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The basics of marijuana- marijuana dependence


addiction medicine Rockville Centre marijuana dependence


 Marijuana is perhaps the most commonly used illegal drug in this country with over 5 million persons noting weekly use or more.     it is increasingly being legalized for medical uses and many states are legalizing it outright.   What is more, the potency of marijuana is increasing which will only serve to increase its abuse liability.



Marijuana can  both eaten and inhaled.   The active component, delta 9-THC, is among a group of compounds known as cannabinoids.   Receptors have been identified for THC.   Additionally, two  naturally occurring molecules that stimulates this receptor have been identified: anandamide and 2-AG.   There is most likely more to be discovered.    These  innate molecules in our brain and body that interact with a wide variety of tissues.  The main effects of these endo-cannabinoids is to effect inflammation  in the brain and body as well as to and to affect brain function.     It  also affects  sugar and fat metabolism;  liver, pancreas and muscle functions. 





Of course, I am more focused on the brain function issues.  Their essential role of is to boost and synchronized nerve impulses.  How does this work?  First, assume that a single nerve is stimulated to fire.   The effect  can be rather weak and lost in all the action of the  surrounding nerve cells.  Therefore, the stimulated nerve releases endo-cannibinoids which drift back to GABA inhibitory cells.  The endocannabinoids turn off the inhibitory cells and reduce GABA.  This is called- dis-inhibition.  The first cell, now dis-inhibited,  will than shoot off even more strongly.  Not only is this cell work more active, the dis-inhibition can affect all the surrounding nerves as well and allow all the neighboring cells to be more active





Therefore cannabinoids boost nerve cell activity.   It will have multiple effects  in the brain depending on what nerves are involved.  It works to increase dopamine in the Nucleus Accumbens to stimulate the target cells there.  This is why many feel a euphoria.   





It often reduces glutamate levels.  This is because the glutamate nerves also contain cannabinoid receptors and are inhibited by them.  The lowering of glutamate levels may cause memory and coordination issues.   



The lateral hypothalamus is the area of out brain  responsible for stimulating hunger.  Nerves which begin here release a neurotransmitter called Orexin into the Nucleus Accumbens and thalamus.  This may be the most significant driver of our appetite.  There are cannabinoid receptors throughout the hypothalamus including the lateral hypothalamus.  Here it intensifies the release of Orexin. This is one major component of why we get the munchies after we use marijuana.



One area where it may have a role is in pain perception.  Stimulation reduces pain.  This may  be due to the intimate nature of the cannabinoid  and opioid receptor interactions.  Often these receptor are located adjacent to each other and may even be attached; they have similar effect on the intra-cellular machinery.   It has been shown that the cannabis magnifies  opioid activity, and blocking the opioid receptor reduces the effects of cannabinoids.  This explains why opioids reduces, but does not eliminate, opioid activity





Cannabis users will experience a euphoria and a state of relaxation.(dopamine and opioid effects)  There are visual perception abnormalities, time perception abnormalities and intellectual function impairment.   These often the effects they are seeking





Of course, there are side effects.





Adrenalin- like hormones are not broken down as quickly due to interference with specific enzymes;  blood pressure and pulse can also increase in some people leading to heart issues and possibly even heart attacks in some 





Anxiety and psychosis can occur.  This is not a well understood effect.  There is increased activity in the Amygdala,the anxiety center  of the brain  The anxiety experienced is related to this.  It is unclear what is happening at the cellular level to cause this effect.





Other areas affected by cannabis include the cerebellum (involved in the coordination of movement) as well as the hippocampus (involved in the formation of new memories).     One last area affected is the prefrontal cortex, the executive part of the brain where complex behaviors are either initiated or inhibited.  This area is also impaired .  As a result, memory formation and coordination and information processing  are impaired during cannabis intoxication.    All these combine to make the intoxicated person an unsafe operator of motor vehicles. 



In addition, the ability to learn new information is impaired.  The long duration of marijuana in the body makes this last impairment more of a concern as  cognitive defects can last relatively long periods of time.  One important question is how long such cognitive effects last.



