Cannabis - Erfaringer Danner Israel - Produktion, Forskning

Cannabis - Erfaringer danner Israel - produktion, forskning.

Lumír Ondřej Hanuš

Lumir Lab, det Hebraiske Universitet i Jerusalem, Israel

Pharma på Tværs 2018 København, Kongeriget Danmark November 3, 2018 Cannabis - experiences form Israel - production, research

Lumír Ondřej Hanuš

Lumir Lab, Hebrew University, Jerusalem, Israel

Pharma på Tværs 2018 Copenhagen, Kingdom of Denmark November 3, 2018 CannabisCannabis sativasativa L.L. (( hemp)hemp) In China 6,000 years ago In China 4700 years ago during the reign of mythical emperor Shen- Nung the first evidence of the use of hemp (chu-ma, female hemp) as medicine to treat:

- malaria - gout (arthritis urica) - beri-beri (a nutritional deficit in thiamine) - constipation He deemed chu-ma one of the Superior Elixirs - rheumatism of Immortality - absentmindedness - menstrual problems Scythians an ancient Iranic people of horse-riding nomadic pastoralists 5th century B.C. seeds of Scythian cannabis Pazyryk, Siberia

Herodotus of Halicarnassus The History, Book 4 - Melpomene

4.74 Hemp grows in Scythia... 4.75. The Scythians then take the seed of this hemp and creep under the felt coverings, and then they throw the seed upon the stones which have been heated red-hot: and it burns like incense and produces a vapour so think that no vapour-bath in Hellas would surpass it: and the Scythians being delighted with the vapour-bath howl like wolves. John Russell Reynolds British neurologist and physician

For the relief of certain kinds of pain, I believe, there is no more useful medicine than Cannabis within our reach.

Archives of Medicine 2, 154-160 (1859)

Indian hemp, when pure and administered carefully, is one of the most valuable medicines we possess.

Lancet 135, 637-638 (1890) University of Illinois UNIVERZITA PALACKÉHO V OLOMOUCI Zdeněk Krejčí (March 25, 1923 – March 31, 1992 ) cannabidiolic acid UNIVERZITA PALACKÉHO V OLOMOUCI František Šantavý (April 23, 1915 – March 27, 1983) 1963; cannabidiol

Mechoulam R., Shvo Y.: Tetrahedron 19, 2073–2078 (1963) Šantavý F.: Acta Univ. Palacki. Olomuc., Fac. Med. 35, 5-9 (1964) Yehiel Gaoni Raphael Mechoulam * September 1, 1928 * November 5, 1930

Endocannabinoid system The endocannabinoid system consists of: genes encoding two major cannabinoid receptors, CB1 and CB2, endocannabinoids, and the enzymes involved in the synthesis and degradation of endocannabinoids Cannabinoid receptors Cannabinoid receptors

* Two types identified

CB1, present in brain and central nervous system, 472 amino acids CB2, present in spleen and immune cells, 360 amino acids * Both types are 7-helix transmembrane spanning receptors. Three extra-cellular and three intra-cellular loops. A glycosylated extra-cellular N-terminal domain, and an intra-cellular C-terminal domain involved in the interaction with the G-protein.

CB1 CB2 360 Devane, 1988 Munro, 1993 472 Brain regions in which cannabinoid receptors are abundant.

______

Brain Region Functions Associated with Region ______

Basal ganglia Movement control Substantia nigra pars reticulata Entopedunculus nucleus Globus pallidus Putamen Cerebellum Body movement, coordination Hippocampus Learning and memory, stress Cerebral cortex, especially cingulate Higher cognitive function frontal, and parietal regions Nucleus accumbens Reward center ______Cannabinoid receptors distribution

CB1 receptor CB2 receptor cerebral cortex lymphoid organs: hippocampus spleen basal ganglia thymus cerebellum tonsils bone marrow reproductive system leukocytes

pancreas macrophages CB1 expression

3.0E+00

2.0E-01 /GAPDH

1 1.0E-01 CB

0.0E+00 cerebellum spleen liver islets of Langerhans

GAPDH = glyceraldehyde 3-phosphate CB2 expression dehydrogenase

1.0E-03

1.8E-05

1.2E-05

/GAPDH 2

6.0E-06 CB 0.0E+00 cerebellum spleen liver islets of Langerhans GPR119 (335) GPR18 (331)

