2006 Another Year Goes to Pot


 (originally written for Cannabis Health)

Dr. Robert Melamede 

Associate Professor and Biology Chairman (ret) 

Biology Department 

University of Colorado 

1420 Austin Bluffs Parkway 

Colorado Springs, CO 80918 


719 262-3135 Work 

719 641-1188 Cell 

http://www.uccs.edu/~rmelamed/ Homepage




The cannabis plant is an amazing source of medicinal chemicals, the reason being it is the 

only plant that truly taps into our endocannabinoid system. While marijuana has been 

used medicinally for thousands of years, it is only within the past fifteen years that we 

have begun to understand why marijuana has so many medicinal properties. As a result, 

research into this area has exploded. One cannot understand medical marijuana without 

first understanding the endocannabinoid system and the fundamental role that it plays in 

the lives of all animals, especially man.  


The endocannabinoid system is composed of receptors (CB1-nervous system and CB2- 

immune system) on cells that bind exocannabinoids like THC, and endocannabinoids that 

our bodies produce, like anandamide (AEA) and 2-arachidonyl glycerol (2AG). Both of 

the latter chemicals are made from essential fatty acids such as are found in hemp oil. 

When cannabinoid receptors are activated, various biochemical properties in cells are 

altered, and these cells then alter communication with other cells. However, all body 

systems must be regulated, therefore, enzymes exist that break down our 

endocannabinoids to keep this system in balance (homeostasis, see below). The most 

studied enzyme that breaks down some endocannabinoids is fatty acid amino hydrolase 

(FAAH). Specifically, FAAH breaks down anandamide, thereby decreasing 

endocannabinoid activity. In order to really appreciate the medicinal properties of this 

plant, we must understand the basic properties of life itself.  How ironic, after so many 

cannabis users have been persecuted for believing that marijuana is the tree of life, in 

many respects it is. 



For the first time in the history of mankind, we can look at life from a truly scientific 

prospective and understand its basic properties. We will not go into the details of the 

physics of life, but rather we will describe some of the basic characteristics of life from 

the perspective of far from equilibrium thermodynamics. For our purposes, these 

ominous terms can be easily understood. Let’s start with equilibrium. Scientifically, 

equilibrium is a state of maximum disorder (entropy), and simultaneously, a state of 

minimum potential (the ability to do something). In other words, equilibrium is the 

opposite of life. Thermodynamics refers to the flow of energy. It is, in fact, this flow that 

keeps life away from equilibrium. The movement towards equilibrium is characterized by 

aging, illness and death. On an organismic level, living systems maintain the critical flow 

of organizing energy by eating, sensing the environment, and getting rid of waste 

products. However, the same principle of extracting potential from the environment is 

true at the cellular level. 


A unique characteristic of matter driven further from equilibrium, is that it possesses a 

natural tendency to create new forms of organization. From the human prospective, 

moving further from equilibrium can mean regaining one’s health and increasing one’s 

organization and energy flow (as occurs with physical training). Similarly, learning and 

enhanced thinking skills (such as state of mind) can represent movement from 

equilibrium. Another irony, our cannabinoid system is totally intertwined with these 





In the biosphere, the creative process is evolution. As evolution proceeds, we see 

increasing complexity, a property most obviously characteristic of man and his society. 

However, this complexity is not only between man and his environment, but within man 

himself, existing at all levels of organization. Before going further into the 

endocannabinoid system and the impact of marijuana on it, a critical term that we must 

understand is homeostasis. It essentially means biochemical balance, but dynamic 

balance not static balance. A simplistic visual image of the dynamic character of 

biochemical homeostasis would be a bunch of jugglers balanced on a bunch of seesaws 

that are balanced on each other, while moving on a roller-coaster ride.  The level of 

complexity in this seemingly impossible task is readily accomplished biochemically by 

living organisms all the time. In fact, the endocannabinoid system plays a critical role in 

coordinating the many balancing acts associated with life and does so across scales of 

organization. The impact of cannabinoids ranges in scale from controlling biochemistry 

within cells to controlling social interactions and regulating political thought 1.  



