An extract from a Wild Rose College’s online course: Cannabis: An Introduction for Healthcare provider, starting mid-January 2020.

 In our last two parts of this blog, we discussed briefly some of the substances that could reduce symptoms of THC over-dose and introduced strategies to help reduce adverse symptoms. In this section we are going to go a bit deeper and look at some of the mechanisms around reducing these symptoms.

For more information on material found in this blog please visit the material written by the great Cannabis researcher; Ethan B Russo. Possibly starting with: Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.  You will find more detail referencing in the source material. I have included my opinions and slant where I see fit.

Symptoms and mechanisms of overdose

Cannabinoid receptors are related to G-protein linked receptor, which inhibits adenylyl cyclase and stimulates potassium conductance. There are at least two active cannabinoid receptors: CB1 and CB2:

• CB1 is found in the central nervous system including the basal ganglia, substantia nigra, cerebellum, hippocampus, and cerebral cortex. It acts pre-synaptically to inhibits release of several neurotransmitters including acetylcholine, L-glutamate, gamma amino butyric acid (GABA), norepinephrine, dopamine, and 5-hydroxytryptamine.
• CB2 is found peripherally in the immune system tissues (e.g., splenic macrophages and B lymphocytes), peripheral nerve terminals, and vas deferens. It is proposed that it plays a role in regulation of immune responses and inflammatory reactions. Anandamide (bliss hormone) and palmitoylethanolamide (PEA, treatment of pain and inflammation) are known endogenous cannabinoid receptor ligands.

Pharmacokinetics — The pharmacokinetics and pharmacodynamics of delta-9 tetrahydrocannabinol (THC) vary by route of exposure as follows:

• Inhaled cannabis– After inhalation of cannabis smoke, onset of psychoactive effects occurs rapidly with peak effects felt at 5 – 30 minutes and lasting up to 4 hours. These effects reflect plasma delta-9 tetrahydrocannabinol (THC) concentrations. Approximately 2 to 3 mg of inhaled THC is enough to produce drug effects in new users. Pulmonary bioavailability varies from 10 to 35 percent of an inhaled dose, determining on several factors including: the depth of inhalation along with the duration of puffing and breath holding.
• Ingested cannabis– has a delayed onset of psychoactive effects that ranges from 30 minutes to three hours. Clinical effects may last up to 12 hours. Orally administered cannabis has low bioavailability (5 to 20%) due to chemical degradation in gastric acid and substantial first-pass metabolism in the liver. In new users, psychotropic effects occur with 5 to 20 mg of ingested THC. Ingested cannabis reaction might be delayed several hours until there are enough oily substances in the digestive tract to be digested. Some people take cannabis in the evening (especially concentrated oil infusions) to help them sleep but find it does not start acting until a few hours after the morning meal that kicks in lipid digestion.

THC is lipid soluble, highly protein bound (95 to 99 percent).

THC metabolism occurs via hepatic cytochrome oxidases, CYP2C9 and 3A4. The primary active metabolite is 11-hydroxy THC, and the inactivated metabolite is THC-carboxylase. After metabolism, THC is mostly excreted as hydroxylated and carboxylated metabolites via feces (65 percent) and urine (20 percent). Although difficult to measure, the elimination half-life of THC is slow, ranging from 25 to 36 hours. This lengthy half-life is likely due to slow release from lipid storage compartments and enterohepatic circulation. Elimination half-life is longer in regular cannabis users.

Toxic effects — Recreational cannabis intake to achieve psychoactive effects can often result in adverse effects because there is no clear demarcation between doses that achieve symptoms desired by a marijuana user.

In adolescents and adults, inhaled doses of 2 to 3 mg of delta-9 tetrahydrocannabinol (THC) and ingested doses of 5 to 20 mg THC impair attention, concentration, short-term memory and executive functioning. More severe adverse effects may occur at doses >7.5 mg THC, including nausea, postural hypotension, delirium, panic attacks, anxiety, and myoclonic jerking. Psychosis has also been associated with use of higher potency/concentrated cannabis products.

Clinical Manifestations: The clinical manifestations of acute cannabis intoxication vary according to age; but contrary to popular opinion, has very little difference on body size.

Neurologic abnormalities are more prominent in children but do happen in adolescents and adults.  Symptoms include ataxia (Couch-lock), excessive and purposeless motor activity of the extremities (hyperkinesis), lethargy, and on rare occasions prolonged coma.

