SweetSue's Class Notes

[SweetSue]

States With Legal Recreational Cannabis Have Fewer Vaping Lung Injuries, Study Finds


Article
Apr 08, 2020


The researchers found that the average recreational cannabis state had 1.7 EVALI cases per million people. In contrast, the EVALI case rate in medical cannabis states was calculated to be 8.8 cases per million, and in prohibition states 8.1 cases per million, though the difference in EVALI case rate between medical and prohibition states wasn’t deemed statistically significant.

“It appears states that have legal access to marijuana have lower rates of EVALI cases, which is consistent with the hypothesis that people have demand for marijuana products, and in states where they don't have access to them in this regulatory fashion, they end up purchasing them elsewhere,” said study author Alex Hollingsworth, to MedPage Today.

 

[SweetSue]

Source

Peptides of love and fear: vasopressin and oxytocin modulate the integration of information in the amygdala.
Debiec J1.
Author information
Abstract
Neuropeptides vasopressin and oxytocin regulate a variety of behaviors ranging from maternal and pair bonding to aggression and fear. Their role in modulating fear responses has been widely recognized, but not yet well understood. Animal and human studies indicate the major role of the amygdala in controlling fear and anxiety. The amygdala is involved in detecting threat stimuli and linking them to defensive behaviors. This is accomplished by projections connecting the central nucleus of the amygdala (CeA) to the brain stem and to hypothalamic structures, which organize fear responses. A recent study by Huber et al demonstrates that vasopressin and oxytocin modulate the excitatory inputs into the CeA in opposite manners. Therefore this finding elucidates the mechanisms through which these neuropeptides may control the expression of fear.

 

[SweetSue]

Is this not the coolest picture? Think of how small an individual cell is.


View media item 1764217

 

[SweetSue]

Emotional Rescue: The Heart-Brain Connection

Emotional Rescue: The Heart-Brain Connection


The silent, often subconscious conversation that is taking place inside us is one of the most vital communications we will ever find ourselves engaged in. It’s the dialogue of emotion-based signals between our hearts and our brains, also known as the heart-brain connection. Our author tells us what research has uncovered and some of the keys to a longer, healthier life.

Published: May 8, 2019
Author: Michael Miller, M.D.
ASSOCIATED PODCAST

Illustration by EGADS

We’ve known for decades that smoking, hypertension, high cholesterol, and diabetes account for most cardiovascular problems. But it wasn’t until publication of the Interheart study (25,000 volunteers spanning 52 countries) that emotional stress was identified as another key risk factor, accounting for about one-third of heart attacks and strokes. Previously, in the 1970s, when volunteers were asked to begin to count to 100 and then to serially subtract seven’s in quick succession (in a test of “mental stress”), blood vessels constricted as if they had taken and failed a cardiac stress test. Except in these cases, testing occurred at rest.

In other words, external stressors that are not effectively managed have direct internal implications by placing undue stress on the heart. Fast forward from the 1970s to the present era, and a recent study of more than 135,000 men and women in Sweden that found a history of stress-related disorders, such as post-traumatic stress syndrome, increased the risk of cardiovascular disease by more than 60 percent within just the first year of diagnosis.

Mechanistically, the underlying cause of a heart attack is a sudden rupture of an unstable plaque within a coronary artery. During stressful situations, the “fight-or-flight” response jumps into full gear, releasing biochemical compounds such as adrenaline, which raises heart rate and blood pressure, and signals platelets to release a chemical, neuropeptide Y, that can cause spasm and transient occlusion of the coronary artery.

Another cardiac condition that can result from acute emotional stress is Takotsubo cardiomyopathy, named for the Japanese octopus-trapping pot that the heart comes to resemble. Most commonly occurring after a sudden catastrophic event such as losing a spouse, an outpouring of adrenaline creates a transiently “shocked” state characterized by markedly abnormal contractions in a section of left ventricle and by heart failure. Resolution of the emotional crisis coupled with supportive care generally, but not always, leads to recovery of heart function.

Beyond single, severely stressful events, living day-to-day with stress is clearly associated with increased risk of heart attack and stroke. We have only recently begun to understand the neurochemical pathways that generate atherosclerosis and cardiovascular disease. They include close communication between the central nervous system, heart, adrenal gland, and kidneys involved in the activation and release of stress hormones such as cortisol and heart damaging neuropeptides.
On another level, we have come to appreciate that chronic psychosocial or mental stress accelerates cardiovascular disease by promoting inflammation, oxidative stress, and abnormal function of the endothelium, the protective inner lining of our blood vessels.

Connecting to the Brain’s Emotional Coding Center
If we are to understand how to improve emotional health, it would be useful to probe the brain’s emotional coding center, the amygdala. As an undergraduate at Rutgers University, I had the opportunity to work with Drs. Arthur Kling and Robert Deutsch, a psychiatrist and a neuroscientist doing seminal research into the role of the amygdala in socialization and emotion. After Kling’s team induced frontal lobe lesions in rhesus monkeys and severed connections to the amygdala, their social interactions came to a near halt. Similar behavioral patterns have been reported following amygdalotomy for other emotional behaviors in humans, including pathologic aggression. Loss of socialization skills also occurred after prefrontal lobotomy, as I directly encountered when recording social interactions in patients who had undergone the procedure.

The association between high levels of social connectivity and favorable cardiovascular effects, including better outcomes after stroke, raises the possibility that a larger amygdala may afford cardioprotection. The Leiden Longevity Study supports this concept: large left amygdala volumes were not only associated with a high level of emotional health, but also correlated with familial longevity. By contrast, reduced social interactions caused by panic disorders have been associated with reduced amygdala volumes in the lateral and basal regions believed to process fear and anxiety. These disorders correlate with reduced parasympathetic tone, a known contributor to cardiovascular disease risk.

Beyond single, severely stressful events, living day-to-day with stress is clearly associated with increased risk of heart attack and stroke.

Amygdala activity has also been suggested to play a role in cardiovascular disease risk prediction. For example, residing in high-paced, crowded, noisy, and polluted cities leads to activation of the perigenual anterior cingulate cortex, a brain region that regulates amygdala activity and response to psychosocial stress. Chronic exposure to stress results in allostatic load that adversely impacts brain plasticity and cardiovascular risk factors, including an exaggerated blood pressure response owing to activation of the perigenual cingulate cortex.

In a study conducted in Boston, increased amygdala activity at rest, assessed by PET/CT imaging, was also associated with blood vessel inflammation and risk of cardiovascular events over the next four years. The authors proposed that emotional stress signals a region of the amygdala to activate the sympathetic nervous system, promoting the production of pro-inflammatory white blood cells that may trigger heart attack, stroke, or sudden death. This study, among the first to demonstrate a direct relationship between emotional stressors and risk of cardiovascular events builds upon prior work identifying a direct association between amygdala reactivity (in response to threatening facial expressions) and increased carotid intima-media thickness, an anatomic biomarker of atherosclerosis and cardiovascular risk predictor.

Does counteracting negative stressors reduce cardiovascular risk? While no clinical outcome trials have been conducted to date, adoption of lifestyle strategies aimed at improving positive emotions seems to improve biomarkers of cardiovascular health, such as inflammation, arterial stiffness, and endothelial function. In my cardiology practice and as elaborated upon below, I recommend that my patients employ these five strategies to reduce day-to-day stressors:

1. Meditation (serotonin activated relaxation practices)
2. Yoga (GABA induced mood stabilization)
3. Laughter (endorphin mediated visual effects)
4. Music (dopamine regulated auditory effects
5. Massages, hugging (oxytocin activated tactile responses)

Relaxation Practices
There are several mechanisms by which relaxation strategies such as these improve biomarkers of cardiovascular risk. The first is improvement in parasympathetic tone, the heart’s ability to maintain blood pressure and/or heart rate in the face of daily stressors. (This contrasts with the “fight-or-flight” response described earlier, an adaptive physiological mechanism characterized by increased sympathetic tone with associated rise in blood pressure and heart rate). Examples include the inordinate or “hysterical” strength that arose in a daughter attempting to save her father who was pinned under a car and a mother fighting off a lion that attacked her son.

Such isolated “spring into action” situations have no lasting cardiovascular consequences in otherwise healthy individuals. But regularly occurring stressful situations can result in persistently heightened sympathetic tone. Under these conditions, the heart is chronically stressed by exaggerated blood pressure and heart rate responses that endure after the stressful situation is resolved. A persistent increase in sympathetic tone, moreover, raises the likelihood of inflammation, abnormal heart rhythms, and increased risk of sudden cardiac death.

On the other hand, reduced sympathetic or increased parasympathetic or vagal tone enables the heart to manage stressors, keeping blood pressure and heart rate under better control during stress, and shortening recovery time after activities that raise heart rate (such as aerobic activity). Relaxation strategies like those described above are among the most effective ways to improve parasympathetic tone. Their benefits are also indicated by tests using heat mapping to evaluate the expression of genes that promote oxidative stress and inflammation, important biomarkers for cardiovascular disease.
One recent study, for example, found that in a group that had practiced meditation on a regular basis, the expression of pro-inflammatory genes was reduced compared to those who had never mediated. In the second stage of the study, one half of the non-meditating group was randomly assigned to relaxation training sessions incorporating meditation, prayer, and yoga. After two months, genetic expression of pro-inflammatory genes resembled that of long-time meditators. Practicing relaxation also reduced the expression of genes promoting insulin resistance, the forerunner of Type 2 diabetes. The results of this study not only affirmed the importance of brain-heart connections on a molecular level but found that relaxation can have a robust effect in a very short time, supporting the adage “never too late to start.”

Mindfulness meditation , which has become one of the most popular relaxation practices over the past decade, combines heightened, non-judgmental awareness of one’s surroundings and feelings with slow deep breathing exercises. A stress-reduction program based on mindfulness has been associated with improvement in hypertension and depression, while strengthening the immune system and raising activity of telomerase, an enzyme that slows biological aging.

Researchers have also studied the cardiovascular impact of practices that incorporate relaxation and movement. Yoga and Tai Chi, for example, improve balance and coordination to help the elderly prevent falls and fractures, and bolster strength and stabilization. In cardiovascular terms, yoga is associated with reduced systolic blood pressure and cholesterol: a recent meta-analysis of 49 trials found that three sessions of yoga weekly reduced systolic blood pressure as much as low-dose antihypertensive medication. Tai Chi has been shown to help suppress inflammation and depression, both cardiovascular disease risk factors. Finally, yoga may also raise brain levels of γ-aminobutyric acid (GABA), a neurotransmitter involved in mood stabilization and stress reduction and both yoga and meditation practices lead to the release of serotonin, another important neurotransmitter involved in mood regulation.

Comic Relief
While it has long been thought that laughter can induce a sense of well-being through the release of endorphins, its connection to cardiovascular health has only become apparent in recent years. Specifically, the β-endorphins released by a hearty belly laugh bind to receptors on the surface of the vascular endothelium to release nitric oxide, a molecule with multiple cardioprotective properties. Recent studies have, in fact, found the risk of heart attack and stroke is reduced in individuals who laugh on a regular basis, compared to those who never or rarely laugh. Laughter also reduces stiffness and aging of blood vessels, including those in the brain.

A popular way to combine laughter with deep breathing techniques is through laughter yoga. The origins of this practice date back to 1995 when Dr. Madan Kataria, a family physician, assembled a small group in a public park in Mumbai, who met each morning to laugh together through a series of funny expressions and movements that Dr. Kataria devised. Nearly 25 years later, more than 15,000 laughter yoga clubs exist in more than 70 countries worldwide.

A typical session lasts from 30 to 60 minutes, during which a leader engages participants in exercises designed to elicit forced laughter that converts to emotional laughter as the session wears on. One popular exercise is “milkshake or cocktail laughter,” where participants pretend to pour a glass of milk (or cocktail) into one hand saying “here” then into the other hand repeating “here” and then pretending to drink it or discard it behind their shoulder with repeated laughter.

The benefits of laughter yoga include decreased cortisol levels and systolic blood pressure, as well as improvement in indices of depression and overall life satisfaction. While research in this field remains sparse, the encouraging results from these small-scaled studies support the development of a clinical trial in which laughter therapy is one component of an integrated therapeutic lifestyle designed to reduce cardiovascular events.

Music to Your Ears
A number of studies have demonstrated that listening to joyful music offers cardioprotective and neurobiological effects, including reduced inflammation, blood pressure and heart rate, improved parasympathetic tone, and shortened recovery following surgery. The “frisson effect,” or the feeling of chills down the spine is a physiological consequence related to the release of dopamine in response to listening to or anticipating pleasurable music. A pilot study suggested that focusing on this sensation (i.e., mindful music) may be a useful intervention to speed recovery following stroke.

The Moral Molecule
The hormone and neurotransmitter oxytocin, released from the posterior pituitary during physical encounters such as touching and hugging, can lower blood pressure and heart rate. More surprisingly, research in recent years has demonstrated that the compound has a direct cardioprotective effect. In animal models, administration of oxytocin not only prevents the death of heart tissue that results in heart failure but may also regenerate new cells. In human studies, intranasal oxytocin has been shown to improve parasympathetic tone during a mental stress test and may offer relief in chronic pain; the latter has intriguing cardiovascular implications, because chronic pain is associated with increased risk of death from heart disease and stroke.

More work needs to be done to pinpoint the impact of many of the practices mentioned above. But there is already enough research to conclude that effective management of day-to-day psychosocial stressors is vital to good overall heart and brain health. Beyond good nutrition and regular physical activity, then, consider practicing meditation or yoga on a routine basis. Laugh, listen to music, and hug your favorite people and pets. Such are the keys to a longer, happier life.

Financial Disclosure: The author has no conflicts of interest to report.