Another fundamental characteristic of living systems is that the whole is greater than the 

sum of its parts. Pieces of a system work together and create something new and 

different, something that would not have been predicted from observing the individual 

components in isolation. How does this phenomenon impact on the health of cells, 

individuals, communities and society, and is the role cannabinoid system? Is 

consciousness an emergent phenomenon, with the cannabinoid system being a critical 

player in the emergence process? 


Before we look at the endocannabinoid system, let’s restate some of the physics of life. 

All foods provide us with building blocks and the energy necessary for organizing the 

building process.  The chemicals that we call food can be viewed as charged batteries. 

They have potential to do things such as promoting growth, health and evolution. Energy 

flow in a living system is similar to what occurs when a battery is used to do something. 

In both cases, energy comes from the flow of electrons. Living systems are essentially 

rechargeable, biochemical batteries, and our biochemical pathways constitute the wires. 

Without going into details, the flow of biochemical electricity produces free radicals, 

biochemical friction.  



Free radicals are highly reactive chemicals that modify life’s chemicals.  Free radicals 

have three critical biological functions. On the one hand, due to their reactivity, free 

radicals alter the chemical properties of DNA, RNA, proteins, carbohydrates and fats.  By 

doing so, they disrupt biochemical organization. Therefore, the destructive nature of free 

radicals may be viewed as the friction of life.  On the other hand, as a result of free 

radical-induced biochemical modifications, free radicals serve to signal the cell that all is 

not right, either with respect to energy flow from environmental, and/or the internal 

energy flows (such as mental stress). Thirdly, the destructive power of free radicals has 

been harnessed by the immune system to help destroy infectious invaders. Immune cells 

actually make hydrogen peroxide and the chemical equivalent of Clorox to help kill 




Over 500 million years ago, cells began to communicate with one another and to develop 

new levels of cooperation that, in turn, allowed for increased levels of complexity 

(spatially, temporally, and physically). These primitive, communicating, multi-cellular 

organisms began the evolutionary process that lead to the body systems that we’re 

familiar with today: circulatory, digestive, endocrine, immunological, musculoskeletal, 

nervous, reproductive, respiratory and tegumentary (skin).  Interestingly, it was at this 

critical time in life’s history that the endocannabinoid system had its origins and found its 

place as a critical modulator of biological activities. As evolution proceeded, and systems 

and their interactions grew more complicated, the endocannabinoid system increasingly 

played an important role in the dynamic balancing acts that characterize not only life, but 

also economic, social, political, and religious institutions.  As our understanding of the 

magnitude and diversity of cannabinoid biology increases, it naturally extends beyond the 

biological realm through its regulation of complex human behavior.  


All cells exhibit basic biological properties. Typically they are replicating, performing 

some differentiation related task, resting or dying, all the while communicating with their 

neighbors, ideally, for the good of the organism as a whole.  Cannabinoids regulate all of 

these basic activities as a function of cell type, dose, etc. What are the implications of this 

broad cannabinoid based activity that spans from sub-cellular activities to consciousness 

and beyond? We will examine some of the cannabinoid-based scientific discoveries that 

occurred in 2006 and see what picture is painted regarding the essential role of 

cannabinoids in human health.  



First, let’s clarify our starting point. Cannabis plant material is highly variable in 

composition. Therefore, even in the absence of governmental interference, the plant 

material is not ideally suited for most scientific experimental studies (which need not 

limit its medicinal usefulness). Accurate dosing and reproducibility are critical 

components of scientific inquiry. These constraints are met experimentally by using 

agonists, chemicals that stimulate specifically the CB1 or CB2 receptors, and antagonists, 

chemicals that inhibit specifically the CB1 or CB2 receptors. Today, we know that many 

of the activities produced by cannabinoids occur via cannabinoid receptor independent 

mechanisms, further demonstrating how complex cannabinoid activities are. In addition 

to the new synthetic cannabinoids, naturally occurring THC and CBD are often used 

experimentally. Thus, we mostly learn about the cannabinoid system without actually 

using products isolated from the cannabis plant. When the science and observations of 

medical marijuana users are put together, the benefits of medical marijuana should be 

obvious to all. 



