The Adolescent Blood-Brain Pathway

victor borras
May 23
9 min read

by Victor A. Borras RN, TNCC, ENPC, BABA

Certified K9 Handler - K9 One Detection Services.

Illustration depicting various substances like THC, nicotine, meth, cocaine, and opioids crossing the blood-brain barrier, emphasizing the critical impact on teen brain health.

A comprehensive understanding of trending drugs, available both online and in local retail stores, can be acquired through webinars, conferences, and seminars conducted by expert presenters. Their research, evaluations of stores and smoke shops, and informative lectures have been invaluable. It is essential for us to recognize the street names of these substances, their packaging, ease of purchase, and the locations where they are accessible to our students. This information holds operational significance for K9 practitioners. To grasp the full impact of both legal and illegal substances used by our teenage students, it is crucial for parents, teachers, administrators, and school healthcare providers to understand how drugs affect organ systems. Additionally, the Blood-Brain Barrier, a critical pathway into the brain that is particularly vulnerable in teenagers, is often overlooked. This blog will provide the essential information needed for your comprehension and awareness.

What is the Blood-Brain Barrier and What Is Its Function?

The Blood-Brain Barrier (BBB) is a protective barrier that separates the brain from the blood stream. The blood-brain barrier (BBB) is located throughout most of the brain and spinal cord, lining the specialized blood vessels (capillaries) in these areas. It's a highly selective semi-permeable membrane that acts as a protective filter, preventing harmful substances, pathogens, and large molecules from passing from the bloodstream into the central nervous system, while allowing essential nutrients to enter. Fetal brain research indicates that the BBB is functional as early as 8 weeks of gestation in humans. The components of the BBB include:

Endothelial Cells.
Pericytes.
Astrocyte End-Feet.
Basement Membranes.

Endothelial Cells: These cells constitute the innermost layer of the brain's capillaries. Distinct from endothelial cells located in other parts of the body, those within the brain are uniquely characterized by:

Tight Junctions (TJs): This is regarded as the most crucial component of the blood-brain barrier (BBB). These specialized protein complexes tightly seal the spaces between adjacent endothelial cells, limiting the paracellular passage of most substances and preventing their diffusion from the bloodstream into the brain. Key proteins involved in tight junctions include occludin, claudins (notably Claudin-5), and junctional adhesion molecules (JAMs).
Lack of Fenestrations: Unlike capillaries in many other tissues that possess small pores (fenestrations) to facilitate substance exchange, brain capillaries lack these, further reducing permeability.
Few Pinocytotic Vesicles: These small sacs transport substances across cells. Brain endothelial cells have fewer of these compared to other endothelial cells, thereby decreasing transcellular transport.
Specific Transporters and Efflux Pumps: While tight junctions limit passive diffusion, endothelial cells also contain specialized transport systems (such as glucose transporter 1 (GLUT1) for glucose and amino acid transporters) to actively import essential nutrients into the brain. They also possess efflux pumps (e.g., P-glycoprotein) that actively remove harmful substances or waste products from the brain back into the bloodstream.

2. Pericytes: These cells are embedded within the capillary basement membrane and are closely associated with endothelial cells. They play a crucial role in:
- BBB Integrity and Development: Pericytes contribute to the induction and maintenance of tight junctions in endothelial cells.
- Angiogenesis: They are involved in the formation of new blood vessels.
- Regulation of Blood Flow: They can influence capillary diameter and blood flow.
3. Astrocyte End-Feet: Astrocytes, a type of glial cell in the brain, have specialized projections known as end-feet that envelop the capillaries, nearly completely surrounding the endothelial cells and basement membrane. Although they do not directly form the barrier, they are essential for:
- Induction and Maintenance of Tight Junctions: Astrocytes release factors that promote and sustain the integrity of the tight junctions between endothelial cells.
- Metabolic Support: They provide metabolic support to endothelial cells and facilitate nutrient exchange between the blood and neurons.
4. Basement Membrane: This thin extracellular matrix, composed of various proteins (such as collagen, laminin, and fibronectin), surrounds the endothelial cells and pericytes. It provides structural support to the capillary wall and acts as a selective filter itself.

Collectively, these components create a meticulously regulated and dynamic interface that maintains the stable internal environment required for optimal brain function, while also permitting the controlled passage of essential molecules.

The Blood-Brain Barrier Of The Adolescent Student

Serving as a protective barrier between the brain and the bloodstream, the blood-brain barrier (BBB) continues to develop and mature throughout adolescence, with some changes persisting into the early twenties. Consequently, the BBB's function—protecting the brain from harmful substances and maintaining a stable environment—is not completely established in teenagers.