 

[SweetSue]

Cannabinoids 101 - Green Flower Media Fundamentals Of Cannabis course

Cannabinoids

• endocannabinoids - made by the body
• phytocannabinoids - made by plants (mostly cannabis)
• synthetic cannabinoids
  • there are hundreds out there
  • some are deadly dangerous
  • Dronabinol (Marinol) used for
    • chemo nausea
    • HIV wasting
  • Dronabinol has
    • low bioavailability
    • significant side effect

Phytocannabinoids are simply referred to as cannabinoids in the cannabis industry

• produced in glandular trichomes
  • tiny, complex factories
  • produce
    • multiple cannabinoids
    • terpenoids
    • flavonoids
    • esters

Cannabinoids and terpene production pathways are intricitly linked

• cannabigerolic acid (CBGA) is first cannabinoid produced
  • is the precursor to all other cannabinoids
• CBGA is made by 'borrowing' compounds first produced via terpenoid pathways
• CBGA goes through oxidocyclization to become
  • cannabidolic acid (CBDA)
  • cannabinochromenic acid (CBCA)
  • tetrahydrocannabinolic acid (THCA)
  • various other cannabinoid acids

With heat or time acid cannabinoids will naturally decarboxylate

• lose their carboxylic groups
  • they lose 2 oxygen atoms and 1 hydrogen atom
• this process is the same for all cannabinoids
• THCA becomes THC, CBDA becomes CBD, and so on.
• Decarb is a function of heat and time
  • drying and curing allow for significant amounts of decarb
  • naturally, it's nearly impossible to control decarb for consistency
  • we have methods of controlled heat and time to consistently decarb
  • heating of combustion or vaping at high temps will decarb
    • enough heat energy to make the carboxyl groups float off
  • decarb is skipped when you want acid cannabinoids in the end product

The major cannabinoids

THC

• most famous because it's psychoactive
• when smoked or vaped, quickly enters the bloodstream
  • transported throughout the body
  • organs and CNS have eCBRs
  • THC activates eCBRs
    • effects biological & cognitive processes like
      • appetite
      • mood
      • motor coordination
      • memory
  • an agonist of eCBRs
    • it activates the receptor
    • causing biological chain reaction (resulting in cascade)
• THC can improve symptoms of
  • spasticity
  • pain
  • muscle spasms
  • viable choice for
    • MS
    • Parkinson's
    • several other neurodegenerative disorders
  • Sativex (1:1 product of GW Pharmaceuticals)
    • available throughout EU, Canada, Australia, NZ, some Latin American countries
    • currently going through approval process in USA
  • THC shows efficacy for opioid tapering and replacement
    • associated with significant reduction in legal states
      • opioid addiction
      • opioid deaths
  • increasingly used as appetite stimulant for cancer and HIV/AIDS
    • these patients consistently find THC
      • improves mood
      • reduces pain
      • reduces depression

CBD

Pick up here later

 

[SweetSue]

Reworking:

In a nutshell, chronic stress changes the plasticity of the receptors that regulate mood, causing depression. This process appears to be triggered by the downregulation of CB1 receptors in certain areas of the brain closely associated with the adrenal system. This downregulation may be caused by the increase in stress hormones floating in the internal sea of the brain.

It's CB1 receptors we want to activate for the mood regulation, and I believe CBD may fascilitate this by working on the receptors in subtle ways. It's been shown that injury to the brain causes an uptick in the number of CB2 receptors, but this is for purposes of reducing inflammatory response, as far as I can understand.

My experience has been that a balanced ratio, or one slightly tilted in favor of CBD, works effectively in the treatment of depression, at least with my patients. Every individual body will have an individual experience. This is why we start low and work up slowly.

To be annotated:



Chronic Stress Impairs α1-Adrenoceptor-Induced Endocannabinoid-Dependent Synaptic Plasticity in the Dorsal Raphe Nucleus

Samir Haj-Dahmane and Roh-Yu Shen
Journal of Neuroscience 29 October 2014, 34 (44) 14560-14570; DOI: Chronic Stress Impairs α1-Adrenoceptor-Induced Endocannabinoid-Dependent Synaptic Plasticity in the Dorsal Raphe Nucleus


Serotonin (5-hydroxytryptamine [5-HT]) neurons in the dorsal raphe nucleus (DRn) (Dahlström and Fuxe, 1964) provide major serotonergic projections to brain areas controlling the behavioral and neuroendocrine responses to stress (Petrov et al., 1994). By modulating the stress-associated neuronal circuits, DRn 5-HT neurons control stress homeostasis and mood (Joëls and Baram, 2009).

Indeed, animal studies have shown that the behavioral responses to various stressors are mediated, at least in part, by the activation of 5-HT system. For instance, exposure to uncontrollable stressors (e.g., tail shock) activates DRn 5-HT neurons and enhances 5-HT transmission (Amat et al., 1998; Maswood et al., 1998; Grahn et al., 1999).

Activation of DRn 5-HT neurons also regulates uncontrollable stress-induced learned helplessness (Grahn et al., 1999), characterized by a set of behaviors, including reduced escape to aversive stimuli, increased fear conditioning, and anxiety (Maier et al., 1994, 1995). Conversely, inhibition of DRn 5-HT neurons reduces the behavioral responses to uncontrollable stressors (Maier et al., 1994, 1995), indicating that DRn 5-HT neurons play a key role in modulating the behavioral responses to uncontrollable stress (Maier and Watkins, 2005).

Furthermore, results from clinical studies have established that stress-induced dysregulation of the 5-HT system is a major contributing factor for the development of mood disorders, such as depression and anxiety (Southwick et al., 2005; Lupien et al., 2009).

The DRn receives a major noradrenergic input from the locus ceruleus (Baraban and Aghajanian, 1981), which activates DRn 5-HT neurons (Baraban and Aghajanian, 1981) and regulates arousal and stress homeostasis (Morilak et al., 2005; Stone et al., 2007).

Previous studies have shown that exposure to various stressors increases noradrenaline release in the DRn (Tanaka et al., 1983; Shimizu et al., 1994) and induces anxiety-like behaviors (Chiba et al., 2012; Kim et al., 2012), at least in part, via the activation of α1-ARs located on DRn 5-HT neurons (Stone et al., 2007).

α1-AR signaling in the DRn also regulates fear conditioning, as blockade of these receptors prevents conditioned fear and impairs escape performance (Grahn et al., 2002). Furthermore, disruption of DRn α1-AR signaling alters the behavioral effects of antidepressant and antianxiety drugs (O'Leary et al., 2007; Doze et al., 2009). Collectively, these studies indicate that α1-AR-mediated control of DRn 5-HT neurons plays an important role in the regulation of stress homoeostasis and that the alteration of α1-AR signaling in the DRn might contribute to stress-related mood disorders.

Remarkably, despite the crucial role of α1-AR signaling in the DRn in controlling the behavioral responses to stress, the effects of chronic stress on α1-AR-mediated control of the excitability of 5-HT neurons and synaptic transmission in the DRn remain unknown. In this study, we show that exposure to chronic restraint stress (CRS) impairs α1-AR LTD of glutamate synapses in the DRn but has no effects on α1-AR-induced membrane depolarization/inward current in DRn 5-HT neurons. The CRS-induced impairment of α1-AR LTD is mediated by a downregulation of eCB signaling. Such results unravel a novel cellular mechanism by which chronic stress could induce long-lasting changes in the function of the 5-HT system.

Discussion

The present study shows that activation of α1-ARs elicits LTD of glutamate synapses onto DRn 5-HT neurons. This form of synaptic plasticity is initiated by the activation of postsynaptic α1-ARs but expressed presynaptically by a decrease in glutamate release.

The α1-AR LTD is signaled by retrograde eCB messengers acting on presynaptic CB1 receptors. More importantly, we report that exposure to CRS profoundly reduces of the magnitude of α1-AR LTD.

The CRS-induced impairment of α1-AR LTD is essentially mediated by a downregulation of presynaptic CB1 receptors. As such, our study reveals a novel cellular mechanism by which noradrenaline controls the function of DRn 5-HT. It also provides the first direct evidence that chronic stress reduces eCB signaling at glutamate synapses of DRn 5-HT neurons, which could have important functional implications for stress-induced maladaptation of the 5-HT system.

Previous studies have examined the regulation of glutamate synapses by α1-ARs in various brain areas (Scanziani et al., 1993; Scheiderer et al., 2004; Choi et al., 2005; McElligott and Winder, 2008; Marzo et al., 2010; McElligot et al., 2010). Generally, these studies have reported that activation of α1-ARs elicits a transient inhibition of glutamatergic transmission.

However, in some brain areas, such as the cerebral cortex (e.g., visual cortex and prefrontal cortex), hippocampus, and the bed nucleus of striata terminalis, activation of α1-ARs induces LTD of glutamate synapses (Scheiderer et al., 2004; Choi et al., 2005; McElligott and Winder, 2008; Marzo et al., 2010; McElligot et al., 2010).

Depending on the brain area studied, the α1-AR LTD seems to be mediated by different cellular mechanisms. In the hippocampus and cerebral cortex, the α1-AR LTD is mediated by a postsynaptic mechanism that involves α1-AR-induced activation of the extracellular signal regulating kinase (ERK1/2) pathways (Scheiderer et al., 2008; Marzo et al., 2010).

Activation of ERK 1/2 induces LTD by reducing the function and/or number of AMPARs. At glutamate synapses of the bed nucleus of striata terminalis, the α1-AR LTD is mediated by a switch of the subunit composition of AMPARs from GluA2-lacking, which exhibit higher unitary conductance and calcium permeability (Kamboj et al., 1995; Dingledine et al., 1999), to GluA2 containing AMPARs (McElligott et al., 2010).

In the DRn, the present study shows that the α1-AR LTD is initiated by the activation of postsynaptic α1-ARs but mediated by a decrease in glutamate release induced by retrograde eCB messengers. This cellular mechanism is supported by multiple lines of evidence. First, inhibition of postsynaptic α1-AR signaling with G-protein inhibitors abolishes the LTD.

Second, α1-AR LTD is associated with a persistent decrease in glutamate release as indicated by the increase in PPR and CV. Finally, blockade of presynaptic CB1 receptors or inhibition of 2-AG synthesis abolishes the α1-AR LTD.

The conclusion that the α1-AR LTD of glutamate synapses onto DRn 5-HT neurons is mediated by 2-AG acting at presynaptic CB1 receptors is consistent with numerous studies showing that activation of Gq/11-coupled receptors, such as Group I metabotropic glutamate receptors (mGluR1/5), M1/M5 muscarinic receptors, and orexin receptors, increase the synthesis/release of 2-AG in various brain areas (Maejima et al., 2001; Kim et al., 2002; Ohno-Shosaku et al., 2003), including the DRn (Haj-Dahmane and Shen, 2005).

Generally, Gq/11 coupled receptor-driven 2-AG synthesis and release mediate transient inhibition of excitatory and inhibitory synaptic transmission (Maejima et al., 2001; Kim et al., 2002; Haj-Dahmane and Shen, 2005). However, growing evidence indicates that this mode of 2-AG synthesis/release also mediates the presynaptic form of LTD at glutamate and GABA synapses and, hence, plays an ubiquitous role in regulating synaptic plasticity in the brain (Castillo et al., 2012).

Results from previous studies have reported that chronic exposure to various stressors increases the expression in the DRn of various synaptic proteins, such as synaptosomal-associated protein 25 and synaptic vesicle glycoprotein 2B (Abumaria et al., 2006, 2007), suggesting that chronic stress can induce a long-lasting alteration of synaptic function and plasticity in the DRn.

Consistent with this idea, we report that CRS impairs the α1-AR LTD of glutamate synapses onto DRn 5-HT neurons. The alteration of α1-AR-mediated synaptic plasticity in the DRn may represent an important cellular mechanism by which chronic stress can induce a long-lasting alteration of the 5-HT system.

The effects of restraint stress on the α1-AR-mediated control of synaptic transmission have also been examined in several other brain areas. In the amygdala, exposure to acute restraint stress combined with tail shock blocks the α1-AR-mediated facilitation of GABA-ergic transmission (Braga et al., 2004). The mechanisms underlying this effect remain unknown.

Here, we find that acute exposure to restraint stress has no effect on the ability of α1-ARs to control the function of glutamate synapses. In contrast, exposure to CRS profoundly impairs the α1-AR LTD of glutamate synapses in the DRn by blocking the induction and maintenance of the LTD. Such finding is in agreement with a previous study showing that exposure to CRS, but not to acute restraint stress, also impairs the LTD of glutamate synapses induced by α1-ARs (McElligott et al., 2010) in the basal nucleus of striata terminalis.

Collectively, these studies suggest that the impairment of the α1-AR-mediated control of the strength and plasticity of glutamate synapses may represent a common response to chronic stress exposure. Importantly, such alterations of synaptic plasticity may mediate the maladaptive behavioral responses to chronic stress, including depression and anxiety.

An interesting finding of the present study is that exposure to CRS has no significant effect on the amplitude of the α1-AR-induced inward current but reduces the effect of presynaptic CB1 receptors on glutamate release.

These results strongly indicate that the CRS-induced impairment of the α1-AR LTD is not mediated by a downregulation of α1-ARs but by a profound reduction of presynaptic CB1 receptor function. However, it remains possible that CRS could also reduce eCB synthesis/release, which may contribute to the impairment of the α1-AR LTD.

The conclusion that CRS reduces the function of presynaptic CB1 receptors is consistent with previous studies showing that chronic exposure to various stressors, including CRS, downregulates CB1 receptors and impairs eCB-mediated control of glutamatergic (Rossi et al., 2008; Wang et al., 2010; Reich et al., 2013) and GABAergic synaptic transmission in other brain areas (Wamsteeker et al., 2010; Hu et al., 2011).

Importantly, in the nucleus accumbens, exposure to chronic stress has also been shown to block the eCB-mediated LTD induced by mGluR1 at glutamate synapses onto medium spiny neurons (Wang et al., 2010). As in the DRn, the blockade of the mGluR1 LTD is mainly attributed to a reduction of presynaptic CB1 receptor function (Wang et al., 2010).