CB1 (472) GPR55 (319)

GPR3 (330)

CB2 (360) GPR6 (362) GPR12 (334) PPARa (468)

TRPV1 (819) PPARd (441) PPARg (505)

Sequence similarities for putative cannabinoid and cannabinoid-like receptors in man. Cannabidiol, a novel inverse agonist for GPR3, GPR6, and GPR12

GPR3, GPR6, and GPR12 are constitutively active, Gs protein- coupled receptor that currently have no confirmed endogenous ligands. GPR3, GPR6, and GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. Cannabidiol (CBD), a major non-psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR3, GPR6, and GPR12. Thus, GPR3, GPR6, and GPR12 are novel molecular targets for CBD.

Gs, but not Gi is involved in the inverse agonism of CBD on GPR3, GPR6, and GPR12 .

Laun et al., 2018 Tetrahydrocannabinolic acid is a potent peroxisome proliferator-activated receptor gamma (PPARg) agonist with neuroprotective activity

Cannabinoid acids are more potent PPARγ agonists and transcriptional activators than their decarboxylated analogues.

Crystal Structure of Human PAPRα complex with agonist

D9-THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington’s disease and possibly other neurodegenerative and neuroinflammatory diseases. These data would strongly suggest Δ9-THCA as a lead structure for the development of novel drugs.

Nadal et al., 2017 Endocannabinoids Anandamide William A. Devane,* Lumir Hanuš, Aviva Breuer, Roger G. Pertwee, Lesley A. Stevenson, Graeme Griffin, Dan Gibson, Asher Mandelbaum, Alexander Etinger, and Raphael Mechoulam Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Devane W. A., Hanuš L., Breuer A., Pertwee R. G., Stevenson L. A., Griffin G., Gibson D., Mandelbaum A., Etinger A., Mechoulam R. Science 258, 1946-1949 (1992)

1 2 3 6 7 8 9 10 1. Inhibition of the specific binding of a radiolabelled cannabinoid probe to the synaptosomal membrain and work on isolation of anandamide (William A. Devane) 2. First isolation of anandamide from porcine brain (Lumír O. Hanuš, Tuesday, March 24, 1992) 3. Inhibition of the electrically evoked vas deferens twitch response (Roger Pertwee) 4. Inhibition of the electrically evoked vas deferens twitch response (Lesley A. Stevenson ) 5. Inhibition of the electrically evoked vas deferens twitch response (Graeme Griffin) 6. NMR spektrum of anandamide (Dan Gibson) 7. First high resolution mass spectrum (Asher Mandelbaum) 8. First high resolution mass spectrum (Alex Etinger) 9. Final structure of anandamide (Raphael Mechoulam, July 13, 1992) 10. First synthesis of anandamide (Aviva Breuer, August 20, 1992)

Asher Gopher Israel Ringel First mass spectrum of anandamide (May 13, 1992) First NMR spectrum of anandamide and TMS-anandamide (May 14, 1992) האוניברסיטה העברית בירושלים HEBREW UNIVERSITY OF JERUSALEM

Ester Fride

The first in vivo examination of anandamide. After i.p. administration in mice caused lowering of activity in an immobility and in an open field test, and produced hypothermia and analgesia (these effects parallel those caused by psychotropic cannabinoids).

E. Fride, R. Mechoulam: Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur. J. Pharmacol. 231, 313-314(1993) O C OH N OH H

O C5H11

D9-tetrahydrocannabinol Anandamide

CB1 Lumir Hanuš,*, Asher Gopher,‡ Shlomo Almog‡, and Raphael Mechoulam*, RAPHAEL MECHOULAM, * SHIMON BEN-SHABAT,* LUMIR HANUŠ,* MOSHE LIGUMSKY,* NORBERT E. KAMINSKI, ‡ ANTHONY R. SCHATZ,§ ASHER GOPHER,॥ SHLOMO ALMOG,॥ BILLY R. MARTIN,§ DAVID R. COMPTON,§ ROGER G. PERTWEE,¶ GRAEME GRIFFIN,¶ MICHAEL BAYEWITCH,** JACOB BARG** and ZVI VOGEL** 2-arachidonoyl glycerol (2-AG) Presence of 2-AG in mouse bone May 2004

