingly available in over-the-counter products with limited safety and efficacy data. On the other hand, Δ9-THC exposure carries dose-dependent adverse effects, yet its therapeutic benefits cannot be overlooked.
The Endocannabinoid System (eCBS)
The discovery of the endocannabinoid system (eCBS) in the 1990s, while investigating the mode of action of Δ9THC, marked a pivotal moment in understanding the intricate regulatory network that influences metabolic pathways throughout the human body. The eCBS is an intrinsic and multifaceted system that extends its influence to various physiological domains, including muscle, adipose tissue, the gastrointestinal tract, liver, and the central nervous system (CNS). This chapter delves into the components, mechanisms, and functional implications of the eCBS, shedding light on its role in shaping neuronal connectivity and regulating neurotransmitter systems.
Components of the eCBS
The eCBS exerts its effects through cannabinoid receptors, primarily cannabinoid-1 receptors (CB1Rs) and cannabinoid-2 receptors (CB2Rs). CB1Rs are abundantly found in the brain, particularly in the cell membranes, while CB2Rs are mainly expressed on immune cells in the periphery and glia/microglia in the brain. Some researchers propose the existence of a third receptor, CB3R, represented by the transient receptor potential cation channel subfamily V member 1 (TRPV1 or vanilloid receptor 1), which is activated by CBD. These receptors can act independently or in concert, modulating physiological effects through various mechanisms, including dimerization.
Neuronal Connectivity and Regulation
The eCBS plays a crucial role in shaping neuronal connectivity in the brain throughout development and into adulthood. It influences neurotransmitter systems, including gamma-aminobutyric acid (GABA)ergic, glutamatergic, opioid, and dopaminergic systems. The interplay between CB1Rs and CB2Rs (and potentially CB3Rs) occurs competitively, cooperatively, or in opposite directions, showcasing the complexity of the regulatory mechanisms involved.
Endocannabinoid Biosynthesis and Signaling
The eCBS operates through endocannabinoids (eCBs), with 2-arachidonoylglycerol (2-AG) and anandamide (AEA) emerging as the principal ligands. These eCBs are synthesized postsynaptically from arachidonic acid by enzymes such as N-acyl phosphatidylethanolamine phospholipase D and diacylglycerol lipase alpha/beta (DAGLα/β). Signaling occurs as eCBs migrate from postsynaptic neurons to presynaptic cannabinoid receptors (CBRs). The binding of CBR to the guanosine-5′-triphosphate (Gi/o)/α-protein subunit dimer initiates a cascade that modulates presynaptic calcium influx and the activity of voltage-dependent ion channels, ultimately regulating neurotransmitter release.
Degradation of eCBs
The eCBs, having fulfilled their signaling role, are subsequently degraded by enzymes. Monoacylglycerol lipase (MAGL) located in the presynaptic cell and fatty acid amide hydrolase (FAAH) in the postsynaptic cell undertake the degradation of eCBs, ensuring the termination of their signaling effects.
Fig. 1 Lipophilic structures for delta-9-tetrahydrocannabinol (Δ9THC) and cannabidiol (CBD) as well as the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA).
Each compound acts at the G protein-coupled receptors cannabinoid 1 and 2 receptors, which affect neurotransmitter release.
Comparison with Cannabinoids: Structure and Toxicity
Figure 1 illustrates a comparison between the lipophilic structures of eCBs (2-AG and AEA) and cannabinoids like Δ9THC and CBD. The toxicity or neuroprotection of these cannabinoids is contingent upon various factors, including potency, exposure, duration/frequency, vehicle, route of administration, and species-specific differences. Pharmacokinetic and pharmacodynamic parameters, such as P450 metabolic activation and glucuronidation elimination, further determine the extent of their effects.
Risk Factors and Individual Variability
Understanding the impact of cannabinoids on health necessitates an appreciation of individual variability. Factors such as age, genetic makeup, health status, diet, and exposure loads contribute to an individual’s ability to handle cannabinoids. The complexity of risk factors, often challenging to characterize in humans, underscores the need for comprehensive research to inform safe usage practices.