Together, the results of these studies indicate that reduced retrograde eCB signaling (e.g., downregulation of CB1 receptors) may represent a common mechanism by which chronic stress impairs Gq/11-coupled receptor-mediated control of synaptic function and plasticity in the brain.

Although exposure to chronic stress has been shown to impair the function of presynaptic CB1 receptors in various brain areas (Hill et al., 2005; Wang et al., 2010), the precise molecular mechanisms underlying this effect remain unknown. It is well established that exposure to chronic stress increases the circulating levels of corticosterone and noradrenaline (Krugers et al., 2012).

Because both of these stress mediators stimulate eCB synthesis and release in the DRn (Wang et al., 2012; present study) and other brain areas (Di et al., 2003), it is tempting to speculate that the high circulating levels of noradrenaline and corticosterone during daily stress lead to chronic increase in eCB release and activation of CB1 receptors, which could induce downregulation of these receptors.

Consistent with this idea, results from previous studies have shown that chronic exposure to stress enhances the release of 2-AG in various brain regions (Patel and Hillard, 2008; Patel et al., 2009). More importantly, chronic activation of CB1 receptors with eCBs or exogenous cannabinoids has been shown to reduce the function of presynaptic CB1 receptors (Sim et al., 1996; Breivogel et al., 1999).

Thus, it is possible that the CRS-induced functional downregulation of presynaptic CB1 receptors reported in this study could be attributed to an agonist-induced downregulation. However, future studies are required to further test this notion and determine the precise cellular mechanisms underlying the downregulation of presynaptic CB1 receptors.

Extensive work has established that noradrenergic inputs from the locus ceruleus provide a major excitatory drive to the DRn, which is mediated by α1-ARs. Activation of these receptors increases the excitability of DRn 5-HT neurons by inducing membrane depolarization (Aghajanian, 1985; Pan et al., 1994) and reducing the amplitude of after hyperpolarizing potential (Pan et al., 1994).

In addition to these excitatory effects, the present study shows that activation of postsynaptic α1-ARs enhances 2-AG release, which in turn reduces the strength of glutamate synapses onto DRn 5-HT neurons (Fig. 8). Combined, these studies indicate that the noradrenergic modulation of 5-HT neurons is more complex than initially thought and that α1-AR signaling in the DRn exerts a bidirectional control on the excitability of 5-HT neurons.

The bidirectional control exerted by α1-AR could play an important role in maintaining the activity of 5-HT neurons within desirable range and prevent excessive excitation of DRn 5-HT neurons, especially during heightened arousal (e.g., stress), which is characterized by increased noradrenergic tone (Krugers et al., 2012).

As such, the reduction of eCB signaling and the impairment of α1-AR LTD induced by chronic stress may lead to an abnormal increase in the excitability of DRn 5-HT neurons and persistent alteration of central 5-HT transmission.

Furthermore, the impairment of eCB signaling in the DRn could mediate, at least in part, some of the behavioral consequences of chronic stress exposure, such as depression-like behaviors. It is noteworthy that pharmacological manipulation that increases eCB signaling has been shown to block chronic stress-induced depression-like behaviors (Zhong et al., 2014).

A model of α1-ARs mediated regulation of glutamate synapses onto DRn 5-HT neurons. Activation of α1-ARs elicits an increase in the synthesis/release of the eCB messenger 2-AG. The release of 2-AG reduces the strength of glutamate synapses by the activation of presynaptic CB1 receptors. Exposure to CRS impairs α1-AR-mediated depression of glutamate synapses by reducing the function of presynaptic CB1 receptors.

 

[SweetSue]

Cannabinoids 101 - Green Flower Media Fundamentals Of Cannabis course
Including notes from video class on Therapeutic Uses Of Cannabinoids with Samantha Miller (President and Chief Scientist of Pure Analytics, LLC)

Cannabinoids

• substances produced by our bodies and by plants
  • responsible for some of effects of cannabis
  • terpenoids and flavonoids also contribute to effects
• endocannabinoids - made by the body
  • ECS is network of receptors
    • a natural architecture that interacts with phytocannabinoids
      • anandamide and 2AG are known eCBs
    • receptors are the cellular antennas waiting for the signalling peptides
    • modulates/regulates important physiological processes like
      • eating
      • sleeping
      • addiction
      • memory
      • mood
• phytocannabinoids - made by plants (mostly cannabis)
  • cannabis is only plant known to produce significant numbers of cannabinoids
  • produced in the viscous resin of glandular trichomes
    • found on surface of flowers and leaves
• synthetic cannabinoids
  • there are hundreds out there
  • some are deadly dangerous
  • Dronabinol (Marinol) used for chemo nausea
  • HIV wasting
  • Dronabinol has
    • low bioavailability
    • significant side effect

Phytocannabinoids are simply referred to as cannabinoids in the cannabis industry

• produced in glandular trichomes
• tiny, complex factories produce
  • multiple cannabinoids
  • terpenoids
  • flavonoids
  • esters

Cannabinoids and terpene production pathways are intricately linked

• cannabigerolic acid (CBGA) is first cannabinoid produced
  • is the precursor to all other cannabinoids
  • CBGA is made by 'borrowing' compounds first produced via terpenoid pathways
  • CBGA goes through oxidocyclization to become
    • cannabidiolic acid (CBDA)cannabinochromenic acid (CBCA)tetrahydrocannabinolic acid (THCA)various other cannabinoid acids

With heat or time acid cannabinoids will naturally decarboxylate

• lose their carboxylic groups
  • they lose 2 oxygen atoms and 1 hydrogen atom
• this process is the same for all cannabinoids
  • THCA becomes THC, CBDA becomes CBD, and so on.
• Decarb is a function of heat and time
  • drying and curing allow for significant amounts of decarb
  • naturally, it's nearly impossible to control decarb for consistency
• we have methods of controlled heat and time to consistently decarb
• heating of combustion or vaping at high temps will decarb
  • enough heat energy to make the carboxyl groups float off
• decarb is skipped when you want acid cannabinoids in the end product

The major cannabinoids
Relative amounts of phytocannabinoids are determined by genetics

• (1:1, 2:1, 20:1, etc)

total concentrations (i.e. 15% THC with 0.5% CBD) will be determined by

• • genetics
  • growing conditions (mostly light)
• three main types of plants and products (determined by genetics)
  • high-THC
  • high-CBD
  • balanced ratio (equal amounts of THC and CBD, or 1:1)
• different ratios are specific to application
  • 2:1 CBD:THC may be better for anxiety
  • 20:1 will be better for seizure disorder

CBC is showing up in almost every cannabis plant as the second most concentrated cannabinoid

THC Tetrahydrocannabinol

• usually most abundant cannabinoid in cannabis
  • this is now changing with aggressive breeding for other cannabinoids
• most famous because it's psychoactive
  • you’ll experience a shift in perceptions
  • referred to in many ways
    • THC
    • Delta-9-Tetrahydrocannabinol
    • symbols for delta-9-Tetrahydrocannabinol
    • all of these mean the same
• can exist in different forms
  • with very different effects
  • i.e. THCA in growing plant, THC in heated plant material
• when smoked or vaped,
  • quickly enters the bloodstream
  • transported throughout the body organs and CNS have eCBRs
• THC activates eCBRs
  • effects biological & cognitive processes like
    • appetite
    • mood
    • motor coordination
    • memory
• an agonist of eCBRs
  • it activates the receptor causing biological chain reaction (resulting in cascade)
• THC can improve symptoms of
  • spasticity
  • pain
  • muscle spasms
• viable choice for
  • MS
  • Parkinson's
  • several other neurodegenerative disorders
• Sativex (1:1 product of GW Pharmaceuticals)
  • available throughout EU, Canada, Australia, NZ, some Latin American countries
  • currently going through approval process in USA
• THC shows efficacy for opioid tapering and replacement
  • associated with significant reduction in legal states
    • opioid addiction
    • opioid deaths
• increasingly used as appetite stimulant for cancer and HIV/AIDS
  • these patients consistently find THC
    • improves mood
    • reduces pain
    • reduces depression
• Therapeutic uses of THC
  • mild to moderate pain relief
    • can be incredible tool for getting away from opioids post-surgery
  • control of nausea
    • particularly beneficial for AIDS/HIV or cancer patients
  • assist in balancing sleep patterns (insomnia)
    • helps you get to sleep and stay asleep
  • stimulates appetite
  • treats symptoms of depression
  • Note: high doses can exacerbate
    • anxiety
    • bipolar spectrum
    • schizophrenia
    • related disorders
    • patients with the above conditions need to avoid high-THC or proceed cautiously with a doctor’s oversight
      • you’ll need to pay closer attention

Expected levels of THC in cannabis material

• average in California market is about 16%
• some current chemovars are above 25%, but there are few in this class

If economics of cannabis use matter to you it’s helpful to know the value of ratios and how to use them to your best advantage

• find what falls into your price range
• learn to use them to best effect
• new classes of patients are looking for mild to moderate ranges of potency
  • older consumers in particular tend to have lower tolerances for THC
• low potency doesn’t mean it’s low grade, just good for someone who wants lo potency

There’s been an explosion of concentrates

• concentrates changed potency threshold
• changed people’s expectations of anticipated and expected effect

Expected THC levels for concentrates

Mechanically-produced concentrates:

• Kief (cannabis run over dry sieve and glandular heads collected) generally doesn’t get over 30-40% THac
  • usually below those levels
• Hash used to come from Middle East, but is rare now
  • averages about 48% THC
• Bubble hash popularity is waning as other concentrates come along
  • averages around 50%
  • usually tops out at around 65%

Chemically-extracted (with solvents) concentrates:

• BHO extracts
• Wax
• CO2 extracts
• more efficient extractions

Concentrates can be therapeutically beneficial to the right patient

• proceed with caution when using such high concentrations of cannabinoids

Pick up here on notes from Samantha Miller

CBD
Cannabidiol has rocketed into public consciousness

• often erroneously called “the medical marijuana“
  • works best when combined with other cannabinoids
• found to be useful for control of seizure disorders
  • Dravet syndrome
  • Lennox-Gastaut syndrome
• in 2018 Epidiolex (GW Pharmaceuticals) became first CBD med to hit legal US markets for treatment of these syndromes
• Evidence exists showing CBD’s efficacy for neurological diseases
  • Parkinson’s
  • Alzheimer’s
  • CBI
• ...as well as
  • arthritis
  • rheumatism
  • osteoarthritis
  • diabetes
  • plus many other conditions chronic pain among them
• Anecdotally, CBD is most often chosen to treat
  • anxiety
  • depression
  • skin conditions (i.e. psoriasis)
  • gastrointestinal problems
  • chronic pain
• Hemp-derived CBD
  • available everywhere
  • unregulated (quality and potency can be problematic)
  • poor lab documentation
  • little to no terpenes or entourage
  • patients all over the world report positive reactions to use
• medical cannabis-derived CBD
  • includes entourage components
  • available in legal states
  • not yet avail. in Idaho, Kansas,S.Dakota, Nebraska

CBN Cannabinol

• third best-known cannabinoid
• metabolite of THC
  • THC degrades and loses 4 hydrogen atoms to make CBN
    • THC is an unstable molecule
    • age, heat, and UV light damage THC
• found in higher concentration with
  • older buds and plant material
  • poorly-stored plant material
• claimed to be sedating
  • but science doesn’t back that up yet
  • 1975 study showed CBN to potentiate THC to create increased feelings of being
    • drugged
    • dizzy
    • drowsy
• CBN is less studied, but shows affinity as
  • antibacterial
  • anticonvulsive
  • appetite stimulating
• CBN influences
  • regulation of sex hormones
  • production & proliferation of skin cells
  • has been shown to slow ALS in mice studies

Minor Cannabinoids

There are at least 90 other cannabinoids, classified as “minor”

THCV Tetrahydrocannabivarin

• propyl cannabinoid
  • has 3 carbon atom chain instead of 5 found in pentane molecules
  • can have very different properties from pentane cousins
• homolog of THC
• thought to act as antagonist of eCB1
  • antagonist attaches to receptor, but has no effect at low doses
  • at high doses may act as eCB1 agonist
    • effects may be similar to THC at high doses
• also partial agonist of eCB2
• can also stimulate 5HT1 receptor
  • serotonin signalling
  • May produce antipsychotic effects as such
• plants high in THCV found in
  • Afghanistan
  • Pakistan
  • China
  • India
  • Nepal
  • Thailand
  • southern and western Africa
• THCV interest in medical circles is on the rise
  • thought to help regulate the immune response, particularly for
    • inflammation
    • inflammatory pain
  • mouse studies suggest efficacy for
    • reducing blood sugar levels in Type 2 diabetics
    • improve glucose to,Teaneck
    • increase insulin sensitivity

CBG

• thought to be non-psychoactive
• weak agonist of eCB2
  • may be the pathway where it exerts most influence
• weak agonist to eCB1 as well
  • unknown effects through this pathway
• shown to have affinity w/
  • 5HT1-receptor
    • releasing serotonin
  • adrenoceptor
    • controls CNS expression of
      • adrenaline
      • noradrenaline

CBC Cannabichromene

• thought to be second most abundant cannabinoid in cannabis
• in rodent studies CBC produces
  • pain relief
  • anti-inflammatory effects
• studies in humans sadly lacking
• agonist of eCB2
• agonist of TRPA1 receptor
  • responds to external stimuli like
    • heat
    • cold
    • itching

Cannabinoid Acids and Their Properties

Many cannabinoid acids show medicinal value in initial research

• patients tend to be confused about THC and THCA

THCA
the cannabinoid acid form of THC (before decarb, or activation)

• decarb is function of time and heat
• controlled heat and time are needed to create significant levels of decarb
• combustion and vaping both decarb with heat
• an unstable molecule, THCA is aggressively trying to become THC

THCA + HEAT = THC
Reliable decarb for THC = 212° F for 90 minutes

In highest concentrations in growing plant and in raw, dried, unheated plant material