5 samples 70.4 mg ______

June 2004

30 samples (femora and tibias) 0.6225 g 2-AG in bone Bone Remodeling Osteoclasts have the function A proper balance between to disrupt the old bone tissue osteoclasts and osteoblasts is the basis for a normal bone density

OSTEOCLAST

OSTEOBLAST

A hyperactivity of osteoclasts is a one Osteoblasts have the function of the causes of the to produce the new bone tissue onset osteoporosis

Medical illustration of the function of osteoblasts and osteoclasts in the regeneration of bone mass Anandamide reversed the inhibitory effect of AM251 on osteoclast formation 300

250

200 # 150

100

Osteoclasts per well per Osteoclasts ** 50

0 Vehicle AM251 AM251 + anandamide Nat. Med. 11, 774 (2005) Government statistics show that in Greece hip fractures are significantly lower than in North America and Northern Europe. Trichopoulou et al., have provided evidence that "The positive association between bone mineral density (BMD) and monounsaturated fat, which in the Greek diet is derived mostly from olive oil, is fairly strong, statistically significant"

(Preventive Medicine 26, 395-400, 1997) Levels of bioactive lipids in cooking oils: olive oil is the richest source of oleoyl serine

J Basic Clin Physiol Pharmacol. 27(3): 247–252 (2016)

O O COOH H H C OH C OH N N arachidonoyl ethanolamide (anandamide) arachidonoyl serine

COOH O H O H C OH C OH N N

oleoyl ethanolamide oleoyl serine (HU-639)

N-Oleoyl-L-serine is an endogenous lipid that has been reported to stimulate bone formation and to inhibit bone resorption. Oleoyl Serine Rescues Ovariectomy-induced Bone Loss

5 p= 0.065 (%) 4 p= 0.017

volume density volume - 2

1 trabecular bone trabecular

0 Sham OVX OVX/VEH OVX/OS

OVX OS treatment Analysis

5 mg/Kg/day

Day 0 Day 42 Day 84 Lumír Hanuš*, Saleh Abu-Lafi, Ester Fride*‡, Aviva Breuer*, Zvi Vogel§, Deborah E. Shalev¶, Irina Kustanovich¶, and Raphael Mechoulam*॥

Prof. Mechoulam: „Whatever THC does, anandamide does as well.“

What is the reason that the synthetic anandamide is not used for medical purposes instead of THC?

It's a very delicate question. When, in 1921, Canadian researchers Fredrick Grant Banting, Charles Herbert Best, John James Richard Macleod a James Bertram Collip discovered insulin, has been used in clinical practice already in January 1922. When, in 1935, Edward Calvin Kendall discovered cortisone, was already given to patients following year and became a successful medicine.

We discovered anandamide twenty six years ago, and it still has never been officially administered to a human. Neither has 2-AG. What do endocannabinoids?

“Relax, eat, sleep, forget and protect”

TINS 21, 521 (1998) Keep in mind that cannabis is a wonderful medicine, but it is no panaceum and therefore it:

1. does not cure every time 2. does not cure everyone 3. does not cure every disease 4. does not cure every stage of the disease CB1 receptor do not appear in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. For this reason, there is no risk of respiratory or cardiovascular failure.

There is no risk of respiratory or cardiovascular failure when these receptors are stimulated – a risk often associated with many other drugs.

Selective CB1 agonists are considered advantageous for treatment. For cannabinoids, important risks include triggering of psychosis, schizophrenia, and cognitive impairments (usually worsening short-term memory).

It seems quite clear, however, that the risk is much higher in children and adolescents (particularly before puberty).

The study of participants who developed cannabis dependency before the 18th birthday showed notable impairments to memory, concentration, and brainpower, adults did not show any such impairment, even if they were heavy users. It may be assumed that cannabis can damage the adolescent brain, but not - in contrast to alcohol - the adult brain.

Marijuana is not a completely benign substance. It is a powerful drug with a variety of effects. However, except for the harms associated with smoking, the adverse effects of marijuana use are within the range of effects tolerated for other medications. Normal Brain Development

Age 5 Age 8 Maturing brain. The National Institute of Mental Health study of 13 individuals over a decade reveals a process — still under way in the late teens — in which gray matter is replaced throughout the Age 12 Age 16 cortex, starting at the rear.