Δ9THC-Associated Mechanisms and Neurotoxicity
Understanding the intricate effects of Δ9THC on the brain requires a comprehensive examination of the areas affected and the associated mechanisms. The endocannabinoid system (eCBS) and cannabinoid receptors (CBRs) play a central role in regulating neurotransmitter release throughout the brain, influencing various systems critical for neuroplasticity, locomotor activity, cognition, executive functions, reward, motivation, and neuroendocrine control. This chapter delves into the specific areas influenced by Δ9THC and the complex interactions among neurotransmitter systems, providing insights into the mechanisms underlying its neurotoxic effects.
eCBS/CBRs and Neurotransmitter Regulation
The eCBS, comprised of cannabinoid receptors CB1Rs and CB2Rs, is distributed widely throughout the brain. These receptors regulate the release of neurotransmitters such as glutamate (excitatory), gamma-aminobutyric acid (GABA, inhibitory), dopamine, and serotonin at presynaptic terminals. The modulation of these neurotransmitter systems occurs through direct and indirect stimulation, overseen by the eCBS, contributing to the regulation of neuroplasticity, excitability, and various cognitive and behavioral functions.
Specific Areas of Influence
- Glutamatergic Regulation
Δ9THC influences glutamatergic neurotransmission, particularly in areas such as the basal ganglia and striatum. The eCBS/CBRs modulate the release of glutamate, affecting excitatory processes crucial for cognitive functions and motor control.
- GABAergic Regulation
Inhibitory GABAergic medium spiny neurons in the striatum, a component of the basal ganglia, are sensitive to Δ9THC. The eCBS/CBRs regulate GABAergic neurotransmission, impacting inhibitory processes that contribute to the intricate balance of neural signaling.
- Dopaminergic Regulation
The dopaminergic system, involving receptors such as D1 and D2, is influenced by Δ9THC. Inputs from the ventral tegmental area (VTA), substantia nigra (SNc), and prefrontal cortex (PFC) converge in the striatum, contributing to the regulation of motivation, reward, and motor functions.
- Serotonergic Regulation
Serotonin, a key neurotransmitter involved in mood regulation, is also affected by Δ9THC. The eCBS/CBRs modulate serotonergic neurotransmission, impacting emotional states and potentially contributing to the psychotropic effects of Δ9THC.
Complex Interactions and Regulatory Functions
The interactions among these neurotransmitter systems are complex, involving direct and indirect stimulation. The eCBS acts as a regulatory mechanism, overseeing neuroplasticity and excitability. The intricate balance maintained by the eCBS contributes to functions such as locomotor activity, learning and memory, executive functions, and neuroendocrine control.
Basal Ganglia and Striatal Impact
The striatum, a vital component of the basal ganglia, serves as a focal point for Δ9THC’s impact. Inhibitory GABAergic neurons in the striatum are influenced by glutamatergic and dopaminergic inputs, creating a delicate balance that can be disrupted by Δ9THC exposure.
Neurotoxicity and Potential Consequences
The modulation of neurotransmitter systems and the disruption of intricate regulatory mechanisms by Δ9THC raise concerns about potential neurotoxic effects. Changes in neuroplasticity, excitability, and neurotransmitter release may lead to adverse cognitive and behavioral outcomes, warranting careful consideration of the risks associated with Δ9THC exposure.