• It used to be thought that acidic cannabinoids had little if any effect in human bodies
  • we know better now
  • dispensaries and individuals took the charge and gathered anecdotal evidence
  • findings from studies of patients using juiced cannabis include usefulness in treating
    • inflammation
    • muscle convulsions
    • spasticity
    • changes in cognitive development
      • seen in children taking acid cannabinoids (both THCA and CBDA)
      • significant shifts in behavior
        • emotional intelligence
        • speech and cognition
• difference in effects is obvious with ingestion
  • your choice is guided by your intentions; depends on patient and their needs
• THCA products like tinctures are popular choice if patient
  • is intimidated by the high
  • wants to try cannabinoid therapies
  • wants an easy way into exploring medical benefits of cannabis
• non-intoxicating
• demonstrates affinity to treat
  • inflammation
  • spasticity
• In very low doses can present as
  • powerful antiepileptic
  • anti-inflammatory
  • anti-nausea properties
• early research suggests value in combining THC and THCA to treat
  • seizures
  • pain
  • arthritis
• Examples of THCA (or other acid cannabinoids) products:
  • cannabis juice (use lemongrass juicer to prevent decarb)
    • the most direct way to get THCA
  • glycerin or alcohol tinctures (No heat!)
  • water-extracted hash
• Note: Acid cannabinoids can take 3-4 weeks of daily use to demonstrate the benefits.
  • combined therapies work most efficiently
    • acidic cannabinoid daily therapies can reduce intensity of chronic pain expression
    • THC may still be needed for breakthrough pain or rough days
    • some THCA will be naturally activated into THC in plant material
      • be alert for some psychoactivity
      • will be much less than if fully activated

CBDA

• appears to have strong properties for
  • antiepileptic
  • anti-inflammatory
  • anti-nausea
    • appears to be much better than CBD for nausea
    • at far lower doses than CBD
• may also
  • stop spread of breast cancer cells
  • improve symptoms of depression
• appears to work well with CBD
  • combining CBD and CBDA may lead to more rapid onset of effects

Cannabinoid Isomers
Cannabinoids that have the same atomic makeup but are structured differently in three-dimensions

• structural isomers are arranged differently
• stereoisomers are more or less mirror images of each other

Slight differences in arrangement make significant differences in effect

Delta-8 THC

• mildly psychoactive
• like delta-9 THC it’s a partial agonist of eCB1
• effects include
  • antiemetic (anti-vomit)
  • antioxylitic (anti-anxiety)
  • antiepileptic
  • anti-tumor
  • neuroprotective
  • appetite-stimulating
    • 2004 study suggests more so than delta-9 THC

 

[SweetSue]

Cannabinoids 101 - Green Flower Media Fundamentals Of Cannabis course
Including notes from video class on Therapeutic Uses Of Cannabinoids with Samantha Miller (President and Chief Scientist of Pure Analytics, LLC)

Cannabinoids

• substances produced by our bodies and by plants
  • responsible for some of effects of cannabis
  • terpenoids and flavonoids also contribute to effects
• endocannabinoids - made by the body
  • ECS is network of receptors
    • a natural architecture that interacts with phytocannabinoids
      • anandamide and 2AG are known eCBs
    • receptors are the cellular antennas waiting for the signalling peptides
    • modulates/regulates important physiological processes like
      • eating
      • sleeping
      • addiction
      • memory
      • mood
• phytocannabinoids - made by plants (mostly cannabis)
  • cannabis is only plant known to produce significant numbers of cannabinoids
  • produced in the viscous resin of glandular trichomes
    • found on surface of flowers and leaves
• synthetic cannabinoids
  • there are hundreds out there
  • some are deadly dangerous
  • Dronabinol (Marinol) used for chemo nausea
  • HIV wasting
  • Dronabinol has
    • low bioavailability
    • significant side effect

Phytocannabinoids are simply referred to as cannabinoids in the cannabis industry

• produced in glandular trichomes
• tiny, complex factories produce
  • multiple cannabinoids
  • terpenoids
  • flavonoids
  • esters

Cannabinoids and terpene production pathways are intricately linked

• cannabigerolic acid (CBGA) is first cannabinoid produced
  • is the precursor to all other cannabinoids
  • CBGA is made by 'borrowing' compounds first produced via terpenoid pathways
  • CBGA goes through oxidocyclization to become
    • cannabidiolic acid (CBDA)cannabinochromenic acid (CBCA)tetrahydrocannabinolic acid (THCA)various other cannabinoid acids

With heat or time acid cannabinoids will naturally decarboxylate

• lose their carboxylic groups
  • they lose 2 oxygen atoms and 1 hydrogen atom
• this process is the same for all cannabinoids
  • THCA becomes THC, CBDA becomes CBD, and so on.
• Decarb is a function of heat and time
  • drying and curing allow for significant amounts of decarb
  • naturally, it's nearly impossible to control decarb for consistency
• we have methods of controlled heat and time to consistently decarb
• heating of combustion or vaping at high temps will decarb
  • enough heat energy to make the carboxyl groups float off
• decarb is skipped when you want acid cannabinoids in the end product

The major cannabinoids
Relative amounts of phytocannabinoids are determined by genetics

• (1:1, 2:1, 20:1, etc)

total concentrations (i.e. 15% THC with 0.5% CBD) will be determined by

• • genetics
  • growing conditions (mostly light)
• three main types of plants and products (determined by genetics)
  • high-THC
  • high-CBD
  • balanced ratio (equal amounts of THC and CBD, or 1:1)
• different ratios are specific to application
  • 2:1 CBD:THC may be better for anxiety
  • 20:1 will be better for seizure disorder

CBC is showing up in almost every cannabis plant as the second most concentrated cannabinoid

THC Tetrahydrocannabinol

• usually most abundant cannabinoid in cannabis
  • this is now changing with aggressive breeding for other cannabinoids
• most famous because it's psychoactive
  • you’ll experience a shift in perceptions
  • referred to in many ways
    • THC
    • Delta-9-Tetrahydrocannabinol
    • symbols for delta-9-Tetrahydrocannabinol
    • all of these mean the same
• can exist in different forms
  • with very different effects
  • i.e. THCA in growing plant, THC in heated plant material
• when smoked or vaped,
  • quickly enters the bloodstream
  • transported throughout the body organs and CNS have eCBRs
• THC activates eCBRs
  • effects biological & cognitive processes like
    • appetite
    • mood
    • motor coordination
    • memory
• an agonist of eCBRs
  • it activates the receptor causing biological chain reaction (resulting in cascade)
• THC can improve symptoms of
  • spasticity
  • pain
  • muscle spasms
• viable choice for
  • MS
  • Parkinson's
  • several other neurodegenerative disorders
• Sativex (1:1 product of GW Pharmaceuticals)
  • available throughout EU, Canada, Australia, NZ, some Latin American countries
  • currently going through approval process in USA
• THC shows efficacy for opioid tapering and replacement
  • associated with significant reduction in legal states
    • opioid addiction
    • opioid deaths
• increasingly used as appetite stimulant for cancer and HIV/AIDS
  • these patients consistently find THC
    • improves mood
    • reduces pain
    • reduces depression
• Therapeutic uses of THC
  • mild to moderate pain relief
    • can be incredible tool for getting away from opioids post-surgery
  • control of nausea
    • particularly beneficial for AIDS/HIV or cancer patients
  • assist in balancing sleep patterns (insomnia)
    • helps you get to sleep and stay asleep
  • stimulates appetite
  • treats symptoms of depression
  • Note: high doses can exacerbate
    • anxiety
    • bipolar spectrum
    • schizophrenia
    • related disorders
    • patients with the above conditions need to avoid high-THC or proceed cautiously with a doctor’s oversight
      • you’ll need to pay closer attention

Expected levels of THC in cannabis material

• average in California market is about 16%
• some current chemovars are above 25%, but there are few in this class

If economics of cannabis use matter to you it’s helpful to know the value of ratios and how to use them to your best advantage

• find what falls into your price range
• learn to use them to best effect
• new classes of patients are looking for mild to moderate ranges of potency
  • older consumers in particular tend to have lower tolerances for THC
• low potency doesn’t mean it’s low grade, just good for someone who wants lo potency

There’s been an explosion of concentrates

• concentrates changed potency threshold
• changed people’s expectations of anticipated and expected effect

Expected THC levels for concentrates

Mechanically-produced concentrates:

• Kief (cannabis run over dry sieve and glandular heads collected) generally doesn’t get over 30-40% THac
  • usually below those levels
• Hash used to come from Middle East, but is rare now
  • averages about 48% THC
• Bubble hash popularity is waning as other concentrates come along
  • averages around 50%
  • usually tops out at around 65%

Chemically-extracted (with solvents) concentrates:

• BHO extracts
• Wax
• CO2 extracts
• more efficient extractions

Concentrates can be therapeutically beneficial to the right patient

• proceed with caution when using such high concentrations of cannabinoids

Pick up here on notes from Samantha Miller

CBD
Cannabidiol has rocketed into public consciousness

• often erroneously called “the medical marijuana“
  • works best when combined with other cannabinoids
• found to be useful for control of seizure disorders
  • Dravet syndrome
  • Lennox-Gastaut syndrome
• in 2018 Epidiolex (GW Pharmaceuticals) became first CBD med to hit legal US markets for treatment of these syndromes
• Evidence exists showing CBD’s efficacy for neurological diseases
  • Parkinson’s
  • Alzheimer’s
  • CBI
• ...as well as
  • arthritis
  • rheumatism
  • osteoarthritis
  • diabetes
  • plus many other conditions chronic pain among them
• Anecdotally, CBD is most often chosen to treat
  • anxiety
  • depression
  • skin conditions (i.e. psoriasis)
  • gastrointestinal problems
  • chronic pain
• Hemp-derived CBD
  • available everywhere
  • unregulated (quality and potency can be problematic)
  • poor lab documentation
  • little to no terpenes or entourage
  • patients all over the world report positive reactions to use
• medical cannabis-derived CBD
  • includes entourage components
  • available in legal states
  • not yet avail. in Idaho, Kansas,S.Dakota, Nebraska

CBN Cannabinol

• third best-known cannabinoid
• metabolite of THC
  • THC degrades and loses 4 hydrogen atoms to make CBN
    • THC is an unstable molecule
    • age, heat, and UV light damage THC
• found in higher concentration with
  • older buds and plant material
  • poorly-stored plant material
• claimed to be sedating
  • but science doesn’t back that up yet
  • 1975 study showed CBN to potentiate THC to create increased feelings of being
    • drugged
    • dizzy
    • drowsy
• CBN is less studied, but shows affinity as
  • antibacterial
  • anticonvulsive
  • appetite stimulating
• CBN influences
  • regulation of sex hormones
  • production & proliferation of skin cells
  • has been shown to slow ALS in mice studies

Minor Cannabinoids

There are at least 90 other cannabinoids, classified as “minor”

THCV Tetrahydrocannabivarin

• propyl cannabinoid
  • has 3 carbon atom chain instead of 5 found in pentane molecules
  • can have very different properties from pentane cousins
• homolog of THC
• thought to act as antagonist of eCB1
  • antagonist attaches to receptor, but has no effect at low doses
  • at high doses may act as eCB1 agonist
    • effects may be similar to THC at high doses
• also partial agonist of eCB2
• can also stimulate 5HT1 receptor
  • serotonin signalling
  • May produce antipsychotic effects as such
• plants high in THCV found in
  • Afghanistan
  • Pakistan
  • China
  • India
  • Nepal
  • Thailand
  • southern and western Africa
• THCV interest in medical circles is on the rise
  • thought to help regulate the immune response, particularly for
    • inflammation
    • inflammatory pain
  • mouse studies suggest efficacy for
    • reducing blood sugar levels in Type 2 diabetics
    • improve glucose to,Teaneck
    • increase insulin sensitivity

CBG

• thought to be non-psychoactive
• weak agonist of eCB2
  • may be the pathway where it exerts most influence
• weak agonist to eCB1 as well
  • unknown effects through this pathway
• shown to have affinity w/
  • 5HT1-receptor
    • releasing serotonin
  • adrenoceptor
    • controls CNS expression of
      • adrenaline
      • noradrenaline

CBC Cannabichromene

• thought to be second most abundant cannabinoid in cannabis
• in rodent studies CBC produces
  • pain relief
  • anti-inflammatory effects
• studies in humans sadly lacking
• agonist of eCB2
• agonist of TRPA1 receptor
  • responds to external stimuli like
    • heat
    • cold
    • itching

Cannabinoid Acids and Their Properties

Many cannabinoid acids show medicinal value in initial research

• patients tend to be confused about THC and THCA

THCA
the cannabinoid acid form of THC (before decarb, or activation)

• decarb is function of time and heat
• controlled heat and time are needed to create significant levels of decarb
• combustion and vaping both decarb with heat
• an unstable molecule, THCA is aggressively trying to become THC

THCA + HEAT = THC
Reliable decarb for THC = 212° F for 90 minutes

In highest concentrations in growing plant and in raw, dried, unheated plant material

• It used to be thought that acidic cannabinoids had little if any effect in human bodies
  • we know better now
  • dispensaries and individuals took the charge and gathered anecdotal evidence
  • findings from studies of patients using juiced cannabis include usefulness in treating
    • inflammation
    • muscle convulsions
    • spasticity
    • changes in cognitive development
      • seen in children taking acid cannabinoids (both THCA and CBDA)
      • significant shifts in behavior
        • emotional intelligence
        • speech and cognition
• difference in effects is obvious with ingestion
  • your choice is guided by your intentions; depends on patient and their needs
• THCA products like tinctures are popular choice if patient
  • is intimidated by the high
  • wants to try cannabinoid therapies
  • wants an easy way into exploring medical benefits of cannabis
• non-intoxicating
• demonstrates affinity to treat
  • inflammation
  • spasticity
• In very low doses can present as
  • powerful antiepileptic
  • anti-inflammatory
  • anti-nausea properties
• early research suggests value in combining THC and THCA to treat
  • seizures
  • pain
  • arthritis
• Examples of THCA (or other acid cannabinoids) products:
  • cannabis juice (use lemongrass juicer to prevent decarb)
    • the most direct way to get THCA
  • glycerin or alcohol tinctures (No heat!)
  • water-extracted hash
• Note: Acid cannabinoids can take 3-4 weeks of daily use to demonstrate the benefits.
  • combined therapies work most efficiently
    • acidic cannabinoid daily therapies can reduce intensity of chronic pain expression
    • THC may still be needed for breakthrough pain or rough days
    • some THCA will be naturally activated into THC in plant material
      • be alert for some psychoactivity
      • will be much less than if fully activated

CBDA

• appears to have strong properties for
  • antiepileptic
  • anti-inflammatory
  • anti-nausea
    • appears to be much better than CBD for nausea
    • at far lower doses than CBD
• may also
  • stop spread of breast cancer cells
  • improve symptoms of depression
• appears to work well with CBD
  • combining CBD and CBDA may lead to more rapid onset of effects

Cannabinoid Isomers
Cannabinoids that have the same atomic makeup but are structured differently in three-dimensions

• structural isomers are arranged differently
• stereoisomers are more or less mirror images of each other

Slight differences in arrangement make significant differences in effect

Delta-8 THC

• mildly psychoactive
• like delta-9 THC it’s a partial agonist of eCB1
• effects include
  • antiemetic (anti-vomit)
  • antioxylitic (anti-anxiety)
  • antiepileptic
  • anti-tumor
  • neuroprotective
  • appetite-stimulating
    • 2004 study suggests more so than delta-9 THC

 

[SweetSue]

It drives me a little nuts to have these pages crash when I go to edit a post.