Several years ago. a study was done to answer this question.  Volunteers, who were clean of marijuana were recruited and a functional MRI was done.  A normal pattern of activity was seen.  They were then given marijuana and a test was repeated almost immediately.  The prefrontal cortex was seen to be less active consistent with cognitive impairment.  24 hours later, there were still deficits in the functioning of this area.  It takes a long time to become cognitively 100%.  Long term users have clear cut deficits in  IQ





Several, years ago. a study was published based on a population in New Zealand.  It addressed a question of whether cognitive issues led to marijuana use or was caused by marijuana use.  The population had an IQ test at age 12 and was retested at age 38.  Every few years, they were contacted to find out if they used marijuana regularly.  In fact, lots of clinical issues were followed but I am concentrating on marijuana.  Then two groups were formed, those that did not use any drugs regularly vs those that used only  marijuana regularly (and no other drugs)  When their scores at 12 years old were compared- they were the same.  They were also matched even in a variety of socio-economic factors.  However, when they retested, those that were marijuana free saw an increase in their IQ while those using regularly saw an 8 point drop.  The conclusion was that the marijuana use over years led to a drop in intelligence.  



I often see patients are much sharper months after stopping marijuana.  Many users protest that they can function well and perform at a high level while using marijuana.  What they do not realize is that without marijuana, they would be doing even better.   If a person has chosen an occupation that requires repetitive behavior, marijuana may not seemingly affect them.  However, if they need to be at their best, than they will see the difference.  How many people will let a brain surgeon operate on them who is intoxicated with marijuana? 

endocannibinoids drifting backwards and affecting the GABA secreting cell

endocannibinoids drifting backwards and affecting the GABA secreting cell

Is marijuana habit forming?

The issue no one talks about

  

When I ask many users if they feel it is addictive, they say no.   No one resorts to crimes(true) and usually a user will become mellow. Besides, they are unaware of any withdrawal symptoms.


There is proof of physical addiction and withdrawal symptoms brought on by regular use. Several studies have shown that daily users reliably demonstrate a rebound increase in blood pressure & heart rate as well as increased irritability, depression, insomnia and a decrease in appetite. It begins 12-18 hours after their last use and will last for several weeks. This constitutes physical withdrawal.


These symptoms make sense when we understand how marijuana works. The active ingredient, THC, leads to the increase of  endorphin activity in the brain.   This gives marijuana a mild morphine/heroin like reaction.  This is part of the reason why we get euphoric from its use.  


When we stop using it, we go through a mild morphine like withdrawal. True, the withdrawal is much milder than that seen with morphine and often experienced only as irritability. Unfortunately, although mild, the little bit of withdrawal will still motivate people to continue ongoing use of marijuana in order to “relax”. 


People convince themselves they’re tense from events of the day and deserve to relax at the end of the day. Of course, the end of the day corresponds to when their withdrawal is getting more significant since it is often 14-18 hours from their last use. Often, after 2-3 weeks of non-use, the need to use a marijuana, in order to relax, is gone..


Many people have used marijuana to boost appetite, why aren't they overweight?  After a while, the withdrawal reduces appetite and people need to use to have a normal appetite.  Again, after a few weeks ob abstinence, the appetite has become normal again


It is estimated that 10% of all regular marijuana users and 50% of daily users will have some level of physical dependence.  It will become a worse issue as the legalization will result in stronger and purer forms of THC.



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Medications to treat marijuana Cravings

  

Marijuana exerts its influence directly on the cannabis receptor which then has downstream effects on the endorphin receptor (which results in euphoria), the orexin receptor (which gives us the munchies) and the dopamine receptor (which makes us want to repeat the behavior). This results in disordered metabolism is these areas and those abnormalities lead us to perpetuate the drug use. Manipulation of these areas can reduce cravings.

Additionally, similar to other drugs, the tendency to repeat behavior will be also involve glutamate biology in certain primitive parts of the brain. Manipulation of this activity can also reduce cravings


FOR MARIJUANA CRAVINGS:


1;Gabapentin- an anti- seizure medicine that calms down large segments of the central nervous system and reduces cravings- take 400 mg three times daily. Side effects include cause fatigue and/or nausea in up to 15% of people


2-Naltrexone- this is an opioid blocker that stabilizes endorphin biology and blocks both cannabis euphoria and cravings. One should take 50 mg twice daily. It may cause nausea (also liver abnormalities in 1 out of 300 people). In some studies- lower doses has resulted in increased use (people probably tried to overcome the blockade) while in other studies, higher doses showed reduced use (when effect could not be overcome??) However, cravings were often reduced.


