Substances-Cannabis

Time Course of Withdrawal

Onset is 1-3 days. Peak is 2-6 days. Duration is 7-14 days.

Effects at Typical Doses

A pleasurable sense of increased well being, but no "rush." Relaxation and drowsiness when alone. In a group, they may cause silliness and increased activity (like alcohol). A subjective sense of intensification and enrichment of sensory perception including vision, hearing, taste, smell, and touch. Vision and hearing are often most affected. Colors may seems richer and brighter. Music may sound more vivid and meaningful. There are all relatively subtle effects. Distortion of time sense (subjective time is usually slowed). There may be subtle distortions of distance and body image (things seem larger). Impairment of short term memory, attention span, and ability to concentrate. Can reduce the ability to reason logically, to engage in conversation and to learn.

Typical dose, onset, and duration of action

A typical single dose by smoking is the amount of marijuana contained in 1/3-1 joint (1/3 of a gram to 1 gram). When eaten, usually about 3 times the smoked dose is required to produce an equal degree of intoxication; this difference issue to erratic GI absorption and first pass metabolism in the liver; absorption is lower.

SMOKING-dose, onset, and duration of action

Absorption and crossing the BBB is VERY FAST. Due to the very high lipid solubility of THC. Both physiological and psychological effects begin in one or two minutes. Peak intoxication achieved by 10-20 minutes. Effects usually last 2-4 hours after a dose.

ORALLY- Dose, onset, duration of action

Absorption is lower and highly variable among persons; onset may take 30-120 minutes. Peak effects may not be reached until 1-3 hours after dosing. It may be up to 12 ours after ingestion before the effect is over. The delay in onset is a major cause of toxicity in the inexperienced user; start eating, won't feel high for 30-120 minutes, so keep eating until they feel high and consume more than they needed to achieve levels they were looking for.

Hashish

Another marijuana preparation seen in the US. More potent in terms of THC content than marijuana (up to 20%). Authentic hashish consists of the pure dried resin; available as dark gold, brown or black chunks or flakes. Much of what is called "hash" is bits of dried flowering top with high potency. Usually smoked in a pipe; can chase the dragon using hot knives.

Cannabis

Any of several drug preparations derived from Cannabis sativa or Cannabis indica=hemp plants. Cultivation of this easily grown plant is prohibited in the US, but large amounts still grown. One of the top 5 cash crops in the US. Recreational use in the US results in demand for 36$ billion annual crop (corn is $42 billion). ACTIVE DRUG in marijuana is delta-9-tetrahydrocannabinol (THC)=psychoactive ingredient. All part of the plant contain THC-most concentrated in a sticky resin, secreted by the flowering tops of the female plant.

Pure THC

Available only as a Schedule 3 prescription product. Consists as a gelcap containing THC dissolved in oil. Brand name is Marinol. Generic name is Dronabinol. FDA APPROVED PRODUCT Could be distributed in pharmacy that is legal, everything else we talk about is illegal. Dronabinol and Nabilone are approved for treatment of anorexia in AIDS patients and for refractory nausea and vomiting of patients undergoing chemotherapy. Medical cannabis advocates assert that these drugs are not as effective as natural cannabis for many medical conditions Natural cannabis contains a better experience for the patient; other natural compounds in cannabis might moderate those negative effects of taking straight THC.

The Cannabinoid Receptors

CB1 receptor: brain, some peripheral organs. CB2 receptor: peripheral immune cells. CB1 and CB2 are G-protein coupled receptors. CB1 and CB2, mu and delta opioid receptors, and D2 dopamine receptors may talk to the same G-protein=possible explanation for common mechanism underlying reinforcing properties of cannabis, opiate drugs, and dopaminergic drugs (cocaine, amphetamine). Activation og CB1 receptors affects signal transduction (cAMP/PKA, MAPK pathways) as well as ion channel activity. Act on presynaptic neurons to inhibit release of GABA and glutamate. Final outcome=increased dopamine release; inhibit inhibitory neurotransmitters.

Effects on the Immune System

CB2 receptor is expressed in cells of the immune system. In normal humans cannabis has no major effect on immune function. Concern about possible immune effects in immunocompromised patients: AIDs, transplant patients and many cancer patients; There is also a concern about infection caused by inhalation of bacterial and fungal contamination.

At Higher than Typical Doses

Can act as a true hallucinogen including LSD-like hallucinations, delusions and altered sense of self.

