THE CANNABIS PLANT AND ITS PRODUCTS

THE CANNABIS PLANT AND ITS PRODUCTS

Cannabis is a highly versatile plant. Hemp, a strong fiber in the stem, has been used to make rope, cloth, and paper. When dried, the leaves and flowers are used as marijuana for their psychoactive and medicinal effects. The roots of the plant have also been used to make medicines, and the ancient Chinese used the seeds as a food. Cannabis seeds are still used for oil and animal feed.

The two most prevalent species of cannabis are Cannabis sativa and Cannabis indica. In years past, people cultivated C. sativa to make hemp. Under natural conditions, it will grow as high as a lanky fifteen to twenty feet, and it still grows wild as a weed across the southern United States. C. indica has been cultivated throughout the world mostly for the psy­choactive properties of its resins. These plants generally grow to no more than a few feet in height and develop a thicker, bushier appearance than C. sativa.

The cannabis plant contains more than four hundred chemicals, and several of them are psychoactive. By far the most psychoactive of these is delta-9-tetrahydrocannabinol (THC), found in the plant's resin. The resin is most concentrated in the flowers. In an unfertilized plant, it provides a sticky coating that protects the flowers from excessive heat from the sun and enhances contact by grains of pollen. The vegetative leaves contain a small amount of resin, as do the stalks, but the concentrations in these parts of the plant are so low as to have little intoxicating effect.

Today, much cultivation of 'drug" strain marijuana plants has occurred, but the amount of THC present in the flowers of individual plants varies considerably. In addition to the genetic makeup of the plant, the growing conditions, timing of harvest, drying environment, and stor­age environment can all significantly influence the potency of the final product. As the plant matures, the balance of various chemicals in the resin changes, as does the amount of resin secreted at the flowering tops of the plant. Early in maturation, cannabidiolic acid (CBDA) predomi­nates and is converted to cannabidiol (CBD), which is converted to THC as the plant reaches its floral peak. The extent to which CBD is converted to THC largely determines the "drug quality" of the individual plant. When the plant matures into the late floral and senescent stages, THC is converted to cannabinol (CBN). A plant that is harvested at the peak flo­ral stage has a high ratio of TFIC to CBD and CBN, and the psychoactive effect is often described as a "clear," or "clean," high, with relatively little sedative effect. However, some cultivators allow the plants to mature past this peak to produce marijuana with a heavier, more sedative effect. The difference between the feelings associated with peak- versus late-har­vested marijuana has been described as the difference between being "high" and being "stoned."

Burning marijuana for smoking produces hundreds of additional com­pounds. So when someone smokes a single joint, hundreds upon hun­dreds of chemical compounds enter the body. We know that many of these compounds act on various organs and systems in the body, but we don't know what effects most of them have, either acutely or after pro­longed use. Many scientific studies have, therefore, restricted their atten‑ tion to THC, allowing us to evaluate at least some of the effects of cannabinoids on the brain and behavior.

INTERACTIONS WITH OTHER DRUGS

INTERACTIONS WITH OTHER DRUGS

Many people who experiment with hallucinogens combine them with other drugs. For example, it is not uncommon for people to take LSD or mushrooms and smoke marijuana at the same time. The effect of these combinations is highly individual and depends on the previous drug experience of the user, the doses, and the particular drugs involved. For example, smoking marijuana often triggers PHPD (flash­backs) in heavy LSD users. Many of these combinations produce bizarre, anxiety-provoking—but not dangerous—states.

The most troublesome reactions are those that are caused by the user taking something without knowing it. PCP is a frequent culprit in this regard. Marijuana can be adulterated with PCP without the user's knowledge and can induce a terrifying or dangerous state in the unsus­pecting users.

What about interactions with prescription drugs? Not surprisingly, other drugs that influence serotonin systems have been involved in reported interactions. There are multiple reports of serotonin-specific rcuptake inhibitors (SSRls) like Prozac (fluoxetine) triggering flashbacks in heavy LSD users. The opposite interaction also can happen: some patients who are taking SSRIs to treat depression report that they do not experience the effects of LSD. A more dangerous interaction could theo­retically happen if people combine SSRIs and avahuasca. The MAO inhib­itor in the ayahuasca can synergize with the increase in serotonin caused by the SSRI, leading to the dangerous "serotonin syndrome" that we dis­cuss in the "Ecstasy" chapter.