Only a little, mind you. I’m having too much fun to feel any less than the thrill of learning.

Time for a righteous buzz!

 

[SweetSue]

Oh.... I didn’t notice the time. No wonder I’m feeling so tired.

 

[SweetSue]

Endocannabinoids – cannabinoids produced naturally by our body. There are 5 kinds of cannabinoids that our body produces, anandamide and 2-AG being the most well researched:

• Anandamide is the main endocannabinoid in your body. It can be found in humans, but also many other animals and plants. It binds more-so to CB1 than CB2 receptors and has similar effects to THC – in fact, the name anandamide is based on the Sanskrit word ananda meaning “inner bliss.”

• 2-AG (2-arachidonoylglycerol) also binds to the CB1 and CB2 receptors and is the most abundant endocannabinoid found in the body. It doesn’t have such cool name as anandamide, but it has been shown to play an important role in regulation of appetite, immune system function and pain management. It is also thought that 2-AG may play a role in the inhibition of cancer cell proliferation – but more research is needed there.

• Virodhamine – named from the Sanskrit word virodha, which means opposition, as it does the opposite of anandamide i.e. it partially blocks the CB1 receptor and binds mostly to the CB2 receptor. One study has shown that Virodhamine can relax pulmonary arteries, helping to relieve hypertension.

• NADA (N-arachidonoyl-dopamine) – a recently discovered cannabinoid that binds to the CB1 receptor and has antioxidant and neuroprotective properties.

• 2-AGE (2-arachidonyl glyceryl ether or noladin ether) also acts on both the CB1 and CB2 receptors.

 

[SweetSue]

 

[SweetSue]

Cannabinoids 101 - Green Flower Media Fundamentals Of Cannabis course
Including notes from video class on Therapeutic Uses Of Cannabinoids with Samantha Miller (President and Chief Scientist of Pure Analytics, LLC)

Cannabinoids

• substances produced by our bodies and by plants
  • responsible for some of effects of cannabis
  • terpenoids and flavonoids also contribute to effects
• endocannabinoids - made by the body
  • ECS is network of receptors
    • a natural architecture that interacts with phytocannabinoids
      • anandamide and 2AG are known eCBs
    • receptors are the cellular antennas waiting for the signalling peptides
    • modulates/regulates important physiological processes like
      • eating
      • sleeping
      • addiction
      • memory
      • mood
• phytocannabinoids - made by plants (mostly cannabis)
  • cannabis is only plant known to produce significant numbers of cannabinoids
  • produced in the viscous resin of glandular trichomes
    • found on surface of flowers and leaves
• synthetic cannabinoids
  • there are hundreds out there
  • some are deadly dangerous
  • Dronabinol (Marinol) used for chemo nausea
  • HIV wasting
  • Dronabinol has
    • low bioavailability
    • significant side effect

Phytocannabinoids are simply referred to as cannabinoids in the cannabis industry

• produced in glandular trichomes
• tiny, complex factories produce
  • multiple cannabinoids
  • terpenoids
  • flavonoids
  • esters

Cannabinoids and terpene production pathways are intricately linked

• cannabigerolic acid (CBGA) is first cannabinoid produced
  • is the precursor to all other cannabinoids
  • CBGA is made by 'borrowing' compounds first produced via terpenoid pathways
  • CBGA goes through oxidocyclization to become
    • cannabidiolic acid (CBDA)cannabinochromenic acid (CBCA)tetrahydrocannabinolic acid (THCA)various other cannabinoid acids

With heat or time acid cannabinoids will naturally decarboxylate

• lose their carboxylic groups
  • they lose 2 oxygen atoms and 1 hydrogen atom
• this process is the same for all cannabinoids
  • THCA becomes THC, CBDA becomes CBD, and so on.
• Decarb is a function of heat and time
  • drying and curing allow for significant amounts of decarb
  • naturally, it's nearly impossible to control decarb for consistency
• we have methods of controlled heat and time to consistently decarb
• heating of combustion or vaping at high temps will decarb
  • enough heat energy to make the carboxyl groups float off
• decarb is skipped when you want acid cannabinoids in the end product

The major cannabinoids
Relative amounts of phytocannabinoids are determined by genetics

• (1:1, 2:1, 20:1, etc)

total concentrations (i.e. 15% THC with 0.5% CBD) will be determined by

• • genetics
  • growing conditions (mostly light)
• three main types of plants and products (determined by genetics)
  • high-THC
  • high-CBD
  • balanced ratio (equal amounts of THC and CBD, or 1:1)
• different ratios are specific to application
  • 2:1 CBD:THC may be better for anxiety
  • 20:1 will be better for seizure disorder

CBC is showing up in almost every cannabis plant as the second most concentrated cannabinoid

THC Tetrahydrocannabinol

• usually most abundant cannabinoid in cannabis
  • this is now changing with aggressive breeding for other cannabinoids
• most famous because it's psychoactive
  • you’ll experience a shift in perceptions
  • referred to in many ways
    • THC
    • Delta-9-Tetrahydrocannabinol
    • symbols for delta-9-Tetrahydrocannabinol
    • all of these mean the same
• can exist in different forms
  • with very different effects
  • i.e. THCA in growing plant, THC in heated plant material
• when smoked or vaped,
  • quickly enters the bloodstream
  • transported throughout the body organs and CNS have eCBRs
• THC activates eCBRs
  • effects biological & cognitive processes like
    • appetite
    • mood
    • motor coordination
    • memory
• an agonist of eCBRs
  • it activates the receptor causing biological chain reaction (resulting in cascade)
• THC can improve symptoms of
  • spasticity
  • pain
  • muscle spasms
• viable choice for
  • MS
  • Parkinson's
  • several other neurodegenerative disorders
• Sativex (1:1 product of GW Pharmaceuticals)
  • available throughout EU, Canada, Australia, NZ, some Latin American countries
  • currently going through approval process in USA
• THC shows efficacy for opioid tapering and replacement
  • associated with significant reduction in legal states
    • opioid addiction
    • opioid deaths
• increasingly used as appetite stimulant for cancer and HIV/AIDS
  • these patients consistently find THC
    • improves mood
    • reduces pain
    • reduces depression
• Therapeutic uses of THC
  • mild to moderate pain relief
    • can be incredible tool for getting away from opioids post-surgery
  • control of nausea
    • particularly beneficial for AIDS/HIV or cancer patients
  • assist in balancing sleep patterns (insomnia)
    • helps you get to sleep and stay asleep
  • stimulates appetite
  • treats symptoms of depression
  • Note: high doses can exacerbate
    • anxiety
    • bipolar spectrum
    • schizophrenia
    • related disorders
    • patients with the above conditions need to avoid high-THC or proceed cautiously with a doctor’s oversight
      • you’ll need to pay closer attention

Expected levels of THC in cannabis material

• average in California market is about 16%
• some current chemovars are above 25%, but there are few in this class

If economics of cannabis use matter to you it’s helpful to know the value of ratios and how to use them to your best advantage

• find what falls into your price range
• learn to use them to best effect
• new classes of patients are looking for mild to moderate ranges of potency
  • older consumers in particular tend to have lower tolerances for THC
• low potency doesn’t mean it’s low grade, just good for someone who wants lo potency

There’s been an explosion of concentrates

• concentrates changed potency threshold
• changed people’s expectations of anticipated and expected effect

Expected THC levels for concentrates

Mechanically-produced concentrates:

• Kief (cannabis run over dry sieve and glandular heads collected) generally doesn’t get over 30-40% THac
  • usually below those levels
• Hash used to come from Middle East, but is rare now
  • averages about 48% THC
• Bubble hash popularity is waning as other concentrates come along
  • averages around 50%
  • usually tops out at around 65%

Chemically-extracted (with solvents) concentrates:

• BHO extracts
• Wax
• CO2 extracts
• more efficient extractions

Concentrates can be therapeutically beneficial to the right patient

• proceed with caution when using such high concentrations of cannabinoids

CBD
Cannabidiol has rocketed into public consciousness

• non-intoxicating
  • will alter your mind
  • a good entry point to cannabinoid therapies
  • easy to try and feel safe
• it's more socially acceptable to use CBD
  • more "permission"
• often erroneously called “the medical marijuana“
  • works best when combined with other cannabinoids
• usually found in low levels in plants
  • CBD-rich = greater than 4% by weight
  • dominance is more rarely seen than with THC
  • breeding programs are underway
    • seed companies and collectives
    • independent growers and breeders
    • scientific research programs
• found to be useful for control of seizure disorders
  • Dravet syndrome
  • Lennox-Gastaut syndrome
• in 2018 Epidiolex (GW Pharmaceuticals) became first CBD med to hit legal US markets for treatment of these syndromes
• Evidence exists showing CBD’s efficacy for neurological diseases
  • Parkinson’s
  • Alzheimer’s
  • CBI
• ...as well as
  • arthritis
  • rheumatism
  • osteoarthritis
  • diabetes
  • plus many other conditions chronic pain among them
• Anecdotally, CBD is most often chosen to treat
  • anxiety
  • depression
  • skin conditions (i.e. psoriasis)
  • gastrointestinal problems
  • chronic pain due to conditions originating in spasticity
    • spasticity
    • convulsions
    • inflammation
    • neuropathy from diabetes and chemo (dramatic results)
• CBD effects pain from a different direction than THC
  • allosteric modulation
• helpful for controlling symptoms of
  • MS
  • fibromyalgia
  • epilepsy
• may cause alertness if taken too close to bedtime
• combined with THC it may have anti-tumor potential for
  • breast cancer
  • brain cancer
• Hemp-derived CBD
  • available everywhere
  • unregulated (quality and potency can be problematic)
  • poor lab documentation
  • little to no terpenes or entourage
  • patients all over the world report positive reactions to use
• medical cannabis-derived CBD
  • includes entourage components
  • available in legal states
  • not yet avail. in Idaho, Kansas,S.Dakota, Nebraska

CBD Classifications

CBD classifications

• SweetSue
• Apr 16, 2020

• CBD chemovars (strains)
  • Harlequin
  • Sour Tsunami
  • Canna tonic
  • Harle-Tsu
  • Canna-Tsu
  • Stinky Pink Diesel ***** first high-CBD strain isolated and identified in California (Harborside)
  • Charlotte's Web (Harlequin x Harle-Tsu)
• With THC
  • many times CBD lessens euphoria of THC (in high enough ratio)
  • can help with recovery of THC overdose
  • CBD prolongs the effects of THC
    • CBD inhibits the liver enzyme that breaks down THC in the body
    • more THC circulates for longer times
    • you'll feel less high, but for a longer window
• The plant has a genetic limitation of expected cannabinoid values
  • it can only hold so many
• CBD expressions usually run less than 10%
  • some high 20:1 CBD:THC
  • most 1:1 are 5% or 7%...