3- N acetyl cysteine- this is an over the counter vitamin/amino acid that stabilizes glutamate activity and therefore stabilizes cravings of many types. It is one of the few things that have been proven to work in HUMANS for marijuana. It is available in many, but not all, vitamin stores. I found it available on line and in the Vitamin Shoppe.  The 600 mg pill is most common form- take two pills twice daily.

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medical marijuana

Its not a medicine- its a category of chemicals

More than half the states have approved marijuana for medical use.  This reflects a movement brought about by public desire and political will.  However, anyone reading the medical literature realizes that medicine as a profession has ot reached the same conclusions.


This is not to say that there are no benefits- there clearly are some.  The question is, what  component of marijuana is causing the benefit.


If I am prescribing a blood pressure medication or an antibiotic, I know exactly what chemical I am prescribing, what the benefits are and what the side effects are.  That exact chemical in that exact dose has been shown to have a benefit greater than its risk.


However, the cannabis plant has more than 60 cannabinoid compounds (some experts say more than one hundred forty ).  In addition there are hundreds of terpenes.  These are botanical chemicals found in multiple types of plants; some of which modify the clinical effects.  Different batches of marijuana have differing mixes of these chemicals so that one strain will do different things than another; the reliability of  effects  of any one strain has not been confirmed by medical studies.


When we say medical marijuana, we are sayin nothing.  Marijuana with different ratios of chemicals have far different effects and side effects.  We need to discuss the specif chemical 


Most of the clinical benefit comes from one of two of its major components: tetrahydrocannabinol (THC) of cannabidiol (CBD).  There is research into the other cannabinoid chemicals but far less is known.


I'll consider THC first, as that is the intoxicating component.  It releases dopamine which causes euphoria and  orexin which stimulates appetite .  It boosts the effects of opioid receptors and therefore, it  will relieve pain and boost the effects of and other opioids that are being used.  That is why it reduces concurrent opioid use.    These are all effects seen early on with use and potentially have major  therapeutic import. It potentially reduces inflammation by its affects on the immune system but this effect has not been well quantified.


One problem is that there will be tolerance so these effects may not be long lasting.  There will be withdrawal which is associated with depression, loss of appetite and depression.  I have also seen individual cases of worsening pain after weeks/months of use.


 It stimulates adrenaline type hormones which can cause blood pressure issues, palpitation and in rare cases lead to heart attack.  


Studies were done with patient who had psychiatric issues of anxiety and depression but never used marijuana.  They were given THC.  They got worse.  This may be in contrast to regular marijuana users who seem to have less anxiety, depression and more focus after they use marijuana; however, these symptoms may represent  withdrawal symptoms and the use of marijuana stops the withdrawal.


In sum, that there is no recognized role for THC except acutely during chemotherapy as a treatment for nausea.  One must be careful; however, because after the chemotherapy course, persistent loss of appetite may be a withdrawal effect.  After three weeks of abstinence, the appetite returns to normal.   While it may have a role in acute pain, opioids are far more effective.  In chronic pain, some studies have shown benefit but others have not.the benefits are modest and there can be paradoxical increases in pain  due to withdrawal.


Cannabidiol (CBD) is another story.  I like this drug.


It does not stimulate CB type one receptors- this means no intoxication, addiction, or withdrawal.  It will block these receptors from interacting with THC.  Therefore, high levels of CBD block the actions of THC


It can relieve pain by inactivation TRPV receptors (the same pain receptors that respond to hot peppers). These are located diffusely throughout the central nervous system.   It also inhibits Sigma 1 receptors which  may reduce pain impulse transmission.


 It can relieve anxiety and depression by stimulating certain types of serotonin receptors.


It can moderate certain seizure disorders but the benefits are more modest than is generally believed.


There are a variety of mechanism through which it reduces inflammation making it valuable for a host of auto-immune disorders.


CBD, THC as well as other cannabinoids are being studied for their ability to treat cancer and other  disorders.  Most of the research has shown reduced growth in tumor cell lines when grown in laboratories; there are no human studies showing reduce growth or prolonged survival.   However, anecdotal reports of benefits are intriguing.  