HOW HALLUCINOGENS WORK

HOW HALLUCINOGENS WORK

Neuroscientists know less about stimulants than most other psychoac­tive medications. To some degree, this is on account of mental trips can be contemplated most accu­rately in people. Nobody would volunteer for the watchful mind injury contemplates that can figure out where basic medication impacts live, however imaging examinations in living people have demonstrated helpful. Also, we do have a considerable measure of data about the neurotransmitter frameworks required from examines in creatures. Since there are such a variety of stimulating medications, it will not shock anyone that there are a few diverse neurochemical courses to hal­lucinatory states and that each medication creates a to some degree particular state caused by an unmistakable component of activity. 

LSD, PSILOCIN, MESCALINE, AND DMT 

The doubt that medications like LSD have something to do with the neu­rotransmitter serotonin (5-HT) has been common since researchers initially depicted the similitude of the synthetic structures of LSD and psilocin to serotonin in the 1940s. It has been a long and convoluted street from this ini­tial doubt to an atomic comprehension of what these medications do. Sero­ton in is an essential neurotransmitter that manages rest, tweak eating conduct, keep up a typical body temperature and hormonal state, and maybe restrain powerlessness to seizures. Medications that improve the greater part of the activities of serotonin are valuable for treating sadness and sup­pressing gorging. How, at that point, can drugs that influence serotonin deliver such odd consequences for observation without disturbing a number of these different activities of serotonin? 

Some portion of the trouble in understanding drugs originated from utilizing LSD as a test psychedelic drug. The greater part of the early test frameworks included organs other than the cerebrum. For instance, serotonin can make the core of a mollusk beat quicker, so these hearts were an early most loved test framework. Researchers would hang the shellfish heart from a wire joined to a pen that would move if the heart muscle contracted. At the point when serotonin was trickled on the heart, it contracted. LSD kept the impacts of serotonin on shellfish hearts and other test frameworks, and for a considerable length of time it was felt that drugs acted by keeping the activities of serotonin. At the point when more advanced trial of serotonin activity in the cerebrum ended up plainly accessible, they appeared to help this thought. Researchers measuring the rate at which serotonin neurons were terminating demonstrated that LSD restrained their terminating. Notwithstanding, this didn't bode well, since closing down the serotonin neurons so significantly ought to have influenced the greater part of alternate procedures that depend on serotonin, however I,SD did not deliver such impacts. Besides, mescaline did not have an indistinguishable impact from LSD in these sorts of investigations, but since the structure of mescaline, not at all like alternate medications, did not look like sero­tonin, researchers were ready to expect that mescaline was working in some extraordinary way. The response to the subject of what psychedelic drugs need to do with sero­tonin needed to sit tight for researchers to find that the neurotransmitter sero­tonin follows up on various distinctive receptors. No less than thirteen sorts of serotonin receptors are currently perceived, and we realize that some appear to have particular impacts on conduct. Just a single of these (as we officially depicted) can trigger mind flights. The thirteen receptors can be gathered into huge classes (1-7), which themselves are subdivided. For all intents and purposes all serotonin-like drugs are agonists (they empower) at two sub­types of the 5-HT2 receptors (5-1-IT2a and 5-HT2c). Analysts feel that the psychedelic action comes about because of the incitement of 5-HT2a. Up until this point, each trial medicate tried that empowers the serotonin-2a receptors causes mental trips. We don't know how this happens, yet we are almost certain that animating these receptors can do it. The greater part of these receptors are in the cerebral cortex, where we think drugs have 

their real activity. 

One puzzle that remaining parts about serotonin drugs is the reason the antidepres­sant drugs that expansion the measure of serotonin in the neural connection (see the "Cerebrum Basics" section) don't for the most part cause mental trips. These medications increment serotonin wherever in the mind, including destinations that have 5-HT2a receptors, yet in spite of the fact that an uncommon patient taking one of these medications encounters mental trips, when the 5-HT2a receptors are animated in adjust with the greater part of the other serotonin frameworks, there are for the most part no 

stimulating impacts.

THE EFFECTS OF DRUGS CHANGE OVER TIME

THE EFFECTS OF DRUGS CHANGE OVER TIME

When people recall the first time they drank alcohol, most remember that they got drunker than they would now if they drank the same amount. This isn't all just fading memory. Many drugs cause much smaller reac­tions in the body when someone uses the same drug regularly. This change is called tolerance. Usually the lesser reaction is due to previous

experience with that drug or a similar drug, but even intense stress might change the reactions to some drugs.

