I think I may have some answers to this issue. I have a very strong working knowledge of Addiction and Neurochemistry. I am a former Heroin and JWH addict, I have been clean for a total of 6 month, yes, in a row. However, my work with Addiction Research totals about 3 years, 1.5 years prior to any Personal Addiction History.
First, I would like to introduce some basic principals of addiction; we will focus on the purely Neurochemical and Neurobiological responses to an Active Addiction at this point, subjective effects will be discussed at a later time.
Let's begin with the way that we learn to love drugs and their effects: One word, Dopamine. Almost every Drug of Abuse(DOA) causes an increase amount of Dopamine in the Mesolimbic Dopanergic Pathway(MDP) of the brain, that shapes our behavior and system of "needs", I put this in quotes for later.*
Basic Human needs for survival are Food, Water, and Sex. Yes,the first two make perfect sense. We must have Water to stay hydrated and we must have Food to stay Metabolically active, that is, alive. But wait...we don't need Sex to survive in life. To procreate yes, but, to continue to be Metabolically active on an internal level, no.*
Sex is needed to survive as a Species, so the Brain needed to find a way to "get it's point acros". It made Sex FEEL good. How you ask...by timing a surge of Dopamine in the MDP to occur at the precise time we preform the action necessary for species survival, that is obviously Ejaculation.*
Because of that release the Brain has effectively trained itself to understand Sex as important as Food and Water. Sex is however, much more rewarding, due to the fact that a much larger amount of Dopamine is released in the MDP upon Orgasm than with any other action we were intended to preform.
As said earlier most Drugs cause a larger amount of Dopamine to be available for use in than MDP, even more than sex. This is the physiological basis of Drug "need", also known as cravings.
When we first experience *a substance and experience it's subjective effects, we consciously "enjoy" it. At the same time, unknown to our Conscious Mind, the brain is in the process of learning an additional "need". This can be learned in as little as one exposure to a substance. As we continue to use, the reward for the use becomes more deeply engrained.*
*Note:*It is VERY important to understand the effect of GABA on Dopamine. GABA is an inhibitory Neurotransmitter and Dopamine is an excitatory Neurotransmitter.*
The body is designed to live in harmony and balance, this is called Homeostasis.*
Due to Homeostasis, when Dopamine is released in the MDP, the Body recognizes the in-natural imbalance and has provided GABA to inhibit Dopamine's effects and return the Body to Homeostasis.*
Also important to mention, the more Dopamine available in the MDP with administration, the more rewarding and therefore the more addictive a substance is.
That being said drug use does not only cause changes in Dopamine levels to be altered, many other Neurotransmitters are effected as well. Because this is a Cannabinoid thread, I will only discuss those specific to these substances. For comparison, reasons I will explain the effect Natural Cannabis has on Brain Chemistry, because it has been extensively studied.*
Serotonin, Marijuana has been shown to be a potent Selective Serotonin Re-uptake Inhibitor(SSRI). Serotonin plays a major role in Themoregulation, mood, sleep and level of subjective energy and motivation.*
GABA, is an inhibitor neurotransmitter that plays a major role in "keeping the Brain in check". That is, if the Brain's Neurons are firing to fast, more GABA is released to slow their action and therefore restore Homeostasis. GABA also plays a role in digestion, and the function of muscle tissue (by keeping their contractions correctly timed and intentional). Marijuana is know to cause *a decease in GABA levels. This is why inexperienced users are more prone to Marijuana induced anxiety.*
In an effort to return to Homeostasis the Body has once again created a clever way to do this. It has the ability to adjust the amount of Receptor Sites(the place where Neurotransmitters are received and exhibit their action) in response to varying levels of specific Neurotransmitters. For example, if your body needs to utilize more Serotonin,*your Brain will increase the number of Receptor Sites that are available to receive Serotonin. If your Brain detects too much Serotonin, then your Brain will decrease the amount of receptor sites available for binding. This is known as Down-Regulation and Up-Regulation, respectively. This processes is slow and occurs over repeated abnormalities in Neurotransmitter levels.
This is not the only thing that Cannabis acts on. It has it's own receptor sites; CB1(Based solely in the Brain) and CB2(Based through the rest of the Body, in Bones, the Digestive Tract, Muscles, so on so forth.) these Receptors can also be Up-regulated due to a lack of natural Endocannabinoids(occurring inside the body) or down-regulated due to chronic Cannabis use. *CB receptors are responsible in part for memory, emotions, appetite, digestion, anger control, and the subjective psychoactive effects of Marijuana.