Age 20 Beckman, 2004 Cannabis and children.

Both doctors and parents will continue to face the difficult decision of giving youngsters a compound and hoping it will do more good than harm. Thankfully, most adolescents who abuse marijuana do not become psychotic adults.

Hilt, 2014 Cannabis use (even long term use) is not harmful to a health of mentally healthy adult person. Overdose is not harmful however very uncomfortable. Throughout the therapeutic use of cannabis it is necessary to identify not only the patients who can benefit from that and which can help them, but also these who would be able to lose and which could harm them! Suppositories

- a viable option for patients who can’t ingest or inhale cannabis - work quickly and last for a long time - are quickly absorbed through the intestinal wall directly into the bloodstream, which results in “superior bioavailability” over other forms of administration - You may feel pain relief almost immediately, without anxiety or a “head high” lasting for hours.

Suppositories are an ideal choice for many patients, such as chemotherapy patients who experience severe nausea and can’t keep oral cannabis down, patients with inflammatory bowel disease, some seizure kids during emergency rectal CBD administration, elderly and babies who can’t smoke or swallow pills, surgery patients who are not allowed to ingest anything immediately before or after a procedure, and patients in severe distress who can’t wait for oral cannabis to take effect. There are also some people who just have sensitive stomachs that are irritated by ingesting cannabis.

The bioavailability of the rectal route is approximately twice that of the oral route due to higher absorption and lower first-pass metabolism. With predictable effects even between different individuals. Inhaled medicinal cannabis and immunocompromised patient At the Hadassah Ein Kerem hospital's Bone Marrow Transplantation department, patients including children and babies are treated using drops of oil derived from Cannabis. "It has no side effects and is largely effective in treating patients," said department chief, Professor Reuven Or. "I would say it is effective in 80 percent of patients, which is a lot." Professor Or continued, "It stimulates the appetite and minimizes nausea and vomiting, which is of great importance in Oncology. It also has anti-inflammatory properties, which helps in cases of infection or inflammation caused by radiation. Along with this, Cannabis eases the coping process for patients - it improves their morale and lowers depression, and these are important parameters for patients battling disease." Lumír Hanuš Influence of sterilization on D9-THC content in medicinal cannabis buds

unprocessed sample 16 plasma sterilization heat sterilisation

14 (autoclave) (%) ethylene oxide 12 gas sterilisation

content inmedicinal cannabis buds 4

THC -

9 2 D

0 Neuroprotection David Panikashvili*†, Constantina Simeonidou*, Shimon Ben-Shabat†, Lumír Hanuš†, Aviva Breuer†, Raphael Mechoulam† & Esther Shohami* Levels of 2-AG in mouse brain after CHI

««« 120 110 100 90 80 «« ««

70 « AG(nM/gr)

- 60 2 50 40 30 20 10

concentration of concentration 0 control 15 min 1 h 4 h 8 h 24 h Time after CHI Anova with Tukey post-test:P<0.0001, F=36.01 ««« -P<0.001 vs. control «« -P<0.01 vs. control Nature 413, 527 (2001) « -P<0.05 vs. control 2-AG Reduces Infarct Volume 24 h After CHI

control 15.0 control 12.5 2-AG 5 mg/kg 10.0 7.5 * 5.0 2.5 infarct volume(%) infarct 0.0 2-AG control 2-AG (5 mg/kg) n=9 n=7 unpaired t-test, P=0.0 3 Alzheimer's disease

D9-THC prevents the formation of deposits in the brain associated with Alzheimer's disease. D9-THC was found to prevent an enzyme called acetylcholinesterase from accelerating the formation of "Alzheimer plaques" in the brain more effectively than commercially marketed drugs. Kibbutz Na’an

Small amount of medicinal cannabis in food

Three started to talk One started to paint One felt so good that wanted return home

Effect of anandamide on food intake in diet-restricted mice.

anandamide (0.001 mg/kg i.p.) vehicle

5 gram/mouse/day

3 0 1 2 3 4 5 6 7 8 Days Eur. J. Pharm. 392, 147 (2000) Ester Fride Physical growth during treatment with 9 D -THC and CB1 antagonist (SR141716A) 7 Control 6 THC SR141716A 5 THC + 4 SR141716A