Think about all the drugs we take that keep working even with many doses: our morning cup of coffee, an occasional aspirin for a headache (imagine how much aspirin we all take over a lifetime!), an antacid to calm the stomach after a spicy meal. Why do these drugs keep working? The reason is that we usually take them only for a short time, or intermit­tently. The more frequently we take the drug, and the higher the dose, the more likely it is that tolerance will develop. So, with just one aspirin once

a week or even once a day, the body has plenty of time between doses to return to normal. Caffeine continues to provide that pleasant arousing effect that peo­ple associate with their morning cup of coffee or tea for years. However, bodies do adapt to the daily cup of coffee (see the "Caffeine" chapter), so that people who are regular coffee drinkers have smaller effects from (show tolerance to) caffeine compared to someone who never ingests it. So, tolerance builds up, but the normal daily dose is not enough lo cause the effect to go away entirely.

Tolerance to some drugs can be dramatic. For example, heroin addicts rapidly build up tolerance to opiate drugs. Longtime heroin addicts will take doses that would have killed them the first time they used the drug. This tolerance can last as long as several weeks or months. Tolerance lasts this long because addicts typically take many doses a day, every day, some­times for years, and some of the body's changes are very long-lasting.

What about antibiotics? Everyone probably remembers being exhorted to be sure to take every one of the two weeks' worth of pills, and tried (and perhaps failed) to be careful to take a dose every six to eight hours. Although no one bacterium adapts to the drug, the population as a whole often does adapt. Bacteria replicate between one and many times a day, so new generations are constantly appearing. When an individual bacte­rium appears that happens to be resistant to the drug, this individual and its offspring survive, and the infection becomes resistant. With the rising use of antibiotics (antibiotics in beef^-, antibiotics for many child­hood diseases, etc.), more and more humans are carrying resistant popu­lations of bacteria in their body that are difficult to treat with currently available antibiotics. This is drug tolerance playing out at the population level rather than the individual level, and it is becoming more of a prob‑

lem worldwide.

Some drugs actually become more effective over time. Cocaine is an example. Some of its effects become greater with each passing dose. 'Mere could be a beneficial side to this effect: drugs that gradually become more active could be delivered only occasionally and still be effective. This cer­tainly would be cheaper! Some researchers have proposed that antide­pressant drugs fit into this category, and that daily treatment may not be

necessary.

Fortunately, many of the drugs we rely on to treat disease are given in doses that do not cause the development of tolerance, so they can con­tinue working over a long period of time. This is especially important for drugs that are used to treat diseases like high blood pressure, which are lifelong conditions that require therapy for years.

HOW DRUGS MOVE THROUGH THE BODY

HOW DRUGS MOVE THROUGH THE BODY

GETTING IN

Drugs must get to their receptors to act. Even a skin cream like a corti­sone ointment that relieves the itch of poison ivy must be able to pass through the fatty membrane that surrounds most cells to heal the cells that are irritated by poison ivy toxin.

Most drugs must go much farther than the skin to act. Drugs used to treat tumors deep inside the body must travel from where they are placed, through the bloodstream, to be delivered to distant organs. A few drugs pass through cells so well that when they are rubbed on the skin they travel through all the skin layers down to the layer of the skin where the smallest blood vessels (capillaries) are, through the capillary walls, and into the bloodstream. Nicotine is one, which is why the nicotine skin patch works. There is also a motion-sickness drug that can travel through the skin to the brain. What is unique about such drugs is their ability to pass through a cell membrane that is very fatty However, most drugs just don't dissolve well enough in these fatty membranes to travel all that dis­tance. Such drugs prefer water to oil, and they have a great deal of trouble passing through cells: these often only enter the body well after injection.

Applying drugs to the mucous membranes is a more effective way to get some drugs into the body, because the mucous membrane surfaces of the body (as in the nose) are much thinner, and the capillaries are much closer to the surface. For these reasons, placing drugs in the nose, mouth, or rectum provides a pretty efficient route for administering some drugs. Cocaine and amphetamine enter the bloodstream easily from these sites, which is why people snort them. In contrast, antibiotics, an example of drugs that prefer water to oil, cannot cross through cell membranes and cannot be given nasally.

The most efficient way to get a drug into the bloodstream is to put it there directly. The invention of the hypodermic syringe provided the most direct means we have of getting drugs into the body: we inject them directly into a vein. The drug then goes to the heart and is distributed throughout the entire body. After intravenous injection, peak drug levels in the bloodstream occur within a minute or two. Then levels begin to fall as the drug crosses the capillaries and enters the tissues.