A good place to begin examining cannabinoid discoveries of 2006 is the nervous system.  

Current knowledge clearly shows that the brain has robust regenerative capacities. One of 

the newly discovered surprises is that nerve regeneration, that develops from neural 

progenitor cells, is regulated by endocannabinoids 2.  In other words, when there is brain 

injury, as occurs from head injury or stroke, the brain produces marijuana-like 

compounds 3 that are important limiters of damage and promoters of healing.  


The ability to feel pain is a critical biological response to injury (it helps us avoid it). We 

now know that the level of cannabinoid receptors is turned up in response to chronic 

inflammation and its associated pain. The body, apparently in effort to reduce pain 4

enhances endocannabinoid activity. This response is not surprising since 

endocannabinoids are direct regulators of pain receptors 5


Superoxide dismutase (SOD) is an enzyme that helps protect cells against free radical 

damage that typically results from biochemical imbalances. Mice that genetically lack the 

ability to produce this enzyme develop ALS (Lou Gehrig’s disease). We now know that 

cannabinoids protect against the development of this disease, however, they do not 

protect against the death associated with this illness 6, a dichotomy not yet understood. 


A source of pain for many individuals involves trigeminal vascular neurons, which are 

thought to be involved with initiating migraine headaches. Ackerman et al 7 conclude 

“CB receptors may have therapeutic potential in migraine, cluster headache or other 

primary headaches, although the potential hazards of psychoactive side-effects that 

accompany cannabinoid treatments may be complex to overcome.” This type of strange 

commentary is pervasive in the scientific literature. The default perspective found in the 

scientific literature is that one should endure pain and suffering rather than bare the 

terrible psychological effects of cannabis consumption. The mind-altering properties of 

narcotic pain-killers, antidepressants, tranquilizers and sleep medications are okay, just 

stay away from the killer weed. Despite ongoing governmental malfeasance, additional 

research examining the role of the cannabinoid system and migraine headaches suggests a 

relationship between the headaches and an endocannabinoid deficiency 8.  


With cannabinoids intimately involved with so many biological processes, what other 

diseases might be associated with cannabinoid deficiencies? Both anecdotally and 

experimentally, cannabinoids seem to benefit those suffering from multiple sclerosis.  In 

one study, the synthetic cannabinoid Nabilone was shown to significantly reduce 

spasticity-related pain 9.  In another study with multiple sclerosis patients, cannabinoids 

decreased the frequency of urination 10. In a commentary on a newly published article 11 

Raphael Mechoulam, the father of cannabinoids chemistry, writes that multiple sclerosis 

may disrupt the endocannabinoid protection mechanism 12



A general theme of cannabinoid activity is inhibition of inflammation and related free 

radical damage. In the immune system, cannabinoids regulate the balance between free 

radical production and their inhibition 13. Inflammation and free radical production are 

important defense mechanisms used by the immune system to fight infectious invaders. 

The immune system regulates the level of inflammation in the circulatory system. A 

chronic pro-inflammatory response is a prime determinant in the development of 

arteriosclerosis, and can be reversed by cannabinoids in mice 14. Unfortunately, the 

comparable experiment in humans has not yet been done. However, mice often serve as a 

good model for human immunology.  