Research conducted by the National Institutes of Health reveals that while the blood-brain barrier (BBB) is functional at birth, it undergoes substantial postnatal development, with changes in its molecular and physiological properties continuing through childhood and adolescence. This maturation process implies that the BBB may have heightened permeability during adolescence compared to adulthood, potentially influencing the brain's responsiveness to external stimuli and substances. Such increased permeability could render the adolescent brain more vulnerable to environmental factors, toxins, or substances of abuse, such as nicotine and alcohol. Greater exposure to harmful substances crossing the BBB may significantly affect the developing brain, which is undergoing critical structural and functional changes. Furthermore, the enzymes within the BBB that metabolize drugs or other compounds may vary in levels or activity in the adolescent brain compared to adults, potentially altering the effects of certain medications or illicit substances on brain function. Due to structural and functional changes resulting from illicit drug use, specific brain areas related to reward, impulse control, and decision-making (such as the prefrontal cortex) may make adolescents more susceptible to the effects of illicit drugs, alcohol, and nicotine. The passage of these substances through the BBB could have a more profound and lasting impact, contributing to an increased risk of addiction.

Impact of Psychoactive Substances on the Blood-Brain Barrier (BBB)

The chart below provides insights into the significance and effects of the blood-brain barrier concerning the influence of commonly used drugs among middle and high school students. It illustrates how these drugs traverse and impact the integrity and functionality of the blood-brain barrier.

Psychoactive Substance	Main Mechanism of Crossing BBB	Primary Impact on BBB Integrity/Function	Potential Long-Term Effects on BBB	Notes
THC (Tetrahydrocannabinol) - from Cannabis	Lipid-solubility: Readily crosses by passive diffusion due to its high lipid solubility.	Generally thought to have minimal direct disruptive effects on BBB integrity at typical recreational doses. However, some studies suggest: - May alter expression/activity of certain transporters. - Potential for subtle changes in permeability under specific conditions or chronic use.	Unclear. Chronic heavy use might lead to subtle alterations in barrier function, but direct damage is not a primary concern compared to other substances.	Psychoactive effects mediated by cannabinoid receptors (CB1) in the brain.
Methamphetamine	Passive diffusion: Highly lipid-soluble, allowing it to cross the BBB easily. Carrier-mediated transport: May also utilize monoamine transporters to enter brain cells.	Significant disruption: - Direct damage: Can cause oxidative stress, neuroinflammation, and excitotoxicity, leading to damage to endothelial cells and astrocytes. - Tight junction disruption: Can impair tight junction proteins (e.g., occludin, claudin-5), increasing paracellular permeability. - Increased permeability: Leads to "leakiness" of the BBB, allowing entry of normally restricted substances.	Persistent BBB dysfunction: Chronic use can lead to sustained BBB breakdown, contributing to neurotoxicity, brain damage, and cognitive deficits. Impaired removal of toxins.	Highly neurotoxic. BBB disruption is a major factor in methamphetamine-induced brain injury.
Opioids (e.g., Heroin, Fentanyl, Morphine)	Passive diffusion: Most opioids are lipophilic enough to cross the BBB, with varying degrees of efficiency (e.g., heroin and fentanyl cross more rapidly than morphine due to higher lipid solubility). <br> Carrier-mediated transport: Some opioids may interact with efflux transporters (e.g., P-glycoprotein), limiting their brain entry to some extent.	Generally considered to cause less direct structural damage to the BBB compared to methamphetamine. However: - Inflammatory response: Can induce neuroinflammation, which indirectly affects BBB integrity. - Acute permeability changes: Some studies suggest acute opioid exposure can transiently increase BBB permeability, possibly via changes in tight junction proteins or transporter activity.	Potential for subtle, chronic alterations in BBB permeability and function, particularly with chronic abuse or high doses, potentially impacting neuroinflammation and neuronal health.	Their effects are primarily mediated by binding to opioid receptors in the brain.
Cocaine	Passive diffusion: Readily crosses the BBB due to its lipophilic properties.	Can cause acute and chronic BBB disruption: - Oxidative stress: Induces reactive oxygen species, damaging endothelial cells. Inflammation: Promotes neuroinflammation, which can compromise tight junctions. - Tight junction alterations: Studies show cocaine can alter tight junction protein expression and localization. Vasoconstriction/Ischemia: Can cause severe vasoconstriction, leading to reduced blood flow (ischemia) and reperfusion injury, which damages the BBB.	Long-term BBB dysfunction: Chronic use leads to sustained impairment of barrier integrity, contributing to neuronal damage, neuroinflammation, and and potentially facilitating the entry of toxins.	Known for its vasoconstrictive properties, which contribute significantly to its neurotoxic effects and BBB impact.
Nicotine	Passive diffusion: Highly lipophilic and readily crosses the BBB.	Generally considered to have relatively minor direct disruptive effects on BBB integrity at typical levels of consumption. Some studies suggest: - May influence the expression and function of certain transporters at the BBB. - Can have pro-inflammatory effects that could indirectly impact BBB in the long term, particularly in the context of other health conditions.	Unclear. While nicotine itself may not be a primary BBB disruptor, chronic smoking involves exposure to numerous other harmful chemicals that can significantly impair BBB function.	Primarily acts on nicotinic acetylcholine receptors in the brain.
Psilocybin (from Magic Mushrooms)	Passive diffusion: Crosses the BBB, although its penetration might be somewhat limited by its structure compared to highly lipophilic drugs. Its active metabolite, psilocin, is more lipophilic and readily crosses.	Current research suggests minimal direct damaging effects on the structural integrity of the BBB at typical psychedelic doses. Some studies indicate potential for: - Increased neuroplasticity: While not direct BBB damage, psilocybin's effects on neuronal connections are significant. The implications for BBB function in the long term are not fully understood. - Anti-inflammatory potential: Some preliminary research suggests potential anti-inflammatory effects, which could theoretically be protective for the BBB.	Long-term effects on the BBB are largely unknown and require further research. Current evidence does not suggest significant structural damage.	Primarily acts as a serotonin (5-HT2A) receptor agonist in the brain. Research is ongoing into its therapeutic potential.
Kratom (Mitragynine, 7-hydroxymitragynine)	Passive diffusion: Main alkaloids (mitragynine and 7-hydroxymitragynine) are sufficiently lipophilic to cross the BBB.	Research on Kratom's direct impact on BBB integrity is limited and emerging. Some in vitro and animal studies suggest: - Potential for minor transient changes in permeability at high doses. - May interact with efflux transporters (e.g., P-glycoprotein), which could influence its own brain penetration and that of other substances. - Neuroinflammatory effects are not well-established, but opioid-like effects could indirectly influence the BBB.	Long-term effects on BBB integrity are not well-characterized. More research is needed to determine if chronic use leads to sustained changes.	Acts primarily as an opioid receptor agonist, but also interacts with other receptor systems. Legal status varies by region.
Dextromethorphan (DXM)	Passive diffusion: Readily crosses the BBB due to its lipophilicity. <br> Active transport: May also involve carrier-mediated transport.	Generally considered to have minimal direct disruptive effects on BBB integrity at therapeutic doses. At high, recreational (abusive) doses: <br> - Excitotoxicity/Neurotoxicity: High doses can lead to excitotoxicity and neuroinflammation, which can indirectly impact BBB integrity. - Oxidative stress: Potential for oxidative stress, which could compromise endothelial cells.	Long-term effects on BBB integrity from chronic recreational abuse are not fully established but are a concern given its neurotoxic potential at high doses.	A common cough suppressant (NMDA receptor antagonist at higher doses). Its metabolite, dextrorphan, is also active.
MDMA (Ecstasy, Molly)	Passive diffusion: Readily crosses the BBB due to its lipophilic nature. May involve specific transporters for entry into neurons.	Significant disruption, especially at high doses or with hyperthermia: - Tight junction disruption: Can directly impair tight junction proteins, leading to increased BBB permeability (leakiness).- Oxidative stress: Induces free radical formation, damaging endothelial cells and contributing to barrier breakdown. - Neuroinflammation: Triggers microglial activation and release of pro-inflammatory cytokines, which further compromise BBB integrity. - Matrix Metalloproteinase (MMP) activation: Increases activity of enzymes that degrade extracellular matrix components and tight junction proteins.	Potential for persistent BBB dysfunction: Chronic use can lead to sustained alterations in barrier function, contributing to neurotoxicity and making the brain more vulnerable to peripheral insults and contributing to neuroinflammation.	Primarily causes massive release of serotonin, dopamine, and norepinephrine. Hyperthermia, often associated with MDMA use, significantly exacerbates BBB damage.