There are other places that drugs can be injected. Most immunizations are done by injecting the vaccine into the muscle (intramuscular). The drug is delivered a little more slowly this way, because it must leave the muscle and enter capillaries before it is distributed to the body. Drugs can also be injected beneath the skin (subcutaneously). This "skin-popping" is a route used by many beginning heroin users who have not yet started injecting heroin intravenously.

Inhaling drugs into the lungs can deliver a drug to the circulation almost as quickly as intravenous injection. Anyone who smokes tobacco takes advantage of this characteristic to deliver nicotine to the brain. The drug simply has to dissolve through the air sacs of the lungs and into the capillaries. The surface area of the lungs is very large and fat-soluble drugs like nicotine can move quickly across a large surface. In addition, the blood supply of the lungs goes directly to the heart and then out to the other tissues. Therefore, smoking can deliver the drugs to the tissues very quickly. However, only certain drugs enter the body efficiently this way. They must be very fat-soluble, and they must form a vapor or gas when they are heated. Several drugs, including cocaine and metham­phetamine, easily form vapors if they are in their uncharged form, which occurs when they are crystallized from an alkaline (basic) solution. In this case, the nitrogen that is present in each molecule is uncharged (it has no positive charge from a hydrogen ion). 'I hese qualities allow drugs to cross into the circulation very quickly. Drug users call this method of delivery "freebasing." Cigarette manufacturers create the same effect by making tobacco leaves alkaline (basic).

The most common way that people get drugs into their system is by swallowing them. Drugs that enter this way must pass through the walls of the stomach or intestine and then enter the capillaries. A large part of any drug that is swallowed never gets to the rest of the body because it is removed by the liver and destroyed. The liver is placed cleverly to do this job. All the blood vessels that take nutrients from the intestine to the body must go through the liver first, where toxic substances can be removed. This protects the body from toxic substances in food. Swal­lowing may be the easiest way to deliver drugs, but it is the slowest way to deliver a drug to the body That is why your headache is not gone five minutes after you take an ibuprofen tablet.

To recapitulate, the way people take a drug (the route of administra­tion) and the amount they take determine the drug's effects. Injecting drugs intravenously or smoking them results in nearly instantaneous effects because the levels of drug in the blood rise very rapidly. This speed accounts for the lure of injecting heroin intravenously or smoking crack. The drug effect occurs much more rapidly than if the drug was snorted. Injecting a drug intravenously or smoking it also offers the greatest risk of overdose. Drugs like heroin can be lethal because they take effect so quickly after intravenous injection that the drug user can reach fatal drug levels before it would be possible to get help. The same dose of drug taken orally will never exert as great an effect—some of it will be lost to metabolism because the process of absorption is gradual.

WHERE THEY GO

Once drugs are in the circulation, getting into most tissues is no chal­lenge. There are big holes in most capillaries, and drugs are free to go into most tissues. The brain is an important exception because it has an espe­cially tight defense—the blood-brain barrier--that prevents the move­ment of many drugs into it. All of the drugs we discuss in this book are psychoactive, in part because they easily pass through this blood-brain barrier.

Although there are myths that drugs "hide" in specific places in the body (such as Ecstasy or LSD hiding in the spinal cord for months), they don't really. Because most psychoactive drugs are fat-soluble enough to enter the brain, they also accumulate in body fat. TI-IC (the active com­ponent in marijuana) and PCP (phencyclidine, or angel dust) are partic­ularly prone to accumulate in fat. As the drug eventually leaves the fat, it enters the bloodstream again and can enter the brain but usually at lev­els so low it produces negligible effects.

There is a legal consequence to this storage in fat. Drugs like 'clic are so well stored in fat that they remain detectable in urine for weeks after the last time the drug was used. It is common in drug-treatment pro­grams for people who have been testing "clean" to show drugs in their urine suddenly if they have been losing weight during their rehabilitation. The drug is simply driven out of the fat as the fat deposits shrink.

GETTING OUT

Most drugs do not leave the body the way they came in. Although a few drugs, like the inhalants, enter and leave through the lungs, most leave through the kidneys and the intestine. Many are changed in the liver to a form that is easily excreted in the urine. This process of metabolism and excretion in the urine determines how long the drug effect lasts. It is very  difficult to change this rate, so once a dose of drug is ingested, there is no

hurrying the recovery. In extreme cases, there are emergency room pro‑

cedures that can accelerate the removal of some drugs by the kidneys, but otherwise we must wait.