 Despite these benefits, the value of CBD on any specific disorder is modest and still being worked out.  The jury is still out on its ultimate benefit at a population level.  Certain individuals seem to have great benefit though. 


One of my peeves is the term medical marijuana.  It is too vague and encompasses to many compounds.  It like calling the entire class of diabetes treatment as a single medicine.  We need to be precise




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Information on various hallucinogens

TI had recently been asked what harm, if any, is posed by the use of hallucinogenic drugs. The answer is complicated because there are many types of these drugs and the degree of harm varies depending on the type.

The first family of drugs that I will discuss includes the anesthetics, Phencyclidine (PCP) and ketamine. These medications work by affecting a certain type of receptor in the brain called NMDA glutamate receptor(which also plays a role in how alcohol affects the brain). This stops certain nerves from firing and depresses certain brain activities. In addition to these drug's hallucinatory effects, they cause depression and psychosis.  Short-term use with high dosages can cause coma, seizures, stroke and death.
 

Their use is associated with tolerance (the same amount of drug becomes less effective with repeated use) and a withdrawal syndrome characterized by depression, fatigue, increased appetite and craving for the drug. 

The use of these drugs are pleasurable and animals will seek out the drug if it is taken away. When animals are taken off high doses, they exhibit irritability, tremors, gooseflesh and other behavioral anomalies that resolve 48 hours after the last drug use.  


A syndrome of agitation occurs with PCP abuse. It can be associated with relative insensitivity to pain; patients can hurt themselves and not be aware of an injury. This is not from acute intoxication but is usually seen in early withdrawal. 


Long-term side effects of these drugs include prolonged depression and nerve damage. While I cannot show any specific studies on the subject, I have always felt there was impairment in the higher intellectual functioning in many chronic PCP users. This was true long after they had last used the drug.


In 2005, Campral became available for the treatment of alcohol problems. Its mechanism of action suggests that it might be useful in people who have abused these drugs.  However, at the present time, there is no known treatment for withdrawal.
 

Interestingly, ketamine is gaining traction as a treatment  for pain, depression and to treat DTs from alcohol withdrawal.  In these cases, the doses are relatively low and given with strict medical supervision 


The second group of hallucinogens include LSD, psilocybin and mescaline as well as other similar drugs (DMA, DOM, DMT) These drugs are interesting in that they are among the few drugs, abused by humans, that animals do not seek out. These drugs do not stimulate dopamine and therefore they do not cause euphoria. These drugs work by mimicking a neurotransmitter called Serotonin. The hallucinatory effects usually resolve in 12 hours with psilocybin or mescaline, but have lasted up to three days with LSD. During acute intoxication, blood pressure is elevated with a fast heartbeat, tremulousness, fever and poor coordination. Tolerance develops quickly so that after 3-4 days, there is far less of a clinical effect. That is the reason that most users will use the drug intermittently. There is no withdrawal syndrome. 


With chronic LSD use, patients have reported flashback phenomena.  These are episodes of perceptual changes that occur long after the last use of the drug.  This phenomenon can be seen to a lesser extent with PCP and ecstasy. It is a short-lived episode when aspects of the original drug experience are unexpectedly re-experienced. Episodes can be triggered by stress, other drug use and in situations that are similar to the original drug experience. It has been associated with depression, panic disorder and suicide attempts.


The last drug is MDMA, which is also known as Ecstasy. This drug works similar to LSD in some ways.  However, it  also seems to produce a great deal of euphoria.  It has  other clinical effects similar to amphetamines. Tolerance is seen but there is no physical withdrawal syndrome.  


The use of Ecstasy is not without risk. In fact, this may be the most toxic drug that is abused. We often hear how drugs kill brain cells. While many drugs may cause nerves to dysfunction, they will not directly kill a nerve. Cocaine will may induce harm through altered blood flow and others though poor lifestyle. Ecstasy is directly toxic. In laboratory settings, a single molecule of Ecstasy has permanently knocked out Serotonin producing cells. This will result in prolonged or permanent imbalances in Serotonin that can cause depression

Short-term use has also been associated with very high fevers, sweating, high blood pressure, irregular heart rhythms that can be life threatening, seizures, kidney problems and muscle breakdown. It also associated with muscle spasms around the mouth. Long-term effects are anxiety, agitation, flashbacks and nerve damage

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