The global homeostatic role of the endocannabinoid system is again demonstrated by 

their control of the skeletal system. Earlier publications lead to some confusion in that 

some data indicated that cannabinoids might promote osteoporosis, whereas others 

suggested the opposite. Experiments published in 2006 provided new insights into the 

regulation of bone mass by the endocannabinoid system. Mice that have had their CB2 

receptor genetically “knocked out,” develop age associated loss of bone mass, a condition 

that appears similar to osteoporosis in humans 15. Thus, CB2 simulation appears to 

prevent bone loss. Similar results were found with CB1 knock out mice16



Many people use and enjoy marijuana because of the effects that it has on one’s 

consciousness. The year 2006 has produced some interesting new science in this area, in 

general, supporting the anti-depressive effects of cannabis. A study by Parish and Nicols 


 showed that stimulation of the serotonin receptor (5-HT2a) produced the 

endocannabinoid 2-arachidonylglycerol. The obvious question is how much of the anti- 

depressive effects produced by serotonin uptake inhibitors is due to the production of 

endocannabinoids? Similarly, another study demonstrated that cannabinoids reduce 

anxiety by stimulating another class of serotonin receptors (5-HT1a)18



The possibility of increasing the levels of endocannabinoids by decreasing their rate of 

breakdown is an exciting new area of drug development. In agreement with earlier 

findings19,  elevating anandamide levels by inhibiting FAAH with an inhibitor  “elicits 

significant, anxiolytic-like, antidepressant-like and analgesic effects” 20. These findings, 

of course, provide unmentioned support for the use of cannabis for these same conditions. 

We know that elevating endocannabinoid levels has affects that are similar to consuming 




Cancer is one of the most exciting areas under investigation for the therapeutic 

application of cannabinoids.  For many years the anti-nausea properties of cannabinoids 

was thought to be the primary use of cannabis for cancer therapy.  Over the past few 

years, the greater potential for cannabinoids in the treatment of cancer has been revealed.  

Cannabinoids have been demonstrated to kill the variety of tumor cells, as well as to 

inhibit activities associated with metastasis (spreading) 22. During this past year THC was 

shown to inhibit the replication of breast cancer cells23. Activation of cannabinoid 

receptors decreased tumor growth, angiogenesis (formation of new blood vessels 

necessary for tumors to grow) and metastasis, while increasing apoptosis (cell death) of 

melanomas in mice24.  Additionally, cannabinoids were found to kill pancreatic cancer 

cells 25. In 2006, the world had its first pilot human clinical trial of THC for cancer 

treatment 26.  This study was too small for proper statistical analysis, however, it seems 

that the drug was safe and inhibited tumor growth albeit temporally.  


Since cannabis is frequently used by cancer patients to relieve nausea, lack of appetite, 

depression, and difficulty sleeping27, a concern has been its possible effect on 

chemotherapeutic drug sensitivity. A recent study demonstrated that a variety of plant 

derived cannabinoids inhibited a protein that pumps therapeutic drugs out of cancer cells 

and is typically associated with drug resistance28, thus providing another possible 

significant benefit to cancer patients who consume cannabis. 


Since smoking is the most widely used route of cannabis administration, a long-term 

concern has been its possible carcinogenic effects. A recent epidemiological study 

demonstrated that cannabis smoking does not seem to cause cancers of the respiratory 

tract 29, confirming my earlier prediction 30



All humans suffer from a common biochemical imbalance. We are all aging, and aging is 

believed to be a consequence of accumulated free radical damage. With respect to the 

biochemistry of aging, cannabinoids appear to be beneficial. They not only appear to 

inhibit age related illnesses such as multiple sclerosis 31 and diabetes 32, but their absence 

increases the probability of premature death 33. However, with respect to the body’s 

method of defense against certain infectious diseases, an excess of cannabinoids could be 

harmful or even lethal, in particular, when fighting intracellular parasites such as those 

responsible for Legionella disease 34 and tuberculosis 35


Another possible danger that may result from cannabis consumption involves the liver. 