Effects on Motor Coordination

Cannabis does not produce an of the typical CNS depressant-like symptoms of intoxication!!! No CB receptor expression in the brainstem. No slurring of speech, ataxia, or serious incoordination (except at higher doses). Cannabis intoxication odes reduce psychomotor coordination and increase reaction time. In combination with the impairment of judgement interferes with driving ability. Significant impairment persists for up to 24 hours after the major subjective effects have worn off. The effects with alcohol are additive.

Medical Cannabis in the US

Cannabis has not been legal since 1937 under federal law. Cannabis treatable conditions: Chronic neurological disease (pain). Nausea and loss of appetite (chemotherapy). AIDS MS Glaucoma Cannabis is not distributed by pharmacies in any US state. Currently unclear whether use of cannabis is superior to THC-only for any condition. Cannabis does contain hundreds of additional compounds that might be pharmacologically active. Politico-legal issues make it very difficult to conduct robust clinical trials for potential cannabis benefits in the US. Smoking cannabis is likely to introduce unwanted harms like lung cancer

Risk of Progressing to the Use of other More Harmful Illicit Drugs

Cannabis users are more likely to later use heroin and/or cocaine than non-users. -Might be due to common actions on the reward center in the nucleus accumbens. -Might be due to ease of access since other drugs are supplied by the same illegal black-market. -Might reflect other common mental, environmental, or genetic risk factors.

Toxic Psychosis

Chronic, extremely heavy use of cannabis can produce marijuana psychosis. These clear up within several days after discontinuation. Thought to be due to cumulative overdosage. Very rare in the US.

Reproductive Effects

Chronic, heavy use of cannabis has not bee proven to affect male or female reproductive ability. Chronic heavy use has been reported to produce decreased testosterone levels. A small, reversible decrease in sperm count and motility. Produces an increase in anovulatory (no ovulation) menstrual cycles.

Subjective Effects of Cannabis Intoxication

Complex Influenced strongly by dose. Influenced by users previous experience with the drug. Influenced by the social and environmental setting.

Abstinence Syndrome

Daily smoking of up to one joint is unlikely to produce a significant withdrawal syndrome on sudden discontinuation. Daily use of 2 or more joints CAN produce a clear abstinence syndrome upon sudden discontinuation. The higher the daily dose and the longer the duration of use, the the worse the symptoms. Symptoms are relatively mild compared to alcohol or opioid withdrawal, strong enough to motivate continued heavy use.

Tolerance

Definitely develops stop many of the effects of THC although not all occur at the same rate. The high and tachycardia tolerate faster than the conjunctival injection. Tolerance is entirely PHARMACODYNAMIC and can be quite extensive. Strong tolerance to the desired effects of THC. Seen only in those who use several times a day. Even 1 joint per day can produce some tolerance. Tolerance is noticeable after 1-2 weeks of daily use and is lost at about the same rate on discontinuation.

Physical Dependence

Does occur but is not of any important in the occasional user. Even very heavy chronic use is unlikely to produce serious physical withdrawal symptoms, nothing dangerous.

Important Limitations for Understanding non-acute Cannabis Effects and Risks

Epidemiology for illegal drug use has many challenges; not always accurate recording. Most chronic/heavy cannabis users also drink and smoke. Chronic/heavy cannabis use is a significant risk factor for the use of other more harmful drugs. Cause and effect often unclear, cannabis use initiated due to other underlying problems.

History and Extent of Cannabis Use

First use of the Cannabis plant was for its fiber content. More than 10,000 years ago. Probably was first used for medicinal purposes and as an intoxicant about 5000 years ago in China. The first mention of its used as an intoxicant in the US is around 1850. 1964- THC discovered as major active ingredient. 1990-CB! receptor mapped. 1992-Anandamide, endogenous natural ligand. 1993- CB2 receptor cloned. 1994- SR 141716A, first receptor antagonist.

Localization of Brain CB1 Receptors

Frontal cortex: psychoactive drug effects. Hippocampus: THC-induced disruption of memory. Cerebellum: movement and postural control. Basal ganglia: movement and postural control. NOT IN BRAIN STEM! Relative non lethality of THC. Inhibit neurotransmitter release, no depression of respiration; lethal dose is 100 or 1000 fold higher than normal drug doses; no lethal effects in brain stem region of the brain.