Table 1 summarizes some of the main brain regions, pathways, and neurotransmitters involving the neuronal connections in the eCBS and affected by Δ9THC.53,78,80,81,84,85,87–98
Table 1 – Brain regions and pathways affected by endocannabinoids, Δ9-THC and/or CBD
|Neurotransmitter/Pathway||Brain region associations||Behavior/processes involving eCBS||Reference|
|Mesolimbic||DA from ventral tegmental area (VTA; midbrain) → ventral striatum (amygdala, pyriform cortex, lateral septal nuclei, nucleus accumbens)||Reward-related cognition (e.g., incentive: wanting; pleasure: liking; positive reinforcement, associative learning) & emotion||78,80,81,88–91|
|Mesocortical||DA from VTA (midbrain) → prefrontal cortex + hippocampus||Cognition: executive function (e.g., planning, attention, working memory, planning, self-control, etc.), emotion|
|Nigrostriatal||DA from substantia nigra (pars compacta; substantia nigra SNc: midbrain) → dorsal striatum (i.e., caudate nucleus + putamen)||Neuromotor function, reward-related cognition, associative learning|
|Tuberoinfundibular||DA from the hypothalamic arcuate (infundibular) + paraventricular nucleus → pituitary gland median eminence||Inhibits the release of prolactin.|
|Glutamatergic||Hippocampus, neocortex and over 90% of synapses in human brain.||Excitatory effects on VTA & SNc neurons, memory, learning, neural communication||53,90,92,93|
|ɣ-Aminobutyric Acid: GABA|
|GABAergic||Hippocampus, thalamus, basal ganglia, hypothalamus, brainstema||Inhibitory effects on VTA and SNc neurons||90,94–96|
|Serotonergic||Dorsal raphe nuclei, cortex, hippocampus||Modulator of receptors with effects depending on subtype (i.e., biphasic effect on VTA neurons)||80,84,85,97,98|
aGABAergic transmission includes inhibitory median spiny neurons in the striatum/basal ganglia affected by the glutamatergic (AMPAR) and dopaminergic (D1 and D2) receptor inputs from the VTA, SNc, and PFC.87
Cannabidiol (CBD), a prominent compound in cannabis extract, has garnered significant attention for its therapeutic potential in a range of neurological, inflammatory, and mental disorders. With its high efficacy, low toxicity, and widespread availability, CBD has become a focus of extensive research. While the exact mechanisms underlying its therapeutic effects are still being explored, this chapter delves into the multifaceted ways in which CBD interacts with various biological targets to exert its beneficial effects.
Neuroprotection through Glial Cells
Central to CBD’s neuroprotective effects is its interaction with glial cells, nonneuronal cells in the central nervous system (CNS). Astrocytes and microglia, components of CNS connective tissue, play vital roles in regulating neurotransmission and immune responses. CBD has been shown to modulate the immune response initiated by microglia, particularly in diseases like Parkinson’s. Additionally, CBD promotes neuronal regeneration through the recruitment of astrocytes, facilitated by brain-derived neurotrophic factor (BDNF), thereby contributing to neuroprotection.
Adenosine Receptor 2A (A2AR) Modulation
CBD’s interaction with adenosine receptor 2A (A2AR) is crucial for its anti-inflammatory effects. By serving as an agonist, CBD decreases adenosine reuptake, leading to increased adenosine signaling and a subsequent reduction in neuroinflammation. This modulation has been implicated in alleviating the effects of conditions such as multiple sclerosis, hypoxic-ischemic brain damage, Alzheimer’s disease, and hepatic encephalopathy.
Influence on 5-HT Receptors
CBD’s impact on the serotonergic system through 5-HT1A receptors is diverse. Acting as an agonist, CBD is associated with various therapeutic effects, including antiepileptic, anticataleptic, neuroprotective, antiemetic, anxiolytic, antidepressant, antipsychotic, and analgesic actions. The intricate modulation of the serotonergic system contributes to CBD’s efficacy in addressing conditions such as cerebral ischemia, seizure disorders, and hepatic encephalopathy.
Cannabinoid Receptors (CB1Rs and CB2Rs) Involvement
CBD’s interaction with cannabinoid receptors, particularly CB1Rs and CB2Rs, plays a pivotal role in regulating excitotoxicity and inflammation. By inhibiting glutamate release and normalizing glutamatergic activity, CBD exerts neuroprotective effects. Additionally, CBD’s activation of CB1R decreases inflammation by modulating the activity of microglial cells, showcasing its potential in mitigating neurodegenerative disorders like ischemic stroke, Tardive dyskinesia, and Parkinson’s disease.
Fatty Acid Amide Hydrolase (FAAH) Inhibition
CBD indirectly influences CB1R through the inhibition of FAAH, leading to increased levels of anandamide (AEA) and subsequent CB1R activation. This mechanism contributes to the overall neuroprotective and anti-inflammatory actions of CBD.
TRPV1 Channel Modulation
The interaction between CBD and TRPV1 channels contributes to pain perception modulation, neuroinflammation reduction, and body temperature regulation. CBD’s activation of TRPV1 channels leads to decreased pain, microglial activation, and oxidative stress, showcasing its potential therapeutic role in conditions associated with these pathways.
GPR55 Receptor Binding
CBD’s high affinity for GPR55, acting as an antagonist, regulates processes such as neuropathic pain and antiepileptic activity. By decreasing glutamate release, CBD demonstrates anti-convulsive effects, providing relief in conditions like Parkinson’s disease and Dravet syndrome.