On the one hand, recent data shows that hepatitis C patients who consume cannabis are 

more likely to successfully complete there treatment regime 36.  On the other hand, 

turning off the CB1 receptors may be beneficial for treatment of liver fibrosis 37since 

CB1 activation seems to be involved in this pathology 38



In the marijuana plant, nature has provided us with a well-stocked medicinal chemistry 

set.  Everyday new peer reviewed scientific publications support and extend the benefits 

that this plant can provide mankind. When you couple the scientific data with the 

observations of medical marijuana users, the support for medical marijuana use is 

overwhelming. How then is it possible that there remains resistance to the medicinal use 

of marijuana? A possible answer may be found in the simple truth that in any population 

of people there will be those who are cannabinoid endowed and others who are 

cannabinoid deficient.  When the deficiency involves the areas of the brain that allow us 

to change our minds and replace out dated information with new information, change 

becomes difficult. These individuals unfortunately lack some of the necessary 

cannabinoid-based biochemistry. This scenario raises the question: are cannabinoid 

deficient people selected for by our political process? 1 










1. Melamede, R. J. Endocannabinoids: Multi-scaled, Global Homeostatic 

Regulators of Cells and Society. 601, (2006). 

2. Aguado, T. et al. The endocannabinoid system promotes astroglial differentiation 

by acting on neural progenitor cells. J Neurosci 26, 1551-1561 (2006). 

3. Ashton, J. C. et al. Cerebral hypoxia-ischemia and middle cerebral artery occlusion 

induce expression of the cannabinoid CB2 receptor in the brain. Neurosci Lett 


4. Amaya, F. et al. TheInduction of CB(1) cannabinoid receptor by inflammation in 

primary afferent neurons facilitates antihyperalgesic effect of peripheral CB(1) 

agonist. Pain (2006). 

5. Lever, I. J. & Rice, A. S. Cannabinoids and pain. Handb Exp Pharmacol 265-306 


6. Bilsland, L. G. et al. Increasing cannabinoid levels by pharmacological and genetic 

manipulation delay disease progression in SOD1 mice. FASEB J 20, 1003-1005 


7. Akerman, S., Holland, P. & Goadsby, P. J. Cannabinoid (CB1) receptor activation 

inhibits trigeminovascular neurons. J Pharmacol Exp Ther (2006). 

8. Sarchielli, P. et al. Endocannabinoids in Chronic Migraine: CSF Findings Suggest a 

System Failure. Neuropsychopharmacology (2006). 

9. Wissel, J. et al. Low dose treatment with the synthetic cannabinoid Nabilone 

significantly reduces spasticity-related pain : A double-blind placebo-controlled 

cross-over trial. J Neurol (2006). 

10. Freeman, R. M. et al. The effect of cannabis on urge incontinence in patients with 

multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS- 

LUTS). Int Urogynecol J Pelvic Floor Dysfunct (2006). 

11. Witting, A. et al. Experimental autoimmune encephalomyelitis disrupts 

endocannabinoid-mediated neuroprotection. Proc Natl Acad Sci U S A 103, 6362- 

6367 (2006). 

12. Shohami, E. & Mechoulam, R. Multiple sclerosis may disrupt endocannabinoid 

brain protection mechanism. Proc Natl Acad Sci U S A 103, 6087-6088 (2006). 

13. Melamede, R. Indications for Cannabinoids: Autoimmune Diseases (Haworth 

Press, 2002). 

14. Steffens, S. et al. Low dose oral cannabinoid therapy reduces progression of 

atherosclerosis in mice. Nature 434, 782-786 (2005). 

15. Ofek, O. et al. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc 

Natl Acad Sci U S A 103, 696-701 (2006). 

16. Tam, J. et al. Involvement of Neuronal Cannabinoid Receptor, CB1, in Regulation 

of Bone Mass and Bone Remodeling. Mol Pharmacol (2006). 

17. Parrish, J. C. & Nichols, D. E. Serotonin 5-HT receptor activation induces 2- 

arachidonoylglycerol release through a phospholipase c-dependent mechanism.

Neurochem (2006). 

18. Braida, D., Limonta, V., Malabarba, L., Zani, A. & Sala, M. 5-HT(1A) receptors 

are involved in the anxiolytic effect of Delta(9)-tetrahydrocannabinol and AM 404, 

the anandamide transport inhibitor, in Sprague-Dawley rats. Eur J Pharmacol 


19. Gobbi, G. et al. Antidepressant-like activity and modulation of brain 

monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl 

Acad Sci U S A 102, 18620-18625 (2005). 