Common Withdrawal Symptoms

Generally classed as non-physical. Craving, anxiety/nervousness, restlessness, irritability, anger/aggression, anorexia/weight loss, insomnia, and strange dreams. Physical symptoms are rare but include sweating, tremor, stomach pain, nausea/vomiting, and diarrhea.

Vaporizer Devices

Heat to liberate volatile compounds. Below the ignition temperature; no burning; process of burning creates new chemicals that can be toxic like cancer-causing chemicals, weed and tobacco smoke. No smell. No combustion or smoke! Similar plasma levels achieved compared to smoking. Similar plasma kinetics to smoking; identical delivery kinetics in vape and smoking at different levels of THC concentrations. Similar high intensity and time course to smoking. Lower CO levels than smoking. CO considered a surrogate for combustion products; product of burning; smoked, no matter the THC content, get more CO expired than with vape, which is bad. CO is surrogate for cancer causing chemicals present in marijuana and tobacco cigs. Lack of proof for above fact. Data for differences in carcinogen levels is anecdotal; there is a lack of definitive published studies. Many form factors. FDA has attempted regulation of vaporizer devices especially with e cigs. FDA authority to regulate successfully challenged in court.

Amotivational Syndrome

Heavy use is associated with a gradual loss of interest in school, work, achievement and other traditional long term goals. There is a change to a simpler lifestyle which is drug dominated. The person is dull, apathetic and not concerned about much of anything. These symptoms are what one might expect in a person who is chronically intoxicated. It is not clear that heavy cannabis use is causal. It is just as likely that lack of motivation leads to cannabis use rather than the converse; outcome of boredom or cannabis ue leading to this?

Physiological Effects of Cannabis Intoxication-Other Acute Effects

Hunger Dry mouth and throat Mild postural hypotension Fine tremor of the hands Muscle weakness.

Pulmonary Effects and Vaporizer Use

In a study of 20 chronic/heavy smokers, pulmonary symptoms and lung function improved after switching to a vaporizer for 1 month. Data on vaporizer use in health effects from only a few studies to date.

Chronic Intoxication

Is another risk of chronic heavy use (stoned all the time). Incompatible with optimal social functioning. Especially a problem in middle school and high school. Being stoned promotes truancy and strongly interferes with learning.

Psychological Dependence

Many people do become psychologically dependent. Discontinuation may be very difficult. Three studies including 55,000 people found a prevalence of DSM dependence ranging from 6-9% of users. Cannabis has a lower tendency to produce compared to some other agents. Cannabis<barbs, narcotics, amphetamines, cocaine. Produces less dependence than many other recreational drugs; lower risk of dependence and a lower potential of physical harm.

Pattern of Use

Many people try the drug a few times and discontinue use for several common reasons: -They don't like the effects of the drug. -They don't want to be associated with the drug taking culture. -They are afraid of legal/professional consequences like random drug tests. Of those who continue to use, most people use on an occasional basis (not more than once a week). There is a significant population of daily users: about half of these use 2 or more joints per day; some very heavy users smoke 5-20 joints per day.

Route of Administration

Marijuana is usually smoked. Most common dose form is marijuana cigarettes (joints) usually containing 0.5-1 g of marijuana. Can be put into hollowed out cigars (blunts), can hold several grams. Can be smoked in a pipe or a water pipe (bong). Marijuana can be vaporized and inhaled; heated to liberate THC but at a temperature much lower than burning; vaporizer devices typically used from 180 deg to 230 deg C vs combustion at >500 degC. The idea is to minimize harmful chemicals found in marijuana smoke (similar to TOBACCO SMOKE). Marijuana can be taken orally; incorporated into foods such as brownies. Can also be made into a tea or extracted with alcohol to form a tincture. "Overdose" risk may be higher because slow absorption leads to user taking a higher dose; delayed production of high, user might perceive that they did not take enough and will take more.

Commercial Products (in some states)

Marijuana with more accurate strain and THC content information. Manufactured food and beverage products made from cannabis (chocolates, gummy bears). E-cigs cartridges, topical patches; readily absorbed in the lungs but can readily be absorbed through the skin.

Preparations

Marijuana: preparation most often used in the US. Officially consists of dried, crushed leaves, flowering tops, stems/seeds of the plant; stems and seeds are usually shaken out before use. THC concentration: Now typically 3-4% compared to about 1.5% in the 1970s. Highly potent varieties may contain 10-15% THC. Sinsemilla: A product of a growing technique, involves separation of the female from the male plants before pollination; results in HIGHER THC CONTENT (up to 20% THC).