Involvement of PPARɣ Receptors
As an agonist of peroxisome proliferator-activated receptor gamma (PPARɣ), CBD elicits anti-inflammatory and antioxidative effects. Through PPARɣ-mediated pathways, CBD demonstrates protective effects against conditions like Alzheimer’s disease.
Modulation of GABAA Receptors
CBD’s stimulation of GABAergic neurotransmission enhances inhibitory neurotransmission, offering anticonvulsant and anxiolytic actions in the CNS. The non-competitive binding of CBD to GABAA receptors makes it a potential treatment option for patients resistant to benzodiazepines, the standard antiseizure treatment.
CBD Neuroprotection in Human Studies
The translational potential of CBD’s neuroprotective effects observed in animal studies extends to human subjects, encompassing a broad spectrum of neurological disorders. Human studies have underscored CBD’s safety and efficacy in addressing various neurological conditions, including neurological damage, brain tumors, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and childhood seizures such as Lennox-Gastaut syndrome and Dravet syndrome.
Therapeutic Benefits in Neurological Disorders
CBD’s efficacy in human subjects has been particularly evident in the treatment of Parkinson’s disease. Characterized by the accumulation of α-synuclein and dopaminergic neuronal degeneration, Parkinson’s disease manifests with motor alterations, depression, and dementia. Human studies have demonstrated improvements in the disease through CBD’s modulation of the endocannabinoid system (eCBS), acting on CB1Rs, CB2Rs, FAAH, and MAGL. The neuroprotective effects of CBD extend to mitigating excitotoxicity, inhibiting dopaminergic neuronal degeneration, and suppressing microglial activation.
Similarly, in Huntington’s disease, an autosomal-dominant neurodegenerative disorder, CBD’s activation of CB1Rs in the striatum has been shown to inhibit glutamatergic transmission, providing protection to damaged neurons and functioning as an antioxidant.
In Alzheimer’s disease, CBD has exhibited promising results by decreasing hyperphosphorylation of tau protein, acetylcholinesterase activity, oxidative stress, apoptosis, neuroinflammation, gliosis, and the deposition and expression of beta-amyloid (βA). The selective activation of PPARɣ by CBD contributes to increased clearance of βA peptides through autophagy, providing a multifaceted approach to alleviating the pathologies associated with Alzheimer’s disease.
Beyond Neurological Disorders: Psychiatric Conditions
CBD’s therapeutic benefits are not confined to neurological disorders alone. Human studies have indicated its efficacy in treating anxiety, depression, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorders. Additionally, CBD has demonstrated antipsychotic properties in individuals with schizophrenia.
CBD-Associated Toxicity: Considerations and Findings
Despite its widespread use and apparent safety, the potential risks associated with CBD consumption, especially during pregnancy and in children, remain areas of concern. While CBD is not intoxicating like Δ9THC, its effects on brain development in utero are not well understood. Studies in rodents have indicated sex-specific behavioral effects in pups exposed to CBD during gestation, suggesting potential psychopathological impacts.
In adults, CBD neurotoxicity appears to be influenced by factors such as sex and strain. Rodent studies have shown varied responses in anxiety and depressive behaviors based on sex, strain, and exposure time. Notably, exposure to CBD during development has raised concerns about its toxic effects on the male reproductive tract. Studies in mice have revealed disrupted sperm development, abnormal seminiferous epithelium, decreased testes weights, and other fertility-related impacts. Although the focus on reproductive effects in humans has traditionally been on Δ9THC, animal studies suggest that CBD in cannabis could contribute to negative effects in males, warranting further investigation.
In vitro studies on human and mouse Sertoli cells postnatally support the toxic effects of CBD observed in animal studies. The multifaceted nature of CBD’s effects is influenced by dose exposure, route, species, sex, frequency of consumption, and individual susceptibility.
Human studies affirm the neuroprotective potential of CBD across a spectrum of neurological disorders, offering hope for therapeutic interventions in conditions previously deemed challenging. As research continues, careful consideration of potential risks, especially in vulnerable populations, is crucial. The complex interplay of CBD with various targets highlights the need for ongoing investigation to unlock its full therapeutic potential while ensuring safety and efficacy in diverse clinical settings.
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