Body Weight (g) Weight Body 2 all mouse pups died 10 (out of 12)  1 pups died

0 1 2 3 4 5 6 7 8 Day of Age Medical Cannabis serves as an orphan drug

Dravet Syndrome (rare form of severe epilepsy )

Tourette Syndrome (neurological-psychiatric disorder)

Stiff Person Syndrome (progressive muscle stiffness and intermittent spasms)

Achalasia (failure of the muscles to relax)

Idiopathic Intracranial Hypertension (neurological disorder characterized by high pressure in the fluid around the brain) Recent study of Pacher and Kunos have suggested that “modulating endocannabinoid system activity may have therapeutic potential in almost all diseases affecting humans, including obesity/metabolic syndrome; diabetes and diabetic complications; neurodegenerative, inflammatory, cardiovascular, liver, gastrointestinal and skin diseases; pain; psychiatric disorders; cachexia; cancer; and chemotherapy-induced nausea and vomiting, amongst many others”. This strong statement supports a long list of examples, although mostly in vitro or in vivo in animals. Anticancer effects of cannabis One of the benefits of cannabinoids is that they fight specifically against cancer cells and all without any toxic effect and without harming normal non-cancerous cells. This is an advantage compared to conventional treatment with chemotherapy that actually fights the entire system. Study of anticancer effects of cannabis at Technion

Professor David Meiri Laboratory of Cancer Biology and Cannabinoid Research, Technion - Israel Institute of Technology, Haifa Vehicle Strain 1 Strain 2 Strain 3 (DMSO) ↑ THC ↑ CBD ↑ CBD ↓ CBD ↓ THC ↓ THC Breast cancer cells

Colon cancer cells

Prostate cancer cells

Non-cancer cells Standardized cannabis drug preparations, rather than pure cannabinoids, could be considered as part of the therapeutic armamentarium to manage breast cancer.

Sandra Blasco-Benito et al., 2018 Cannabis and autism

Autism is a developmental disorder characterized by troubles with social interaction and communication and by restricted and repetitive behavior.

It is necessary to test whole plant as well as single cannabinoids. If one or more isolated cannabinoids do not work it can be concluded that cannabis doesn’t work.

Sometime it is necessary to go through quite a lot of trials and errors to find correct strain.

Patients should be in the first place and only then profit. Total 5,027 2013 Israeli cannabis licenses Numbers/primary conditions, 2013

7631 Pain 1692 Cancer 551 Gastro 431 Parkinson’s 342 Post traumatic stress disorder

208 Multiple sclerosis 178 Fibromyalgia and rheumatology 115 AIDS 96 Various neurological Total: 11255 11 Asthma

Source: Ministry of Health November 2015 In Israel are 8 growers, they give to the patient instructions of cannabis use and plant material or cannabis extract in vegetable oil. For children - cookies. At present, a permit to treatment with medicinal cannabis was issued to about 32 thousand Israelis. Most of them suffer from chronic pain or disease in the terminal stage. Patient has permit from Ministry of Health on request of physician- specialist (only for Ministry of Health approved indications). Adjustment of the treatment with cannabis in Irael

physician designated by Specialist physicians submit the Ministry of Health an application for a permit responsible for issuing permits

Distribution Grower A Grower B ...... Grower Z Trainings Payments

patient The National Authority for cannabis in Israel, the proposed model

The allocation of permits and the land where it is allowed to grow cannabis

Quality Exclusive ownership assurance of cannabis stocks

National authorities Report to Issuing permits to allow treatment the UN to import/export with cannabis

Documentation, monitoring Issuing permits and supervision required to possession by the UN Convention

Determination of indication Cannabis in Israel

How it was:

370 shekels per month for an unlimited amount of dry cannabis (usually between 20 – 200 grams/month). – known strain. “The government says people were abusing that”

How it is now:

140 shekels per 10 grams "Cannabis consumers will now benefit from a better product. Despite higher production costs resulting from improved quality and standards, the price will be more attractive than the pricing method before the reform.” – without a strain designation

Dry cannabis flowers

* Variation values are shown in parentheses and larger variation will not be allowed! Cannabis oil

* Variation values are shown in parentheses and larger variation will not be allowed! Cannabis cookie (only for children)