CBN Cannabinol

• third best-known cannabinoid
• approx 10% psychoactive potency of THC
  • may cause grogginess
• metabolite (byproduct) of THC
  • THC degrades and loses 4 hydrogen atoms to make CBN
    • THC is an unstable molecule
    • age, heat, oxygen, and UV light damage THC
• found in higher concentration with
  • older buds and plant material
  • poorly-stored plant material
  • can be an indicator of freshness
• outdoor plants can express about 5% CBN
  • due to exposure to UV light
• claimed to be sedating
  • but science doesn’t back that up yet
  • 1975 study showed CBN to potentiate THC to create increased feelings of being
    • drugged
    • dizzy
    • drowsy
• CBN is less studied, but shows affinity as
  • antibacterial
  • anticonvulsive
  • appetite stimulating
• CBN influences
  • regulation of sex hormones
  • production & proliferation of skin cells
  • has been shown to slow ALS in mice studies
• decreases heart rate without decreasing blood flow

Minor Cannabinoids

There are at least 90 other cannabinoids, classified as “minor”

THCV Tetrahydrocannabivarin

• propyl cannabinoid
  • has 3 carbon atom chain instead of 5 found in pentane molecules
  • can have very different properties from pentane cousins
• homolog of THC
• thought to act as antagonist of eCB1
  • antagonist attaches to receptor, but has no effect at low doses
  • at high doses may act as eCB1 agonist
    • effects may be similar to THC at high doses
• also partial agonist of eCB2
• can also stimulate 5HT1 receptor
  • serotonin signalling
  • May produce antipsychotic effects as such
• like CBD can temper euphoric effects of THC
• a quicker high, more intense, less duration (They call it "the Quickie")
  • intensifies effects of THC
  • lessens the duration of THC's euphoria
• may inhibit some of THC's appetite stimulation
• plants high in THCV found in
  • Afghanistan
  • Pakistan
  • China
  • India
  • Nepal
  • Thailand
  • southern and western Africa
• small community in Mendocino have some plants testing at around 5% THCV
• THCV interest in medical circles is on the rise
  • thought to help regulate the immune response, particularly for
    • inflammation
    • inflammatory pain
  • mouse studies suggest efficacy for
    • reducing blood sugar levels in Type 2 diabetics
    • improve glucose to,Teaneck
    • increase insulin sensitivity

CBDV Cannabidivarin

• non-intoxicating
• low levels of expression
• rat studies suggest use for spasticity and convulsions
• CBDV may be a marker for strains more effective in treating seizure disorders
  • CBDV + CBD appear to make for a better medicine for seizure disorders and spasticity

CBG (Cannabigerol)

• thought to be non-psychoactive
• weak agonist of eCB2
  • may be the pathway where it exerts most influence
• weak agonist to eCB1 as well
  • unknown effects through this pathway
• anti-inflammatory
• pain relieving effects
• shown to have affinity w/
  • 5HT1-receptor
    • releasing serotonin
  • adrenoceptor
    • controls CNS expression of
      • adrenaline
      • noradrenaline
• may relieve intraoculor pressure (glaucoma)
• CBGA is precursor to THCA, CBDA
  • high levels may indicate immature plant
  • levels of CBG is indicator of THC, CBD potential
• mature plants may have 1-1.5% CBGA at harvest
  • plants with 5 - 7% CBGA at harvest were not ready, by most industry standards
    • it depends on what the grower was after
    • the balance of cannabinoids and terpenes at different points of maturity are part of what shapes preferences for early to late harvest products

CBC Cannabichromene

• usually found in juvenile plants
  • as plant flowers CBC levels fall off
  • GW Pharmceuicals has at least CBC-rich plant
    • mutant plants that lack express ability of THC or CBD
    • genetics determines the total volume of CBG, and the expressions of cannabinoids from that base pool
      • all the synthesizing enzymes go to that same pool
  • there are probably others
• has 10x anti-depressant effects of CBD
• thought to be second most abundant cannabinoid in cannabis
• in rodent studies CBC produces
  • pain relief
  • anti-inflammatory effects
• studies in humans sadly lacking
• agonist of eCB2
• agonist of TRPA1 receptor
  • responds to external stimuli like
    • heat
    • cold
    • itching

Cannabinoid Acids and Their Properties

Many cannabinoid acids show medicinal value in initial research

• patients tend to be confused about THC and THCA

THCA
the cannabinoid acid form of THC (before decarb, or activation)

• decarb is function of time and heat
• controlled heat and time are needed to create significant levels of decarb
• combustion and vaping both decarb with heat
• an unstable molecule, THCA is aggressively trying to become THC

THCA + HEAT = THC

Reliable decarb for THC = 212° F for 90 minutes​

In highest concentrations in growing plant and in raw, dried, unheated plant material

• It used to be thought that acidic cannabinoids had little if any effect in human bodies
  • we know better now
  • dispensaries and individuals took the charge and gathered anecdotal evidence
  • findings from studies of patients using juiced cannabis include usefulness in treating
    • inflammation
    • muscle convulsions
    • spasticity
    • changes in cognitive development
      • seen in children taking acid cannabinoids (both THCA and CBDA)
      • significant shifts in behavior
        • emotional intelligence
        • speech and cognition
• difference in effects is obvious with ingestion
  • your choice is guided by your intentions; depends on patient and their needs
• THCA products like tinctures are popular choice if patient
  • is intimidated by the high
  • wants to try cannabinoid therapies
  • wants an easy way into exploring medical benefits of cannabis
• non-intoxicating
• demonstrates affinity to treat
  • inflammation
  • spasticity
• In very low doses can present as
  • powerful antiepileptic
  • anti-inflammatory
  • anti-nausea properties
• early research suggests value in combining THC and THCA to treat
  • seizures
  • pain
  • arthritis
• Examples of THCA (or other acid cannabinoids) products:
  • cannabis juice (use lemongrass juicer to prevent decarb)
    • the most direct way to get THCA
  • glycerin or alcohol tinctures (No heat!)
  • water-extracted hash
• Note: Acid cannabinoids can take 3-4 weeks of daily use to demonstrate the benefits.
  • combined therapies work most efficiently
    • acidic cannabinoid daily therapies can reduce intensity of chronic pain expression
    • THC may still be needed for breakthrough pain or rough days
    • some THCA will be naturally activated into THC in plant material
      • be alert for some psychoactivity
      • will be much less than if fully activated

CBDA

• less is known about effects of CBDA than CBD
• non-intoxicating
  • if THC is present it may contribute to feelings of intoxication with your CBD medicines
• appears to have strong properties for
  • antiepileptic
  • anti-inflammatory
  • anti-nausea
    • appears to be much better than CBD for nausea
    • at far lower doses than CBD
• may also
  • stop spread of breast cancer cells
  • improve symptoms of depression
• patients say it relieves
  • inflammation
  • seizures
• appears to work well with CBD
  • combining CBD and CBDA may lead to more rapid onset of effects
• onset time is different
  • CBD is immediate
  • CBDA provides subtle relief over time (3 days - 4 week so)

Samantha shared a story of a family that dosed their dying mother. (ALS patient) with juice of CBD-rich plant

• they were able to keep her from feeding tube and improve her quality of life with CBDA therapy

CBDA + HEAT = CBD

295° F for 90 minutes​

Cannabinoid Isomers
Cannabinoids that have the same atomic makeup but are structured differently in three-dimensions

• structural isomers are arranged differently
• stereoisomers are more or less mirror images of each other

Slight differences in arrangement make significant differences in effect

Delta-8 THC

• mildly psychoactive
• like delta-9 THC it’s a partial agonist of eCB1
• effects include
  • antiemetic (anti-vomit)
  • antioxylitic (anti-anxiety)
  • antiepileptic
  • anti-tumor
  • neuroprotective
  • appetite-stimulating
    • 2004 study suggests more so than delta-9 THC

[/QUOTE]

 

[SweetSue]

Go to bed already woman.

 

[SweetSue]

Introduction To The Endocannabinoid System - Green Flower Media Fundamentals of Cannabis course

Written material first:

ECS is present in all vertebrae and invertebrate species

• means it was from a common ancestor when the lines split over 600 million yrs ago

In simplest terms, the ECS

• is set of proteins (eCBRs)
• eCBRs bind with specific signaling peptides (eCBs)
• eCBs are fatty acid based molecules
  • signaling
  • regulating
  • controlling a vast range of metabolic functions
    • sleep/wake cycles
    • appetite
    • mood
    • memory
    • fertility
    • pre-, postnatal development
    • motor control
    • motivation and reward
    • immune system functions
    • many more........

ECS has two main identified receptors

• CB1, CB2
• also many additional secondary receptors
  • modifying actions of CB1 or CB2
• receptors are located throughout the body, incl
  • brain
  • spinal cord
  • all major organs
  • bones
  • skin
  • digestive system
• receptors depend on signaling of cannabinoids
  • endocannabinoids are produced in the body
    • major known eCBs are anandamide and 2-Arachidonoylglycerol (2-AG)

eCBs are produced in CNS neuronal synapses

• in response to various biological signals
• signals give precise readings of biological processes
• cannabinoids are produced when need to regulate responses is required
• many disease states can now be attributed to disregulation of the ECS
  • IBS
  • fibromyalgia
  • migraine
• treating the ECS first may be the solution to effectively treating these disease conditions
• entourage effect comes into play in significant ways with cannabis products

In 2013 only 13% of medical schools included study of the ECS in their curriculums

In cannabinoid therapies

• cannabinoids interact with ECS receptors
  • results depend on
    • what part of the body is being treated (cellular interactions in hat domain)
    • patient's medical conditions
    • patient's genetics
    • dosage
    • patient's state of mind or mood when medicating
    • patient's general health

ECBRs
Receptors are proteins spanning cell membranes

• interacts with extracellular substances
• effects change inside cells
• ligands are the binding molecule
• bind in one of three way
  • Agonist binds with effect
    • also called "blockers"
  • Antagonist binds with no effect
    • they block the effects of agonists by getting in the way (ex: beta blockers for heart health)
  • Inverse agonist binds to create opposite effect of agonist
    • can also be blocked by antagonist
    • naloxone counteracts action of opioid receptors to counter opioid OD

THC, CBD, anandamide and 2-AG all bind to eCBRs

• all produce different effects upon binding

Allosteric modulators

• bind to alternate receptors
• change the way the main receptors receive agonist signals
  • positive effect = incr axes biological activity of agonist
    • many benzodiazepines positively effect GABA to increase
      • sedation effects of GABA
      • relaxant effects of GABA
      • using GABAA receptor in subtle ways
  • negative effect decrease biological activity of agonist
    • other benzodiazepines will negatively affect GABA
• phytocannabinoids from cannabis act as positive and negative allosteric modulators

eCB1R

• found in dense concentration in
  • brain
  • CNS
  • peripheral NS
  • glands of
    • adrenal
    • pituitary
    • thyroid
  • cells of
    • liver
    • kidneys
    • digestive tract
    • lungs
  • fat cells
  • some immune cells
    • not as common as CB2 expression
• various cannabinoids act as ligands, incl.
  • 2-AG (the only true agonist, the rest are weaker agonists)
  • anandamide (partial agonist)
  • THC (partial agonist)
  • CBD (weak binding as negative allosteric modulator)
• eCB1R regulates homeostasis by modulating
  • temperature
  • fluid balance and sweating
  • appetite and food intake
  • blood sugar levels
  • ion concentration
  • immunological response (i.e. inflammation)
  • many other biological functions
• homeostasis = all body systems working smoothly for optimal conditions
• ECS and eCB1R constantly recieve messages from ligands
  • In various concentrations
  • in varying ratios
  • in varying doses
• ECS responds to the messages and creates cannabinoids to regulate as needed

eCB2R

• primarily expressed in
  • peripheral nervous system
  • spleen
  • thymus gland
  • tonsils
  • gastrointestinal system
  • certain immune cells
  • Also in brain and CNS
    • much lower density than CB1
• primary role seems to be regulating immune response
  • inflammation
  • cell migration
  • programmed cell death
• also responsible for bone
  • mass
  • density
  • health
  • destruction of old bone tissue
  • removal of old bone tissue
  • production of new tissue
• Ligand effects:
  • anandamide: not as strong a bonding as with CB1
  • 2-AG is only truebinding agonist
    • 2-AG may be the more important of the two known major eCBs
  • THC: partial agonist
  • CBD: partial agonist

Phytocannabinoids and the ECS

• can interact in various ways
  • alone
  • in combination with other canna components
  • entourage effect potentiates all components
• entourage effect means we have unlimited combinations to play with
  • can benefit specific conditions
  • can be customized for
    • disease states
    • genetic makeup of patient
    • patient's general health
    • all other variables that may arise
  • lack of research is our only limitation to explaining and understanding entourage effect and how best to exploit it
• research into specific cannabinoids is still so new we keep changing the rules as we learn

THC in the body

• administration pathway will determine outcome
  • smoked
  • vaped
  • sublingually
• when smoked, vaped or used sublingually
  • large quantities of THC quickly get absorbed through mucus membranes of
    • mouth
    • lungs
  • can make its way around the body through circulatory system
    • interacting with white blood cells and other immune cells as it goes
    • can reach major organs and CNS
• eaten
  • absorbed by GI tract
  • some will bind in GI tract as it pass s
  • passes to liver for metabolization
  • enters bloodstream after liver pass
  • metabolized into 11-hydroxy THC
  • more highly psychoactive
  • more easily penetrates BBB
    • may be more medically effective than delta-9 THC
  • topical application
    • may not make it to bloodstream
    • will encounter and bind to eCBRs in
      • skin
      • subdermal tissue
  • injected

• when THC encounters an eCBR
  • it binds imperfectly, but with strong effect (partial agonist), causing
    • hunger
    • drying of eyes and mouth
    • euphoria
    • loss of motor coordination
    • dizziness

CBD in the body

• used in similar ways as THC
  • enters bloodstream in similar ways
  • has very different effects
• CBD has weak interaction with both receptors
  • negative allosteric modulator of eCB1R
  • partial agonist of CB2R
  • many effects achieved in more indir ct ways than eCBR direct contact
    • CBD may influence density of eCB1R in brain
      • would increase THC's potential action
• CBD inhibits breakdown of anandamide
  • binds to fatty acid binding proteins (FABPs)
  • effectively increases overal systemic levels of anandamide
• may also affect secondary eCBRs
  • GRP55
  • GRP18
• also effects other signaling systems
  • vanilloid
  • dopamine
  • serotonin
• is negative allosteric modulator of GABBAA receptor

CBD's 5 main ways of modulating effects of THC, other cannabinoids

1. principal eCBRs
2. secondary eCBRs
3. opioid and serotonin rceptors
4. increasing eCB1Rs in the brain
5. increasing circulating anandamide

More ways surely exist

CBD's effects are not always positive

• can sometimes interfer with medical value of THC
  • Ex: by way of CB1 and GPR18 CBD can offset pressure release of THC in glaucoma

We still understand very little of what CBD does, and how it does it in the human body

 

[SweetSue]

I corrected the many typos Shed

 

[SweetSue]

Introduction to the Endocannabinoid System - Dr. Samantha Miller: Green Flower Media Fundamentals of Cannabis course

What we’ll cover

• the concepts of therapy and psychoactivity around cannabis
  • how those concepts are related
  • how those concepts can be pulled apart
• how cannabinoids produce effects in the body
  • different results from administration methods
  • metabolism
  • excretion
• take a closer look at some specific receptor interactions
  • will help you understand the biochemical actions and reactions driving the experience

Cannabis doesn't come with instructions

• patients do well to practice the same consistency they do with other medications
  • if you take with food, be consistent with that, if you don't, don't
  • take cannabis meds with water
  • if you don’t take meds with alcohol, do the same with cannabis
  • for more consistent response, be consistent in
    • usage
    • context
  • a more consistent approach leads to repeatable successful therapeutic results

Cannabinoids bond to fats and proteins pretty quickly

• in the body they’re bound to
  • proteins
  • blood cells
  • lipoproteins (fat and protein combined)
• they attach to receptor sites
  • found in brain and throughout the body
  • docking sites that cannabinoids can communicate with

ECS is a key and lock system (receptor is the lock, cannabinoids the key)

• there's a specific fit between the cannabinoids and the receptors
  • keeping other molecules from also attaching
• The specific fit is determined by the shape of the receptor
  • more than one component can fit the receptor

We now know

• receptors are more like specific antennas than a lock and key system
• some terpenes, and many other cannabinoids appear to activate eCBRs
  • modifying receptor shape and function
  • creating calls for different peptides
• also, receptors can join and create entirely different receptors that create signals for unique pharmacological effects
  • In other words, the ECS will do everything imaginable to get the body back to homeostasis.