Some drugs, like cocaine, leave the brain and bloodstream quickly. The combination of quick onset of action and rapid removal can lead to cycles of taking the drug repeatedly. Drug levels shoot up, then plummet, taking the user to an intense high followed by a "crash," which motivates him to take another dose of the drug. Some cocaine users get into "runs" of repeated doses and end up using grams of cocaine in a single sitting. This pattern often leads to overdosing—the user takes another dose as the drug effect wanes but before the earlier dose has been completely eliminated. Drug levels in the brain gradually accumulate to dangerous levels.

Marijuana presents the opposite problem. THC, the active compound, is extremely fat-soluble (and thus accumulates in body fat), and its break­down products are also active compounds. So, as the body tries to remove it, the metabolic products continue to have psychological effects. These

two characteristics of marijuana mean that users can be under its influ­ence for many hours or even days after it is smoked.

THE ADDICTION CYCLE. CRISIS RESOLUTION, AND OUTCOME

THE ADDICTION CYCLE. CRISIS RESOLUTION, AND OUTCOME

We examined the 39 cases to see whether there was the expected relationship between crisis resolution and outcome. The degree of success was measured by the extent to which the addict abstained from legal or illegal opioid use (the addiction cycle) during the 6 months following the end of treatment. In those families where a major crisis did not occur during therapy, we predicted poor outcome, since the addiction cycle had not been challenged. In families where a crisis was manifested by the addict during treatment, and where this crisis was not resolved, treatment was also expected to be unsuccessful.
More positive outcomes were anticipated in cases where the addictive crisis was successfully handled, setting the stage for other family issues to emerge and be resolved. Based upon the typology described earlier, these emerging family problems could take one of four forms, with the particular form expected to be related to outcome.
The expected order of the forms, from best to worst outcome, was
(1 ) family issues were resolved without reaching crisis proportions;
(2) such crises developed and were clearly resolvable by the therapist

which was expected to allow the addict to continue to improve and move toward more autonomy from his family; (3) in families where interparental issues were not resolved, continued improvement on the part of the addict was less likely; to the extent that the addict did improve, such improvement was likely to be offset by physical illness of a parent or the emergence of significant problems in a sibling; (4) in the fourth type of family, the breakdown of the addiction cycle was followed by a chain reaction of violence and even death.

The type of reaction mentioned above, in item 4, was unusual in our sample, occurring in only 4 of 39 cases. When it occurred, the violent reaction was not necessarily precipitated by the therapy, but seemed to be an example of the level of crisis under which some of these families attempted to survive, never seeking professional help.* Exactly what would constitute a helpful intervention in this type of family is beyond the scope of this chapter, but it seems that the development of methods for identifying them prior to treatment would be a fruitful direction for future research.

The topic of interest here is the relationship of crisis occurrence and resolution to outcome. However the family patterns described are, although important, too refined to detect any correlations in our own sample of 39 cases; for example, some "types- had as few as 3 families. Consequently, it was decided to compare outcome based on one distinction: those families where the therapist considered the addictive crisis to be successfully resolved versus those families in which either no crisis occurred or the occurring crisis was not success-fully resolved. A listing of the various categories, and the number of families in each, is presented in Table 2.

Outcome data addressing the primary issue of opioid addiction, in the form of days free of legal opiates (e.g., methadone) and days free of illegal opiates during the first 6 months posttreatment, were available for the IP in 37 of the families; for two families these data were incomplete and thus insufficient for inclusion here (see Chapter 17 for a detailed explanation of the methods for obtaining and calculating outcome data). An outcome was classified as -Good- for a given IP if he was free of that particular class of drugs for more than 80% of the days within the 6-month period. We then examined the distribution of cases across these two dimensions--Good" versus -Not Good- outcome, and crisis resolution versus nonresolution (or no crisis)—separately for both legal opiates and illegal opiates.*

Inspection of these distributions revealed that, for illegal opiates, 18 of 25 families in which crisis resolution was attained had Good outcomes (i.e., 72%), whereas Good outcomes occurred in only 5 of 12 (41.7%) of the families in which either no crisis or no crisis resolution occurred. This difference, using a one-tailedt test for the difference between two proportions, was significant at the .05 level. For use of legal opiates, 17 of the 25 families that resolved the crisis (68%) had Good outcomes, while 5 of 12 (41.7% ) of the families without crisis resolution had Good outcomes—a difference signifi-cant at the .10 level using the same one-tailed test.

These results tend to support the idea that occurrence and resolution of a crisis within the course of therapy are important variables in helping the addict to both get off and remain off opioids, that is, to break the addiction cycle. Certainly this is a topic that merits further investigation with larger samples, more detailed meas-ures, and continuous sampling throughout treannent.

M. DUNCAN STANTON/THOMAS C. TODD