Adolescents and adults — The physiologic signs of cannabis intoxication in adolescents and adults can include:

• Tachycardia
• Increased blood pressure or, especially in the elderly, orthostatic hypotension
• Increased respiratory rate
• Conjunctival injection (red eye)
• Dry mouth
• Increased appetite
• Nystagmus (involuntary eye movement)
• Ataxia, Catalepsy (Couch-lock)
• Slurred speech
• Anxiety
• Paranoia

Cannabis intoxication in adolescents and adults also results in the following neuropsychiatric effects:

• Mood, perception, thought content– Ingestion typically leads to feeling “high,” marked by a euphoric, pleasurable feeling and a decrease in anxiety, alertness, depression, and tension. However, first-time cannabis users, as well as anxious or psychologically vulnerable individuals, may experience anxiety, dysphoria (opposite of euphoria), and panic. Increased sociability usually occurs during intoxication, although dysphoric reactions may be accompanied by social withdrawal. Inexperienced users who ingest cannabis products may not be aware that effects may not be felt for up to three hours which may cause them to continue to consume high potency products with an increased likelihood of dysphoria. (See’Pharmacokinetics’ above.)

Perceptual changes include the sensation that colors are brighter and music is more vivid. Time perception is distorted in that perceived time is faster than clock time. Spatial perception can also be distorted, and high doses of potent cannabis products may cause hallucinations. Mystical thinking, increased self-consciousness, and depersonalization may occur, as well as transient grandiosity, paranoia, and other signs of psychosis.

• Cognition, psychomotor performance– Cannabis use slows reaction time and impairs attention, concentration, short term memory, and risk assessment. It also seems to increase procrastination in many users. These effects appear more chronic when cannabis is used in conjunction with other central nervous system depressants. Acute cannabis use will impair motor coordination and interferes with the ability to complete complex tasks that require divided attention (multi-tasking).

Impairment of cognition, coordination, and judgment lasts much longer than the subjective mood change of feeling “high.” Psychomotor impairment lasts for 12 to 24 hours due to accumulation of cannabis in adipose tissue, slow release of THC from fatty tissue stores, and enterohepatic recirculation. However, a cannabis consumer may think that he or she is no longer impaired several hours after the acute mood-altering effects have resolved. As an example, a placebo-controlled trial with licensed pilots found that smoking cannabis impaired performance on a flight simulator for up to 24 hours, although only one of the nine subjects recognized this impairment.

Acute psychomotor impairments interfere with the ability to operate other heavy machinery, such as automobiles, trains, and motorcycles. A meta-analysis of nine studies found an association between cannabis intoxication and an increased risk of a motor vehicle collision involving serious injury or death. Drivers using cannabis are 2-7 times more likely to be responsible for accidents compared to drivers not using any drugs or alcohol. Furthermore, the probability of causing an accident is directly proportional to plasma levels of delta-9-tetrahydrocannabinol.

Several other commonly used recreational drugs have some overlapping clinical features with cannabis intoxication in adolescents and adults including:

• Cocaine
• Amphetamines and methcathinones (bath salts)
• Lysergic acid diethylamide (LSD) and other hallucinogens (eg, phencyclidine [PCP],dextromethorphan, or psilocybin)
• MDMA (ecstasy)
• Synthetic cannabinoids

Cannabis use may exacerbate pre-existing mental illness (e.g., psychosis, anxiety, or depression). Thus, clinicians should ask about cannabis use in patients who display worsening of known psychiatric disease.

• Adolescents and adults– Most symptoms after acute marijuana use in adults and adolescents resolve within a few hours and will not require hospital admission.

Hospital admission may rarely be needed for prolonged delirium or agitation requiring repeated doses of benzodiazepines or antipsychotics.

CBD

In regard to an unpleasant THC experience, CBD happens to be a natural mediator of its effects. THC binds to cannabinoid receptors in the human endocannabinoid system, causing psychoactive effects. In the presence of CBD, THC is partially obstructedfrom binding fully, thus tempering the outcomes.

Although CBD doesn’t incite psychoactive effects, it does encourage an enjoyable sensation of sedation that can help to calm down the heart rate and cool anxiety after ingesting too much THC.