The receptors are embedded to pass through the cell membrane. Below them are the G-proteins

• When a cannabinoid attaches to the receptor it causes the G-protein to change shape and move
• When the G-protein changes shape this causes it to kick off a different ligand (a neurotransmitter) to start a cascade of event
• You'll have
  • a binding of the THC molecule to the receptor
  • a conformational change in shape
    • stimulates the g-protein to move
    • releases of a new neurotransmitter
    • creating another cascade
    • and so on, and so on….

The primary receptors THC binds to are CB1 and CB2.

• There are other receptors that THC binds to, these are simply the primary ones.

CB1

• central nervous system
  • brain
  • spinal cord)
  • in cases of brain injury CB2 receptors will arise spontaneously in the brain to get to work reducing inflammation
• the most abundant cannabinoid receptor.
  • Makes sense, considering the number of brain cells in the average human.
• thought to affect
  • memory and adverse memories (think PTSD)
  • appetite
  • response to rewards (dopamine)
  • our propensity to addiction
  • how we deal with stress
  • how we experience pain
  • how pain can be managed.

These are big quality of life issues.

• Create balance and
  • you improve the patient's life
  • and enhance the journey to homeostasis.

CB2

• peripheral nervous system, including
  • immune system tissue
    • spleen
    • tonsils
    • white blood cells
    • etc

• thought to effect
  • inflammation
  • pain, especially inflammatory GI response
  • immune response
  • in some cases it's thought that activation of the CB2 receptor can induce immune suppression

The primary receptors CBD binds to are

• A2A
• VR1
• GPR55
• 5-HT

GPR55

• generating excitement in cancer treatment
• Different cancers respond to different cannabinoids in different ways.
  • Some respond well to THC
  • some don't respond well to CBD
  • In some cases CBD seems to be the wisest choice.
  • We need more studies.

• When GPR55 is active it promotes tumor cell proliferation.
  • More cancer cells are being made.
  • It's believed that CBD can inhibit the activity of this receptor.
• Researches are looking into whether this pathway can be used to treat gliomas

A2A Adenosine receptor

• Thought to influence anti-anxiety properties of CBD to
  • give broad anti-inflammatory effects
  • regulate cardiovascular function
    • from blood flow to oxygen levels.
• will down-regulate certain neurotransmitters like glutamate
  • Certain diseases are caused by imbalance of neurotransmitters causing over activity in the system.
    • Excess glutamate, for example, is responsible for certain seizure conditions.

VR1 Vanilloid receptor 1

• Has a role in
  • our perception of pain
  • the regulation of body temperature
  • inflammation
  • may be why CBD works as a pain medication for neuropathy.

• Plays a role in sexual arousal
  • has a dose-dependent response.

• At high cannabinoid doses other parts of the receptor are activated
  • explains why some benefits of cannabis are dose-dependant.
    • The receptors sometimes react differently to lower doses than higher doses.
    • More isn't necessarily better.
    • Find the sweet spot for you.

5-HT Seratonin receptor

• the same one that SSRI drugs target
  • Wellbutrin
  • Prozac
  • Lexapro
  • etc
• CBD can be a safe alternative to these anti-anxiety drugs
  • without the significant side effects they present.
  • SSRIs interrupt REM sleep
    • Disrupt it for years and you end up with things like
      • fibromyalgia
      • IBS
      • anxiety
      • etc.
  • Sometimes when these drugs stop working they can create anxiety responses.
  • CBD has anti-anxiety properties

• The receptor is also involved in
  • addiction
  • appetite
  • sleep
  • pain
  • nausea
  • vomiting.
• An important receptor to keep in balance. Witness the number of humans on anti-anxiety drugs.

The reasons cannabinoids offer the relief they due is based on biochemistry and the architecture of the ECS

How cannabinoids produce effects in the body

• Alpha helix proteins form the receptors.
• They pass through the cell membrane to form a link to the interior.
• Below the receptor is a G-protein subunit.
• When a neurotransmitter drops into the receptor it changes the shape of the receptor.
  • This change causes a corresponding change in the shape of the G-protein that
    • initiates a chemical event
    • that creates a new sub unit
    • that goes on to become a neurotransmitter.
  • This new neurotransmitter then
    • goes on to activate another receptor
    • starting the sequence all over again
    • extending the reach of the neurotransmitters.
• The resultant sequence of new neurotransmitters being created is called a cascade event.
  • A cascade of signal events.

This is the way all neurotransmitters work in your body.

More receptors are being discovered all the time.

CBD can act as a regulatory molecule as well as the main receptor activator.

• There are auxiliary attachments on the cell
  • CBD can activate them
    • changing the affinity of that receptor for that molecule
    • and thereby the function of the CB receptor.
• CBD can interact with the CB1 receptors
  • down-regulate the sensitivity of the receptor
  • This is how CBD modifies the euphoric experience of THC.

Metabolism of cannabinoids

Enzymes essentially do a shape change of the cannabinoids

• binding to the molecule
• then splitting the components apart
  • for elimination from the system.
  • Sometimes there will be a sugar molecule added
    • to hasten elimination
• Most cannabinoids (about 80%) are excreted in feces.
  • Your urine is what's tested because the labs don't want to be testing feces.
  • Heavy users can hold onto detectable cannabinoids for up to 80 days.
• Cannabinoids hide out in fat cells.
  • If you have excess fat you have a plethora of binding spots.
  • It can take up to 80 days to clear THC from the system of a heavy user.

• There are receptors in placenta tissue.
• Cannabinoids are found in breast milk.
  • Just worth knowing.
  • No studies have linked cannabinoids in an infant that caused detrimental effects.
• Consider the potential effects and make your own decisions.

 

[SweetSue]

Delivery Methods Of Cannabis with Martha Montemayor, CNC (Certified Nuteitional Consultant) - Green Flower Media Fundamentals of Cannabis course

Founder, Cannabis Clinicians Colorado
Founder/Producer Marijuana for Medical Professionals Certificate (Trains and consults with physicans to be qualified to recommend cannabis as a medicine.)

How to put you in control of your psychoactivity.


Martha Montemayor : Dosing and Titrating

Forms covered:

• Inhaled
  • very fast onset
  • onset in 1-3 min
  • great for
    • acute conditions
    • things you want to treat right now!
  • short duration - only 1 - 3 hours
    • 90% of cannabinoids that get absorbed are diffused and out of the system in about 90 minutes
  • dose easy to control
    • you're the only one who knows when enough was enough
    • 10 - 15 minutes between hits gives you a better feel for what effect it's having on you systemically
  • includes
    • smoke
    • vapor
    • concentrates or dabs
  • when you take a 500° flame to cannabis plant material
    • about 50% of the cannabinoids are destroyed
    • exhale loses another 25% of available cannabinoids (medical standard for inhaled medications)
    • low bioavailability by weight
      • 15 - 25% of original cannabinoids transfer to blood
    • low dose / milder effects
  • Safety?
    • NO known cases of lung cancer from cannabis smoking alone
      • despite polyaromatic hydrocarbons in the smoke from burnt materials you inhaled
    • vaporization is an alternative
      • doesn't have as many polyaromatic hydrocarbons
        • you're not lighting it on fire
      • low temp, electronic "cigarette"
        • heats low enough to release oil vapors without combustion
      • same quick onset/short duration of smoking
      • less waste
        • cannabinoids don't burn up
        • more bang for your buck when less plant material gives comparable results
        • testing out of UC San Francisco showed measurably higher blood concentrations of THC after vaporization vs smoking
        • bioavailibity as high as 60 - 70%
      • can get vaporizers for both forms
        • whole plant material
        • concentrated oils
  • Dabs
    • highly potent concentrated cannabis oil
    • "Dab" is a single hit of the concentrate right to the frontal cortex
      • potentially 40-60+ mg of THC per hit
    • The medical professional concern is that with 60 - 70% bioavailibility of vaporization do we really need to be hitting the ECS this hard?

Experienced patients only! NOT for new patients.​

The most common result of an initial dab is fainting

Puff, Puff, Pass Out.​

• You won't die, but gravity may make you go "Ouch!"
  • Dabs are legitimate medicine
    • cluster headaches can sometimes be stopped at the onset of the aura with a dab hit
    • I have a 420 friend that has extreme ADHD, and dabs are the most effective way he's found to keep his brain in control that he's comfortable with so he can keep up his high-powered lifestyle.
  • why you're at risk of fainting
    • quick onset of high dose of THC
    • rapid drop in blood pressure
      • pale face
      • slight sweating
      • rapid, shallow pulse

Do Not hold in the dab hit. It'll accelerate the process.

Know your tolerances before you try dabs.​

• Oral absorption
  • absorbed through membranes of mouth (oral cavity)
  • includes
    • tinctures (sublingual; drops put under the tongue)
    • sprays
    • mints
    • gum
    • suckers
    • hard candies
  • 15 - 20 min onset (with almost all forms)
    • you're holding it in your mouth before swallowing
    • speeds onset (faster than edible
  • short duration of 2 - 4 hours
  • good for measured doses
    • micro-dosing
      • small doses across the day to keep the ECS active
      • can keep chronic diseases more manageable
      • can keep disease from advancing further
    • initial titration
  • take a couple drops and record your experience
    • wait about 20 minutes before trying any more

• Edibles/GI absorption
  • particularly valuable when treating long-term chronic conditions
  • onset 30 - 90 minutes
    • you absorb through small intestines, not your stomach
    • absorption takes time
  • common mistake: Overdose of THC
    • take a bite, wait 15 minutes
    • "I don't feel anything!"
    • take another bite, wait another 15 minutes
    • repeat above until "WHAM!" it starts to register all at once
  • solution: take one bite and wait at least an hour to 90 minutes before following it with another dose
  • duration of 6 - 8+ hours
  • musculoskeletal patients say smoking may get you to sleep but you'll wake up every two hours when you unconsciously roll over in your sleep
    • edibles help you
      • stay asleep all night long
      • get the restful sleep that gets you through the days
  • can be much more psychoactive
    • delta-9 gets converted to 11-hydroxy
  • dosing varies widely
  • easy to overconsume

Edible absorption: First-Pass Absorption

• You eat and it goes to the stomach
  • filled with hydrochloric acid that breaks down food
• through intestines alkaline is absorbed
  • enter the liver and gallbladder which turn acidic from stomach to alkaline for the intestines
  • first-pass metabolizes delta-9 THC into 11-hydroxy THC
• Low-dose edibles are excellent for night doses to prevent complications of conditions from returning tomorrow
  • nobody cares if you're stoned in your sleep

• Skin absorption
  • Topicals
    • skin balms and salves
    • local anti-inflammatory
      • for patients ove 60 starting on topicals alone, 50% get immediate relief from pain of
        • osteoarthritis
        • rheumatoid arthritis
      • a good entry point for those intimidated by other modalities
    • non-psychoactive
      • shouldn't show up in bloodstream
      • In 2019 suddenly there began a scare about topicals and psychoactivity that could stand to be tracked and documented better than scare tactics allow.
        • What are they identifying as being "high?"
        • How pronounced are the effects?
        • Could this be a matter of too little education and experience?
    • localized effects
    • onset 30 minutes
    • duration 3 - 6 hours
    • may stimulate CB2 receptors in immune system through skin
  • Transdermal Patches / Gels
    • contain uptake agent to get into bloodstream
      • place on a vienous area for uptake instead of over painful area
    • active and non-psychoactive forms
    • onset 20 -30 minutes
    • duration 6-8 hours
    • can be cut to size for dose control
    • you can remove if dose is too strong
      • simply pull patch off
      • if using gel, wash it off the area you applied it to

• Suppositories

There was nothing in this video about dosing suppositories. ​

• Non-psychoactive options (keeping you in control of the buzz)
  • THCA, CBDA
    • Trichomes full of essential oil exist on plants to protect plant and discourage grazers
    • difficult to digest
  • Raw cannabis juice has few glandular trichomes full of oil
    • nutritional supplement
    • normally prepared from green leaves, not flowers
      • Dr. Courtney would encourage flowers, I'm almost positive of it.
    • non-psychoactive (no "high")
    • potent anti-oxidant
      • like wheatgrass on steroids
      • all the anti-oxidant value of chlorophyll
      • chlorophyll is structurally similar to hemoglobin
        • blood-builder
        • energizing when taken in the AM
    • used to
      • improve gut absorption
      • support immune system

Cannabis is safe to experiment when your looking for the proper dose

• No one will die, or be harmed.
• A THC overdose feels intimidating, but it won't do more than make you uncomfortable.
  • You will survive to take a wiser dose the next time.
  • If you have a THC overdose experience
    • have a friend sit with you
    • stay in a safe place
    • sleep it off
    • there's no real antidote
      • Personal experience says otherwise. A good couple hits of CBD will, indeed, offset the euphoric feelings of THC.