Under the terms and a decision of the General Director

* Variation values are shown in parentheses and larger variation will not be allowed! T10/C2 chemotherapy (T10/C10, T15/C3, T20/C4) T10/C2 cancer pain (T10/C10, T15/C3, T20/C4) T0/C24 hepatocellular carcinoma patients (T1/C20) T5/C10 Crohn's disease, ulcerative colitis (T3/C15, T1/C20, T0/C24) T10/C10 neuropathic pain T10/C10 acquired immune deficiency syndrome (HIV/AIDS), cachexia (T10/C2, T15/C3, T20/C4) T10/C10 multiple sclerosis (T10/C2, T15/C3, T20/C4) T10/C2 Parkinson’s disease, chronic pain, rheumatic pain (T10/C10, T15/C3, T20/C4) T10/C2 Tourette syndrome (T10/C10, T15/C3, T20/C4) T1/C20 epilepsy (T0/C24, T5/C10, T3/C15) T0/C24 uncontrolled severe epilepsy (T1/C20, T3/C15) T10/C10 terminally ill patients (T10/C2, T15/C3, T20/C4) T10/C10 or T10/C2 posttraumatic stress disorder (PTSD) (T5/C10, T3/C15, T1/C20, T0/C24, T15/C3) Company Tikun Olam 11 strains THC : CBD = 20 : 1

THC CBD type name of strain treatment (%) (%) 20 1 H Zohar 20 1 S Tal 20 1 S Oz Chronic pain, PTSD, MS, ALS, Parkinson 20 1 S Shira Chronic pain, Cancer, Nausea and vomiting, Loss of appetite, ALS

20 1 S Alaska Chronic pain, Nausea and vomiting, Loss of appetite, MS, Crohn’s and Colitis 20 1 I Eran Almog Chronic pain, PTSD, Tourette, Tremor, Loss of appetite

20 1 I Or Chronic pain, Nausea and vomiting, Loss of appetite, Parkinson, ALS

20 1 I Dorit PTSD, Cancer, Nausea and vomiting, Loss of appetite, Tremor,

20 1 I Omer Chronic pain, Cancer, Lack of sleep, Nausea and vomiting, Loss of appetite 20 1 I Barak 20 1 I Erez Chronic pain, PTSD, Tourette, Crohn’s and Colitis, ALS Cannapedia Encyclopedia of Medical Cannabis Strains in Israel

https://cannapedia.co.il/ Company Canndoc “Cannacopeia” contains five sections on Israel Medical Cannabis:

IMC-GCP (Good Clinical Practice) IMC-GAP (Good Agricultural Practice) IMC-GMP (Good Manufacturing Practice) IMC-GDP (Good Delivery Practice) IMC-GSP (Good Safety Practice) Woman and pain Endometriosis – the endometrium, the layer of tissue that normally covers the inside of the uterus, grows outside of it.

Dysmenorrhea - painful periods, or menstrual cramps, is pain during menstruation.

Dysuria - painful or difficult urination.

Hyperemesis gravidarum – the most severe form of nausea and vomiting in pregnancy.

Symptoms of menopause Uterine Fibroids - the most common noncancerous tumors in women of childbearing age.

Gynecologic Cancer - any cancer that starts in a woman’s reproductive organs. Cervical cancer begins in the cervix, which is the lower, narrow end of the uterus. Ovarian cancer begins in the ovaries, which are located on each side of the uterus. Uterine cancer begins in the uterus, the pear-shaped organ in a woman’s pelvis where the baby grows when a woman is pregnant. Vaginal cancer begins in the vagina, which is the hollow, tube-like channel between the bottom of the uterus and the outside of the body. Vulvar cancer begins in the vulva, the outer part of the female genital organs

Interstitial Cystitis - a chronic bladder condition resulting in recurring discomfort or pain in the bladder or surrounding pelvic region.

Polycystic Ovary Syndrome - happens when a woman’s ovaries or adrenal glands produce more male hormones than normal.

Adenomyosis - a condition in which the inner lining of the uterus (the endometrium) breaks through the muscle wall of the uterus (the myometrium).

Vulvodynia - pain that affects the vulva for no apparent reason. Compounds identified in cannabis up to November 3, 2018

Total in cannabis identified 1384 compounds

144 are cannabinoid compounds, which are typical for this plant and do not occur in any other plant

1240 are all other identified substances cannabinoids (144)

terpenes (110) terpenoids (121)