General Considerations (apply to all substances):

Dose and Duration: The impact on the BBB is often dose-dependent and more pronounced with chronic and high-dose use/abuse.
Individual Variability: Genetic factors, pre-existing health conditions, and individual metabolic differences can influence the BBB's response.
Route of Administration: How the substance is administered (e.g., smoking, injecting, oral) can influence the speed and concentration with which it reaches the brain, potentially affecting BBB impact.
Poly-substance Use: Using multiple substances simultaneously can lead to complex and potentially synergistic (or antagonistic) effects on the BBB.
Neuroinflammation: Inflammation within the brain is a common consequence of many forms of substance abuse and is a significant contributor to BBB dysfunction and neuronal damage.
Research Limitations: Studying the direct impact of psychoactive substances on the human BBB is complex. Much of the current understanding comes from in vitro studies, animal models, or indirect clinical observations. More human-specific research is continually needed.

Concluding Comments

Addressing the intricate challenges of substance use, whether illicit or readily accessible, requires a proactive and informed approach from our communities. As highlighted in this blog, understanding trending drugs, their street names, packaging, and points of access is essential not only for K9 practitioners but also as a critical protective measure for our youth. For parents, educators, administrators, and healthcare providers, it is crucial to recognize the impact of these substances on the organ systems, particularly the sensitive Blood-Brain Barrier in developing teenagers. By utilizing expert insights from webinars, conferences, and seminars, we can equip ourselves with the essential knowledge necessary to protect the health and future of our students, creating environments where informed choices can prevail.