Myth: CBD is medicine, and THC is a drug

• The individual major cannabinoids work on their own for some patients
  • most benefit from a blend of THC and CBD (" 2 + 2 = 12.")
    • entourage effect comes into play
  • journaling the experience is the way to get to the right doses, chemovars, etc. for you

Four types of medications patients will be using:

1. Prophylactic - Prevent the problem from starting

• Use any or all:
  • edible or capsule at bedtime
  • non-psychoactive CBD / THCA during the day
    • micro dosed to keep ECS active
  • raw cannabis acids
    • THCA
      • patches
      • drops
      • raw cannabis juice

2. Daily Support - Activate ECS without being high

• balms and salves used topically
  • good option for those who can't test positive for THC
• micro-dosing: 1 - 5 mg a few times a day
• drops, single puff from vape pen, etc
• whatever ratio benefits patient and is available
  • CBD alone
  • high-CBD with THC
  • THCA

3. Acute or Episodic Relief - Immediate Relief

• smoking or vaping
• oral sprays, and in turns held in mouth
  • there are nano-molecular sprays now that enter bloodstream up to 8x faster than ordinary drops
• combine gels
• dabs for severe onset
  • keep to minimum

4. Relaxation - Stress Relief to Recover

• inhaled cannabis
• teas or drinks
• bath soaks (Epsom salts infused with cannabis oils)
  • good for MS patients with spasms
  • good for patients with musculoskeletal pain
  • can relax neuropathic pain
  • can stave off headache by encouraging relaxation
• balms or salves

The important take-away is that most patients wil benefit from multiple pathways using diversified products.

• Cannabis isn't one-size-fits-all, but there Is a size for everyone

Start patients on

• 1 mg for every 20 pounds of body weight every 8 hours for THC alone
• 1 mg for every 10 lbs of body weight for THC:CBD
  • She likes to start with balanced ratios to reduce psychoactivity.
• 1mg per 10 lbs of body weight for CBD alone
• Titrate up to desired effect

When you take too much
Too much CBD feels like

• grumpy
• lethargic
• emotionally flat
• sleepy
• SOLUTIONS: simply back off the dose until things feel better
  • or increase THC to get better balance

Too much THC feels like

• Mild signs:
  • rapid heartbeat
  • dry mouth
  • red eyes
  • dizziness
  • anxiety
• Acute signs
  • acute paranoia
  • difficulty standing
  • feel like you're dying
  • difficulty staying awake
  • uncomfortably out of control
• SOLUTIONS: drop down THC and/or increase CBD
  • journal it so you know what you're doing

Guidelines:

Everyone increases by only 2.5 mg at a time​

• Wait for a scheduled period before increasing again
• Keep self-titrating until you find relief

Basic weight to cannabinoid guidelines

• Under 150 lbs: 2.5 mg - 5 mg
• Up to 200 lbs: 5 mg - 10 mg
• 200 + lbs: 5 mg - 15 mg

Administration Methods

Drops or sprays

• 2.5 - 5 mg
• wait 20 minutes

Inhaled

• one puff
• wait 5 minutes for effect

Edibles

• 2.5 - 5 mg
• wait 1 hour

Potential drug interactions

• High blood pressure meds that reduce BP need to be taken at a different time of day than inhaled cannabis
  • you don't want to get BP so low that you faint
• Type 1 diabetics
  • cannabis has a positive effect on metabolism
  • CBD alone can reduce need for basal insulin to half
  • monitor how much insulin you need if you're taking a CBD product
  • we know THC also has positive effect, but lack the research to explain it
• Type 2 diabetes can be controlled by CBD alone if
  • dosed every 8 hours
  • at about 1 mg for every 20 lbs of body weight

Write it all down so you can see the patterns and fine tune

 

[SweetSue]

Delivery Methods and Products - Green Flower Media Fundamentals of Cannabis course

Cannabis products may be

• smoked
• vaped
• dabbed
• consumed as edibles
• applied topically
• applied using transdermal carriers
• applied using suppositories
  • anal
  • transvaginal
• injected

"delivery methods" = route of administration

route determines bioavailability

• the % of pharmacologically active compound that
  • enters bloodstream
  • is able to exert an effect
  • what happens next
• for greater efficacy, method can be matched to
  • condition being treated
  • desired effect
• may be as low as 4% to as high as 100% bioavailable
  • depending on how rapidly and completely they get into the bloodstream

onset of action - time it takes for cannabinoids to become medically effective

• depending on delivery method onset can vary from just minutes to over 1 hr

peak effect - the time it takes delivery method to get max cannabinoid effectiveness

• from practically instantaneously to over 2 hrs

duration of action - length of time you can expect cannabinoids to

• remain medically effective
• provide an effect
• depending on delivery method can be less than 2 hrs to over 24 hrs

First-Pass metabolism

• significant to therapies that direct cannabinoids through liver to bloodstream
  • liver is metabolizing point for cannabinoids
  • after metabolization, transformed cannabinoids are released into bloodstream
    • metabolized cannabinoids don't register as bioavailable in their original forms after metabolization
      • their new metabolite identities have their own, often more powerful medicinal values
        • may be more medically active than original cannabinoids
• bioavailability of original cannabinoid may be low in bloodstream but
  • metabolites are more medically active
  • bioavailability numbers don't tell the whole story

Major Delivery Methods for Cannabis Products

Oral/Gastrointestinal Consumption through the gut

Through the stomach, to the liver for First-Pass

• we assume some signal eCBRs as they pass
• in liver cannabinoids will be metabolized by enzymes
• bioavailability is only considered to be 4 - 20%
  • this is because original cannabinoids get transformed and no longer register as the originals
  • metabolites are actually more medically active
    • delta-9 THC is converted to 11-hydroxy THC
      • 4 to 10 times more
        • psychoactive
        • medically active than delta-9 THC
      • the high numbers of metabolites that hit bloodstream make edibles a viable option for medical use
  • onset typically 30 - 90 minutes
  • peak effect usually reached at 2 - 4 hours
  • duration depends on
    • body mass
    • metabolism
    • biological sex
    • eating habits

With such low bioavailability medical community prefers other methods

• sublingual/oromucosal
• rectal or transvaginal
• inhalation
  • vaporizers
  • inhalers

Pick up at smoking tomorrow

 

[SweetSue]

Delivery Methods and Products - Green Flower Media Fundamentals of Cannabis course

Cannabis products may be

• smoked
• vaped
• dabbed
• consumed as edibles
• applied topically
• applied using transdermal carriers
• applied using suppositories
  • anal
  • transvaginal
• injected

"delivery methods" = route of administration

route determines bioavailability

• the % of pharmacologically active compound that
  • enters bloodstream
  • is able to exert an effect
  • what happens next
• for greater efficacy, method can be matched to
  • condition being treated
  • desired effect
• may be as low as 4% to as high as 100% bioavailable
  • depending on how rapidly and completely they get into the bloodstream

onset of action - time it takes for cannabinoids to become medically effective

• depending on delivery method onset can vary from just minutes to over 1 hr

peak effect - the time it takes delivery method to get max cannabinoid effectiveness

• from practically instantaneously to over 2 hrs

duration of action - length of time you can expect cannabinoids to

• remain medically effective
• provide an effect
• depending on delivery method can be less than 2 hrs to over 24 hrs

First-Pass metabolism

• significant to therapies that direct cannabinoids through liver to bloodstream
  • liver is metabolizing point for cannabinoids
  • after metabolization, transformed cannabinoids are released into bloodstream
    • metabolized cannabinoids don't register as bioavailable in their original forms after metabolization
      • their new metabolite identities have their own, often more powerful medicinal values
        • may be more medically active than original cannabinoids
• bioavailability of original cannabinoid may be low in bloodstream but
  • metabolites are more medically active
  • bioavailability numbers don't tell the whole story

Major Delivery Methods for Cannabis Products

Oral/Gastrointestinal Consumption through the gut

Through the stomach, to the liver for First-Pass

• we assume some signal eCBRs as they pass
• in liver cannabinoids will be metabolized by enzymes
• bioavailability is only considered to be 4 - 20%
  • this is because original cannabinoids get transformed and no longer register as the originals
  • metabolites are actually more medically active
    • delta-9 THC is converted to 11-hydroxy THC
      • 4 to 10 times more
        • psychoactive
        • medically active than delta-9 THC
      • the high numbers of metabolites that hit bloodstream make edibles a viable option for medical use
  • onset typically 30 - 90 minutes
  • peak effect usually reached at 2 - 4 hours
  • duration depends on
    • body mass
    • metabolism
    • biological sex
    • eating habits

With such low bioavailability medical community prefers other methods

• sublingual/oromucosal
• rectal or transvaginal
• inhalation
  • vaporizers
  • inhalers

Smoking/Vaporizing Quick Response

• Large quantities of cannabinoids quickly enter the bloodstream
  • some via mucous membranes of mouth and throat
  • rest through lungs
• bioavailability relatively high
  • can also be as low as 4%
  • up to 56%
• considerably less efficient than other methods
  • significant amount (~50%) of cannabinoids and terpenes destroyed by heat of flame
  • another 25% lost at exhale
• peak effect within 20-30 minutes
• total duration usually around 2 - 3 hours

Dermal/Topical Localized Relief

• refers to localized skin application of
  • creams
  • lotions
  • salves
  • unguents
  • etc
• epidermal permeability barrier
  • 5-layer shield to keep foreign matter out of the bloodstream
  • tightly-linked keratinocytes
    • most common cell type found in skin
  • helped by presence of other skin components
    • enzymes
    • lipids
    • peptides
    • acids
• cannabinoids applied to skin do not get into bloodstream
  • they activate eCBRs in the epidermis
    • both CB1 and CB2 are represented in the skin
• ECS plays a role in
  • dermatitis
  • psoriasis
  • rosacea
  • skin cancer
• dermal application makes cannabinoids and components available right where they're needed
  • only tiny amount will make it into bloodstream
  • usually biologically indiscernible
  • usually non-psychoactive
• different cannabinoids and terpenes penetrate more efficiently
  • CBN and CBD are 10x more permeable than delta-8 THC
  • limonene and nerolidol assist cannabinoid permeability
• evidence exists that ECS regulates effectiveness of epidermal permeability barrier by
  • controlling barrier formation and maintenance
  • regulating cell growth
  • regulating cell differentiation
  • regulating skin inflammatory response (controlling actions of nociceptors)
• bioavailability of applied cannabinoids may be low
  • not an indicator of efficacy
• onset and duration vary according to
  • cannabinoid concentrations
  • terpene profiles
  • dermal region being treated
  • not a one-size-fits-all figure for onset or duration
    • may be 10-20 min onset and duration of 2-3 hours
    • My daughter gets 4-5 hours of relief from menstrual cramps with topicals applied to the lower back and abdomen.

Transdermal Super-Duper Topicals

• topicals designed to permeate the epidermis and enter the bloodstream
  • entering the bloodstream through the fine capillaries in dermis
  • may be very high concentrations
  • alternatively, may include permeability enhancers
    • propylene glycol
    • ethanol
    • terpenoids like limonene or nerolidol
• most commonly used as patches
  • pads of surgical glaze soaked in cannabinoids and permeating agents
  • designed to be applied to areas having lots of blood vessels close to skin
    • i.e. wrists
• offers slow, long-lasting release of cannabinoids into bloodstream
• bioavailability thought to be high
  • avoids First-Pass metabolism
• evidence suggests mean, steady plasma concentrations at 1.4 hours
• can continue to release cannabinoids up to 48 hours
• onset = less than 1 minute, up to 2 hours

Sublingual & Buccal/Oromucosal Easier Access to the Bloodstream

• oral mucosa 4-400 times more permeable than epidermis
  • can pass through to bloodstream more easily
  • can get to organs, CNS, and internal tissues without First-Pass metabolism
    • If any is swallowed it will go through GI tract and be metabolized in the liver
• applied to oral mucosa or gums
  • enter bloodstream as rapidly as sublingual
  • doesn't stimulate swallowing reflex
    • avoiding first-pass
• bioavailability difficult to pinpoint without research
  • one study said only a little improved over GI absorption
• onset 30 - 60 minutes
• duration usually 1 - 6 hours

Rectal The most unconventional approach

• Suppositories
  • allow for some localized effects
  • allows absorption, within limits
  • avoids psychoactivity
    • cannabinoids unlikely to get to brain
• overall bioavailability numbers are about double of oral/GI tract
• can be used for
  • conditions affecting GI tract
  • systemic relief
    • allows for sustained, consistent release of cannabinoids into bloodstream
• bioavailability pegged at 13.5 - 40%
  • cannabinoid-dependant (Marinol appears to be best tested)
• onset 10 - 15 minutes
• peak at 2 - 8 hours
  • plasma levels don't begin to drop until 6 - 8 hours

Transvaginal Womens' Concerns

• similar to rectal suppository therapies
• localized effects
• some degree of bloodstream penetration
• no psychoactivity
• shows promise in treatment of
  • endometriosis
  • menstrual pain and cramping
• onset 0 - 15 minutes
• peak effect at 2 - 8 hours
  • plasma levels don't drop off for 6 - 8 hours

Reports of efficacy of suppository treatments are mostly anecdotal

Injection 100% Bioavailability

• intravenous injection of isolate cannabinoids
• disadvantages
  • instantaneous onset and peak effect
  • greatly increases adverse side effects
    • acute paranoia
    • psychosis-like symptoms
• subcutaneous injections may be more useful
  • avoids rapid onset and peak
  • offers sustained delivery of cannabinoids
  • less likely to reach the brain