20. Piomelli, D. et al. Pharmacological Profile of the Selective FAAH Inhibitor KDS- 

4103 (URB597). CNS Drug Rev 12, 21-38 (2006). 

21. Solinas, M. et al. The endogenous cannabinoid anandamide produces THC-like 

discriminative and neurochemical effects that are enhanced by inhibition of fatty 

acid amide hydrolase (FAAH) but not by inhibition of anandamide transport.

Pharmacol Exp Ther S (2007). 

22. Grimaldi, C. et al. Anandamide inhibits adhesion and migration of breast cancer 

cells. Exp Cell Res 312, 363-373 (2006). 

23. Caffarel, M. M., Sarrio, D., Palacios, J., Guzman, M. & Sanchez, C. Delta}9- 

Tetrahydrocannabinol Inhibits Cell Cycle Progression in Human Breast Cancer 

Cells through Cdc2 Regulation. Cancer Res 66, 6615-6621 (2006). 

24. Blazquez, C. et al. Cannabinoid receptors as novel targets for the treatment of 

melanoma. FASEB J (2006). 

25. Fogli, S. et al. Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 

cells via a receptor-independent mechanism. FEBS Lett 580, 1733-1739 (2006). 

26. Guzman, M. et al. A pilot clinical study of Delta(9)-tetrahydrocannabinol in 

patients with recurrent glioblastoma multiforme. Br J Cancer (2006). 

27. Martin, B. R. & Wiley, J. L. Mechanism of action of cannabinoids: how it may lead 

to treatment of cachexia, emesis, and pain. J Support Oncol 2, 305-14; discussion 

314-6 (2004). 

28. Holland, M. L. et al. The effects of cannabinoids on P-glycoprotein transport and 

expression in multidrug resistant cells. Biochem Pharmacol 71, 1146-1154 (2006). 

29. Hashibe, M. et al. Marijuana use and the risk of lung and upper aerodigestive tract 

cancers: results of a population-based case-control study. Cancer Epidemiol 

Biomarkers Prev 15, 1829-1834 (2006). 

30. Melamede, R. Cannabis and tobacco smoke are not equally carcinogenic. Harm 

Reduct J 2, 21 (2005). 

31. Pryce, G. et al. Cannabinoids inhibit neurodegeneration in models of multiple 

sclerosis. Brain 126, 2191-2202 (2003). 

32. Li, X., Kaminski, N. E. & Fischer, L. J. Examination of the immunosuppressive 

effect of delta9-tetrahydrocannabinol in streptozotocin-induced autoimmune 

diabetes. Int Immunopharmacol 1, 699-712 (2001). 

33. Zimmer, A., Zimmer, A. M., Hohmann, A. G., Herkenham, M. & Bonner, T. I. 

Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor 

knockout mice. Proc Natl Acad Sci U S A 96, 5780-5785 (1999). 

34. Lu, T., Newton, C., Perkins, I., Friedman, H. & Klein, T. W. Cannabinoid treatment 

suppresses the T helper cell polarizing function of mouse dendritic cells stimulated 

with Legionella pneumophila infection. J Pharmacol Exp Ther (2006). 

35. Munckhof, W. J., Konstantinos, A., Wamsley, M., Mortlock, M. & Gilpin, C. A 

cluster of tuberculosis associated with use of a marijuana water pipe. Int J Tuberc 

Lung Dis 7, 860-865 (2003). 

36. Sylvestre, D. L., Clements, B. J. & Malibu, Y. Cannabis use improves retention and 

virological outcomes in patients treated for hepatitis C. Eur J Gastroenterol 

Hepatol S 18, 1057-1063 (2006). 

37. Teixeira-Clerc, F. et al. CB1 cannabinoid receptor antagonism: a new strategy for 

the treatment of liver fibrosis. Nat Med (2006). 

38. Hezode, C. et al. Daily cannabis smoking as a risk factor for progression of fibrosis 

in chronic hepatitis C. Hepatology 42, 63-71 (2005).