Effects on Pregnancy Outcomes

Mother smoked at least 4 times per week have effects (not with occasional cannabis use). Slight decrease in both weight (smaller effect than tobacco). Minor but persistent neurological and cognitive deficits (but no difference in IQ). Higher rates of delinquency and behavior problems. Difficult to separate cannabis use by the mother from poor parenting and/or genetic factors.

Psychomotor Performance

Naive User: Low doses affect simple tasks. Moderate or high dose affects even experienced user. All available evidence suggests that marijuana is not a major risk factor for auto accidents in comparison to alcohol (but probably has some risk). and WI drugged driving law sets a zero tolerance limit for detectable THC or THC metabolites while driving.

Dangers from Moderate Recreational Use-CV Effects

Probably minimal danger to young users with health hearts. Those with coronary artery disease, congestive heart failure and arrhythmias should not use due to dangers from tachycardia and peripheral vasodilation. Risk of heart attack for those with significant risk factors increased 5 fold in the first hour after use in one study, suggesting that there is a causal relationship. Risk of mortality for those with significant CV risk factors increased 3 fold over a 4 year period.

Physiological Effects of Cannabis Intoxication-Peripheral Vasomotor Effects

Produces generalized peripheral vasodilation, especially in skeletal muscles and conjunctiva (red eyes). Causes vasoconstriction in fingers and toes. Blood shot eyes is frequently seen and is a good clue a person is using. This is not due to smoke irritation as one CAN get with oral use- blood shot eyes happens with any route of administration. Due to the vasodilatory effects of THC on conjunctival blood vessels. Users may try to mask with OTC topical vasoconstrictors.

Rate of THC Clearance from Marijuana, once peak plasma level is attained.

Smoked similar to IV, typical high: 3 hours; peak right away and the exponential decay. Oral: prolonged but poor absorption; low and variable plasma concentration, reduced bioavailability: degradation in stomach, first pass hepatic metabolism.

Reverse Tolerance

Some new users seemingly become more sensitive to the intoxicating effects of marijuana. Occurs over the first few smoking sessions. -May be due to increased smoking efficiency. -May be due to the acquisition of favorable expectations and attitudes about the experience; placebo effect: positive attitudes can enhance experience.

Accumulation of THC in the Body

THC and some if its metabolites are highly lipophilic and tend to partition into body fat stores. These substances accumulate in the body. The heavier the use, the greater degree of accumulation. This is often cited as CONCERN. No evidence that any kind of adverse effect results from such accumulation, even if you discontinue smoking. Leakage from fat produces very low plasma THC levels and no CNS effects. The main consequence of accumulation is that THC can be tested in urine drug tests; can detect for a long period of time than if you are smoking for a short period of time.

THC-Mechanism of Action

THC mimics the action of a family of endogenous substances called endocannabinoids. Most widely known form which is called anandamide These substances serve as presynaptic inhibitory neuromodulators. In certain neuronal systems in the brain and spinal cord, they inhibit the release of neurotransmitters by acting on CB1 receptors. The euphoric effects seems to be due to an activation of ventral segmental area (VTA) dopaminergic neurons.

Drug Testing for Marijuana Use

The bottom line is that for persons who worked a standard work week, there is no way to use pot and avoid detection. Using the standard 50 ng/ml or urine cutoff point the urine can remain positive for THC...for up to 72 hours after a single joint, for as long as 30 days after discontinuation of daily smoking. A positive test due to passive inhalation is highly unlikely but possible if a person spends several hours in a small enclosed space (car) with several smokers. THC can also be detected in hair for months after smoking (false positive to passive exposure is more likely when this test is used); hair takes months to grow, this can accumulate over time.

Massive Overdoses

The risk of severe toxicity or death due to cannabis is extremely low. No well documented deaths in humans. Based on animal studies, lethal dose is many thousands time the intoxicating dose. Massive overdose can produce a toxic psychosis which dissipates in a few days. Can occur after smoking a high potency product or accidentally eating too many brownies. Can produce acute panic reactions due to the strong sensory distortions and hallucinations. These generally require no medical treatment. Reassure and protect the patient from self-injury.

Hash Oil

Thick, syrupy liquid which is made by extracting cannabis material with organic solvents. THC content is typically 15-30% and can be as high as 60%. Usually used by placing a drop or two on a joint or tobacco cigarette and smoking; a way to boost THC content or deliver with tobacco.

