1 AANP 2016 Annual Conference Khara Lucius, N.D., FABNOPsychoactive Botanical Medicines in Clinical Practice: From Coffee to Cannabis and Beyond AANP 2016 Annual Conference Khara Lucius, N.D., FABNO
2 Outline Background Coffea species Piper methysticumSolanaceae family (Atropa Belladonna, Nicotiana species, and Datura species) Mushroom species. Cannabis. The role of cannabinoids and other plant constituents, medical Cannabis, and the endocannabinoid system will be discussed.
3 History and BackgroundPsychoactive plants have been used ritually, medicinally and recreationally for thousands of years. Many aspects to these plants: Economic Environmental Cultural Legal Therapeutic
4 Types of psychoactive plantsStimulants- increase focus or sense of alertness, increase energy, cause excitation by altering norepinephrine or dopamine, may produce euphoria or sense of well-being at lower doses. Sedatives- CNS depression, may induce sleep, relaxing, anxiety reducing Hallucinogens- alter sensation or perception, tend to stimulate a shift in perception of reality.
5 Dose, set, and setting DosageSet- person’s internal attitudes they bring to an experience. Includes expectations, wishes, and fears. Cultural influences such as worldview and mythology. Setting- surroundings, place, and time. Same drug can produce different effects in different individuals. Even in the same individual, the same plant may create variable effects depending on changes in dose, set, and setting.
6 Addiction Psychological versus physical dependenceDx of substance use disorder is based upon a pathological set of behaviors which fall into four main categories: 1. Impaired control 2. Social impairment 3. Risky use 4. Pharmacological indicators (tolerance and withdrawal) Grant et al 2016: Survey of nationally representative sample of 36,000 US adults from 2012 to % of respondents said they had a drug use d/o in the past 12 months, while 10% said they had ever had a drug use disorder (amphetamines, cannabis, club drugs, cocaine, hallucinogens, heroin, opioids, sedatives, tranquilizers, solvents, and inhalants).
7 Schedule I substances and researchSchedule I classification: 1. substance has high potential for abuse. 2. substance has no current accepted medical use. 3. lack of accepted safety data. The only legal source of Cannabis for research in the US is the National Institute on Drug Abuse (NIDA). NIDA has a congressional mandate to study substances of abuse ONLY as substances of abuse (not as therapeutic interventions). NIDA can supply Cannabis for clinical trials to assess its effectiveness, but funding must come from elsewhere. Even when necessary licenses/approvals for a study are granted, obtaining substance may be difficult and pricy Nutt 2013: One custom synthesis company in Boston quoted psilocybin at cost of $12,000 per gram. UK researcher was quoted £100,000 for 100 doses of psilocybin for a trial.
8 Alkaloids Almost all compounds that have psychoactive properties contain nitrogen, and most are alkaloids. Exception: cannabinoids Alkaloids are considered secondary compounds Not directly related to plant survival Discourage consumption, inhibit bacterial or fungal pathogens Alkaloids share several characteristics: Nitrogen Bitterness Typically alkaline Affect physiology in several ways but most pronounced actions are on the nervous system. Caffeine, nicotine, cocaine, morphine, ephedrine, pipermethystine
9 Coffea species “Tumble outta bed and stumble to the kitchen, pour myself a cup of ambition…” - Dolly Parton, 9 to 5
10 Coffea Originally chewed as a stimulantBeverage: approximately 11th century 16th-17th centuries: Europe and African coast East Africa: spirits live in coffee beans which therefore possess specific powers
11 Coffee and all cause mortalityAnalysis of 210,000 U.S. health professionals free of cancer and cardiovascular disease at baseline. Participants completed food-frequency questionnaires at baseline and every 4 years thereafter. Roughly 32,000 died during 4.7 million person-years of follow-up. Participants who drank 1 to 5 cups of coffee (decaf or regular) daily had slightly lower risk for all-cause mortality than nondrinkers. For heavier coffee drinkers, there was no association. For nonsmokers, there was an inverse linear relationship between coffee consumption and all-cause mortality, with those drinking over five cups daily having the lowest risk (HR, 0.88). Among never smokers, coffee appeared protective against mortality related to cardiovascular disease, neurological diseases, and suicide. Ding et al, 2015
12 Coffee and colon cancer riskAssessed coffee intake in 5100 people with colorectal cancer and 4100 controls free of colorectal cancer. After multivariable adjustment, any coffee consumption was tied to a 26% reduced risk for incident colorectal cancer, compared to no coffee intake. Risk was lowest in the highest consumption group (>2.5 cups daily). Benefits were seen with both decaf and regular. Schmit et al. 2016
13 Coffee and colon cancer recurrenceProspective observational study 953 subjects with stage III colon cancer prospectively reported intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea during and for 6 months after adjuvant chemotherapy. People consuming 4 cups coffee per day had a 41% reduced risk of recurrence compared to nondrinkers. Increasing total intake of coffee was also associated with a significant improvement in OS (P=0.008). Caffeinated coffee seemed to confer stronger risk reduction. People consuming 4 cups of caffeinated coffee per day had a 51% reduction in risk of recurrence or mortality (HR:0.49; P=0.003) compared to nondrinkers. Nonherbal tea and decaffeinated coffee did not affect outcomes. Guercio et al 2015.