Natural cannabis is a partial agonist(it activates and therefore enhances the action of at about 50% of their potential action)CB1 and CB2 receptor sites as evidenced by increased hunger, loss of short term memory, mild euphoria and other subjective effects. Also, Serotonin is prevented from being eliminated due to the action of THC as an SSRI. This can cause a decrease in body temperature, more energy and even increase motivation and mood.*
The production of GABA is decreased during use, leading to possible anxiety, increased heart rate and dilated pupils. Pupil dilation is caused by a decreased level of GABA in the optically located GABA-a receptors that allow for proper contraction of the Iris.*
It is important to understand that Marijuana does NOT cause Dopamine to be released in the MDP. But. because of the decrease in GABA levels there IS effectively an increase of the levels of Dopamine in the MDP because it's action is no longer properly controlled.*This explains why there is not a well recognized Subjective Physical Withdraw Syndrome upon Cannabis discontinuation.*
There is*Down-regulation of CB1, CB2, *and Serotonin Receptors, due to the increased action of these sites upon repeated dosing, this is the cause of tolerance to MJ.*
However, because THC is a Partial Agonist of CB receptors and only partially inhibits the reuptake of Serotonin there will never be a point where effects are limited by the number of available receptor sites.
When the amount of receptors is decreased because the Body is expecting that "this will be enough receptor sites" due to external administration of chemicals that sufficiently act on them, then is not provided the external stimulus; there are not enough receptors left to elicit the action they should. Down-regulation can be though of as an effective reduction in sensitivity to a certain Neurotransmitter or substance that binds to it's Receptor.*
On to Synthetic Cannabinoids; finally, I know. But, it is essential to understand the concepts listed above to understand the unique disturbances these compounds cause overtime.*
Synthetic Cannabinoids(at least ones used recreationally) are FULL agonists of the CB1 and CB2 receptors, this means that they cause the Receptors to be active at 100%.
Here in lies the first issue with repeated use of Synthetics; because of their full agonist qualities CB, and Serotonin Receptor Down-regulation will be completed at a much faster and a much increased rate. This is why tolerance to Synthetics *builds so quickly and unlike MJ given time, will become almost complete.
Also, given the increased potency of these compounds in comparison to THC there is an exponential decrease in the amount of GABA available for use in the Body and MDP. This explains the incredible ability for Synthetics to cause incredible anxiety in even very long term Marijuana users.*
This is also the key to these substance's addictive qualities. Even with their increased potency, Synthetic Cannabinoids do not cause an increase production of or decrease in re-uptake of Dopamine in the MDP. However, as explained earlier, GABA is the main Neurotransmitter responsible for keeping Dopamine levels in check. With a marked decrease in GABA levels the amount of Dopamine available for use in the MDP is dramatically larger than with Pot and even Sex.*
Because of this, it is entirely possible for the Brain to learn that this substance will allow it to use more of its available Dopamine because it is not counteracted as it should be. Which will without a doubt cause an addiction similar to other "hard drugs".*
Depending on the amount of Cannabinoids consumed in a dose, it is entirely possible that there is more dopamine available in the MDP than with a standard dose of heroin. Leading the "need" to re-dose immediately and almost instinctually upon cessation of it's effects. This unfortunately proves that this substance has the ability to cause a major physiological addiction, on the level of Crack Cocaine.*
This is due to the level of agonism of these compounds and their ability to affect the MPD in a similar way as other drugs. Yes, the subjective effects may be different from "hard drugs" but, unfortunately the Pharmacology of these substances is effectively(although by a different mode of action) identical.
On to the withdraw: It is real, and here is why. Down-regulation of CB1, CB2, Serotonin Receptors and because of effects on GABA levels an therefore Dopamine receptors as well. This cause upon cessation, the lack of activity at these Receptor Site because of their decreased sensitivity to their activiating partners.*
This causes the exact opposite effects as their agonists. The effects would be;
CB1: increased agitation, apathy, lack of interest, lack motivation, short term memory issues.
CB2: decreased appetite, nausea, slightly increased White Blood Cell count, increased inflammation, increased sensitivity to pain and possible inflammation of the spleen(due to over activity of the Body's Immune System)
Serotonin: insomnia, increased body temperature(which leads to the natural physiological attempt to lower Body temperature, which is sweating and shivering), problems maintaing a constant body temperature(due to Serotonin receptors located in the hypothalamus, the Bodies thermostat), decreased pleasure, lack of motivation, suicidal ideations, violent thoughts, mood swings and depression.
Dopamine: muscle rigidity, muscle spasms, internal unrest, twitching. Drug cravings, obsessions with using, body aches, loss of appetite, nausea and lack of happiness in normally pleasurable activities, Parkinson type symptoms, trouble sleeping.
Due the fact that the levels of available GABA are markedly decreased up-regulation of the GABA-a receptor will occur in an attempt to obtain proper levels of utilized GABA. Because of this, upon return of normal GABA levels, the body will be overwhelmed and experience the opposite effects of a lack of GABA: upset stomach, nausea, diahreahha, increased gastric acid production, muscle twitching, mild trailing visuals, loss of cognition and memory, headaches, and lack of inhibitions(leading to a lower chance to resist relapse).
The most unfortunate event would be a decrease of available Dopamine, due to the fact that the added GABA would inhibit Dopamine from reaching already de-sensitized receptors(this is an added aspect that makes this such an addictive substances).*
It is important to note that while these effects are most prevalent during withdraw, due to Synthetics full agonism and ability to produce almost 90% tolerance over a period of time; these symptoms may be noticeable and potentially disturbing while chronic use is being continued.
Read more:
http://www.drugs-forum.com/forum/showthread.php?t=168986&page=4#ixzz1hgQ72600
Keep us updated man