Dangers from Moderate Recreational Use

This equals about a "few" joints a week or less. Actually there are relatively few dangers, but certainly this is not totally risk free. Risk of progression to heavy use or dependence. Impaired driving ability does occur and is additive with alcohol. Acute panic reaction is probably the most FREQUENT adverse reaction of moderate recreational use: can result from lack of familiarity of a novice user to the effects of the drug; can result from having a "bad trip." Generally lasts only a few hours and requires no medical treatment. Mobilization of latent psychosis is a ver rare event, but may occur as an acute psychotic reaction to cannabis; occurs in a person with pre-existing psychopathology and can persist for a long time, rare, but effects can last a lifetime. Cannabis use is associated with a ~2.4 fold increase in risk of developing schizophrenia; cause vs. effect is unclear; trigger schizo in someone who would otherwise never get schizo, or trigger in someone who is not yet diagnosed has to be considered as risk. Relationship between cannabis use and schizo is DOSE DEPENDENT. Flashbacks occur, but probably less frequent than with LSD. Postural hypotension is common and can lead to falls. Cold fingers and toes may occur due to peripheral vasoconstriction- generally not a big problem, may be a higher risk of frostbite.

Lung Cancer

This is a possible lethal effect that is of great concern. Marijuana smoke "tar" contains many of the same carcinogens as tobacco smoke. Concentration of carcinogens is 3x higher than in tobacco smoke. The way people smoke joints doesn't help: deep, maintained inhalations and smoking the "roach." 33% more tar deposited in the lungs than with tobacco smoke. Each joint probably has the carcinogenic potential of 4-5 typical unfiltered cigarettes. Significant potential risk of lung cancer due to even moderate cannabis smoking. There are limited number of studies on lung cancer that definitively link it to cannabis use. That fact that many cannabis users also smoke tobacco is a confounding issue. Cannabis use has also bee associated with head and neck cancers. There are reports of pre-malignant changes in the lungs of heavy cannabis smokers. Using a bong to filter the smoke doe reduce concentration of several carcinogens without much effect on THC concentration. Vaporizers may help; very few peer reviewed studies on this issue.

Dangers Associated with Heavy Cannabis Use

This means at least one joint almost everyday. Moderate use risks are all enhanced including lung cancer. Other pulmonary effects: acute and chronic respiratory problems observed in chronic cigarette smokers are seen. It takes fewer joints than tobacco cigarettes to cause these pulmonary effects. Laryngitis Hoarseness Chronic cough Chronic sputum production Wheezing Abnormal pulmonary function tests. Production of emphysema has not been shown but is suspected.

Physiological Effects of Cannabis Intoxication-Tachycardia

Time-course correlates well with THC blood levels. Substantial increase of 20-100% is typical.

History of Cannabis Use in the US

Until about 1960, recreational use in US was uncommon in the general population. Medical use was once common and returning. It was in the US Pharmacopeia from 1850-1942. Some US states have recently enacted medical cannabis laws. In the 1920s and early 1930s, it was used extensively by Hispanics and some other immigrants. Marijuana Tax Stamp Act of 1937: legislation based against these groups, effectively outlawed cannabis use. In 1970 it was made a federal Schedule 1 drug, declaring there is no legit use for marijuana and it still remains this way today. In the 1960s and 1970s, use in this country increased greatly in the general population. Use peaked in 1979 and has declined substantially since then. Cannabis is still the most widely used illicit drug in the US. 33% of the adult population has tried it at least once. 19% of adolescents between 12 and 17 years of age have tried it at least once. Results based on surveys and probably significantly underestimate usage rates.

Persistent Neurocognitive Deficits

Very controversial Issue. Neurological and/or cognitive dysfunctions that persist for a long time after discontinuation have been suggested. No evidence for severe loss of function. Evidence for subtle deficits in some studies. Once recent study looked at three groups of users who had smoking 11, 42, or 94 joints per week for 3 and 5 years: found measurable dose-dependent deficits in memory, executive function, and in motor dexterity. Persisted for at least 28 days after discontinuation of cannabis use. Only 22 people involved in the study and no non-smoking control group. Small study, no severe long term consequences. Another recent study looked at 63 current smokers who had smoked at least 5000 times in their lives showed no such defects persisting beyond 7 days after discontinuation.