14 Piper methysticum Courtesy library of Univ of Hawaii at Manoa
15 Kava for anxiety Cochrane Database Syst Rev. 2003;(1):CD Kava extract for treating anxiety. Pittler MH, Ernst E. 11 RCTs with a total of 645 participants met inclusion criteria. Meta-analysis of 6 trials that utilized Hamilton Anxiety scale as a common outcome measure suggested a significant reduction in patients receiving kava extract compared with patients receiving placebo (p = 0.01; n = 345). Adverse events were mild, transient and infrequent. Compared with placebo, kava appears to be an effective symptomatic treatment option for anxiety. Data from the reviewed studies suggest that kava is relatively safe for short-term treatment (1 to 24 weeks).
16 Kava for anxiety Sarris et al 2009: 3-week placebo-controlled, double-blind crossover trial of 60 subjects with at least 1 month hx of generalized anxiety. 5 Kava tablets daily (250 mg of kavalactones/day). Kava produced significant anxiolytic and antidepressant activity. No safety concerns at the dose and duration studied. Sarris et al Phytother Res. 2013: 6 week DBRPCT of Kava 1 tablet BID titrated to 2 tabs BID (120mg kavalactones per day; 240 mg kavalactones) or placebo for subjects with GAD. Kava reduced anxiety and this also correlated with improved sexual function. Sarris et al J Clin Psychopharmacol. 2013: 6 week DBRPCT Kava dosed at 120/240 mg of kavalactones QD depending on response. Significant reduction in anxiety for the kava group compared with placebo. Effect was larger in pts with moderate to severe GAD. Aside from more headaches reported in the kava group (P = 0.05), no other significant adverse effects, and no difference in liver function tests.
17 Hepatotoxicity: Teschke R, Schwarzenboeck A, Hennermann KH. 2008Excess dose or duration Highly probable: 1 case Probable: Possible: 5 cases Used as recommended
18 Solanaceae family Atropa BelladonnaRoots, leaves and berries contain tropane alkaloids (atropine, hyoscyamine and scopolamine). Anticholinergic Photo courtesy of RBGE Physic Garden
19 Solanaceae family Atropine Scopolamine Hyoscyamine (Hyoscyamus niger)IM, IV, SC Atropine sulfate ophthalmic Scopolamine SC, IM, IV, transdermal Hyoscyamine (Hyoscyamus niger) Regular and ER oral tabs, SL, IV, IM, SC Datura species Photo courtesy An Entangled Bank
20 Mushroom species
21 Psilocybin N=12, ages 35 to 58 All subjects had advanced-stage cancer and a DSM-IV diagnosis of: acute stress disorder generalized anxiety disorder anxiety disorder due to cancer adjustment disorder with anxiety Within-subject, double-blind, placebo-controlled study to examine the safety and efficacy of psilocybin in the treatment of psychological distress associated with the existential crisis of terminal disease Grob et al. Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Arch Gen Psychiatry. 2011
22 Grob et al 2011 Subjects with breast, colon, ovarian, peritoneal, salivary gland cancers and multiple myeloma. All in advanced stages. Duration of primary cancers ranged from 2 months to 18 years. 2 subjects died of their cancer during the follow-up period, and 2 others became too ill to continue participating. The study was conducted from 2004 to By the time the study was submitted in 2010, 10 of the 12 subjects had died. 4 subjects had no prior hallucinogen experience. 4 had hallucinogen experience 30+ years ago. 2 had their last experience 5+ years ago, and the other 2 had taken a hallucinogen within the year prior. LSD (7 subjects), hallucinogenic mushrooms (5 subjects), peyote (2 subjects), and ayahuasca (2 subjects).
23 Grob et al 2011 Each subject acted as his or her own control and underwent 2 treatment sessions several weeks apart. Subjects were informed they would receive psilocybin (0.2 mg/kg) on one occasion and the placebo, niacin (250 mg), on the other. Subjects demonstrated sustained reduction in anxiety that reached significance at the 1- and 3-month points after treatment. This reduction might reflect a reduced level of stress and anxiety over time. Mood also improved for 2 weeks after treatment with psilocybin, with sustained improvement at the 6-month follow-up point. No reductions in pain perception or lessened need for narcotic pain medication.