CBG (the parent phytocannabinoid compound), has a relatively weak partial agonistic effect at

CB1 and CB2. Older work supports gamma aminobutyric acid (GABA) uptake inhibition greater than THC or CBD that could suggest muscle relaxant properties. Analgesic and anti-erythemic effects and the ability to block lipooxygenase have been said to surpass those of THC.

Finally, CBG behaves as a potent α-2 adrenoreceptor agonist, supporting analgesic

effects previously noted, and moderate 5-HT antagonist suggesting

antidepressant properties. Normally, CBG appears as a relatively low

concentration intermediate in the plant, but recent breeding work has yielded cannabis chemotypes lacking in downstream enzymes that express 100% of their phytocannabinoid content as CBG.

THCV is a propyl analogue of THC, and can modulate intoxication of THC, displaying

25% of its potency in early testing. A recrudescence of interest accrues to this compound, which is a CB1 antagonist at lower doses. THCV produces weight loss, decreased body fat and serum leptin concentrations with increased energy expenditure in obese mice. THCV also demonstrates prominent anticonvulsant properties in rodent cerebellum and pyriform cortex. THCV appears as a fractional component of many southern African cannabis chemotypes, although plants highly predominant in this agent have been produced. THCV recently demonstrated a CB2 -based ability to suppress carageenan-induced hyperalgesia and inflammation, and both phases of formalin-induced pain behaviour via CB1 and CB2 in mice.

CBDV, the propyl analogue of CBD, was first isolated in 1969, but formerly received little investigation. Pure CBDV inhibits diacylglycerol lipase [50% inhibitory concentration (IC) 16.6 μM] and might decrease activity of its product, the endocannabinoid, 2-AG. It is also anticonvulsant in rodent hippocampal brain slices, comparable to phenobarbitone and felbamate.

Finally, CBN is a non-enzymatic oxidative by-product of THC, more prominent in aged cannabis

samples. It has a lower affinity for CB1 and CB2; and was judged inactive when tested alone in human volunteers, but produced greater sedation combined with THC. CBN demonstrated anticonvulsant, anti-inflammatory and potent effects against MRSA (MIC 1 μg.mL ).

CBN is a TRPV2 (high threshold thermo sensor) agonist of possible interest in treatment of burns. Like CBG, it inhibits keratinocyte proliferation, independently of cannabinoid receptor effects. CBN stimulates the recruitment of quiescent mesenchymal stem cells in marrow (10 μM), suggesting promotion of bone formation and inhibits breast cancer resistance protein, albeit at a very high concentration.

Cannabis terpenoids: neglected entourage compounds?

Terpenoids are EO components, previously conceived as the quintessential fifth element, ‘life force’ or spirit, and form the largest group of plant chemicals, with 15–20,000 fully characterized. Their yield is less than 1% in most cannabis assays, but they may represent 10% of trichome content.

Monoterpenes usually predominate (limonene, myrcene, pinene), but these headspace volatiles, while only lost at a rate of about 5% before processing, do sufferdiminished yields with drying and storage, resulting in ahigher relative proportion of sesquiterpenoids (especially caryophyllene), as also often occurs inextracts. A ‘phytochemical polymorphism’ seems operative in the plant, as production favors agents such as limonene and pinene in flowers that are repellent to insects (cannabis is wind, not insect pollinated), while lower fan leaves express higher concentrations of bitter sesquiterpenoids that act as anti-feedants for grazing animals. Evolutionarily, terpenoids seem to occur in complex and variable mixtures with marked structural diversity to serve various ecological roles. Terpenoid composition is under genetic control, and some enzymes produce multiple products, again supporting Mechoulam’s ‘Law of Stinginess’. The particular mixture of mono- and sesquiterpenoids will determine viscosity, and in cannabis, this certainly is leveraged to practical advantage as the notable stickiness of cannabis exudations traps insects, and thus, combined with the insecticidal phytocannabinoid acids, provides a synergistic mechano-chemical defensive strategy versus predators.

As observed for cannabinoids, terpenoid production increases with light exposure.

In our next and last blog in this series, we are going to tie it all together and make suggestions of what to do in various situations. I will dig into my clinical bag and come up with some solutions. There is no one solution fits all here!

So if you have any question or comments, please make them below. This will determine what will be in the blog. We already see the controversy over Black Pepper heating up. What about the Yin/Yang camps of symptoms? How about, “I am not completely couch-locked, but just don’t like the feeling;” what do I do?

Add your comments to fuel the conversation.

to be continued . . . .