24 Case #1 45 y/o female presented to her doctor in 2014 with chief complaint of rectal bleeding x 4-6 weeks. She would have occasional intermittent episodes of rectal pressure and would pass stools mixed with bright red blood per rectum. Colonoscopy revealed rectal mass involving at least half of the wall of the rectum. Biopsy revealed adenocarcinoma, intermediate grade, admixed with tubular venous adenoma fragments. Pathological Stage II , T3N0, K-RAS+ She underwent chemoradiation with capecitabine followed by resection. She then started adjuvant CAPOX
25 Case #1 Family member gave her medicinal mushroom to takePt ground the hard, dried mushroom and mixed the powder with hot water. She was unsure if the person who harvested properly identified the correct mushroom, or how long he stored it for prior to giving it to her. Photo courtesy mushroom-collecting.com
26 Case #1: Serum bilirubinmushroom
27 Case #1 Inonotus obliquus Other polypores?Capecitabine: approximately 12% in pts without hepatic metastases Oxaliplatin: approximately 13%
28 Cannabis
29 Cannabis Long history of traditional or medicinal use.Yanghai Tomb: Male of high social status with estimated age 45. Buried with materials supporting probable identity as a shaman. Courtesy Russo et al 2008
30 Cannabis: receptors and constituentsCB1 receptor: CNS, more densely concentrated in cortex, hippocampus, basal ganglia, amygdala, hypothalamus, and cerebellum. Also found in several peripheral sites, including the peripheral nervous system. CB2 receptor: mainly peripheral. GI tract, immune cells. Anandamide- higher affinity for the CB1 receptor subtype. 2-AG- affinity for CB1 and CB2 The 2 endocannabinoids are found in systemic circulation at equal concentrations, but concentration of 2-AG is about 200x higher than that of anandamide in the brain. Plant constituents: THC, CBD, CBN, terpenes, CBC
31 Cannabis in pain managementModulate nociceptive threshold Inhibit release of pro-inflammatory molecules Synergistic effects with other systems that influence analgesia, such as the endogenous opioid system Activation of presynaptic CB1 receptors acts as a synaptic circuit breaker to inhibit neurotransmitter release (either excitatory or inhibitory) from the presynaptic neuron.
32 Role of Cannabinoids in Pain Management, by Ethan B. Russo and Andrea G. Hohmann. T.R. Deer et al. (eds.), Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches.
33 Clinical studies on CannabisIntractable epilepsy: Devinsky N= 214. Open-label ages Oral cannabidiol 2-5 mg/kg per day, up to max dose 25 mg/kg or 50 mg/kg per day (dependent on study site). Median reduction in monthly motor seizures was 36.5%. Crohn’s Dz: Naftali N= 21. Smoked Cannabis cig containing 115 mg THC or placebo of cannabis flowers from which THC was extracted BID. CR in 5/11 tx subjects and 1/10 in placebo group. Clinical response in 10/11 tx subjects and 4/10 placebo pts. Three pts in cannabis group were weaned from steroids. Parkinson’s: Lotan N=22. Smoked cannabis significantly improved Parkinson’s sxs including tremor, rigidity, and bradykinesia. Neuropathy: Wallace 2015 Diabetic neuropathy. Abrams 2007 HIV ass’d neuropathy.
34 Case #2 48 y/o BRCA(-) female with unremarkable PMH aside from dx of IDDM 2 years prior Presented with small, palpable left breast mass which was biopsied and determined to be invasive ductal carcinoa, ER/PR/Her2(-) She underwent exicision for stage I disease and was recommended adjuvant Carboplatin/Taxotere x 6C. Pt had significant N/V and did not tolerate prochlorperazine (Compazine) or ondansetron (Zofran) due to constipation. Few “puffs” a few times a day. 1 ounce lasted her approx. 6 months. This allowed her to complete chemo without using other antiemetics on a platinum based regimen.
35 Classification Incidence of N/V Chemo Agents High risk >90% Cisplatin, Carmustine, Dacarbazine, Cyclophosphamide ≥1500 mg/m2 Moderate risk 30-90% Carboplatin, Cyclophosphamide <1500 mg/m2, Doxorubicin, Epirubicin, Ifosfamide, Irinotecan, Oxaliplatin Lower risk 10-30% Docetaxel, Eribulin, Etoposide, 5FU, Gemcitabine, Ipilimumab, Ixabepilone, MTX, Mitomycin, Paclitaxel, Panitumumab, Pegylated liposomal doxorubicin, Pemetrexed
36 2015 Cochrane Review Cochrane Database Syst Rev Nov 12. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Smith LA et al. Analysis of 23 RCTs comparing Cannabis to either placebo or conventional anti-emetic. Trials conducted between 1975 and No trials involved comparison with newer anti-emetic drugs such as ondansetron. Compared to placebo: People had more chance of reporting no N/V (moderate quality evidence) when they received cannabinoids compared with placebo. Increased chance of withdrawing due to adverse event (very low quality evidence) and less chance of withdrawing due to lack of efficacy with cannabinoids, compared with placebo (low quality evidence). More chance of 'feeling high' with cannabinoids compared with placebo. People reported a preference for cannabinoids rather than placebo (low quality evidence). Comparison with other anti-emetics: No evidence of a difference between cannabinoids and prochlorperazine for N/V (low quality evidence). More chance of withdrawing due to adverse event (low quality evidence), lack of efficacy (very low quality evidence) with cannabinoids compared with prochlorperazine. Greater chance of reporting dizziness, dysphoria, euphoria, “feeling high”, sedation with cannabinoids compared with prochlorperazine. People reported a preference for cannabinoids rather than prochlorperazine (low quality evidence). Cannabis-based medications may be useful for treating refractory CINV. However, methodological limitations of the trials limit our conclusions and further research reflecting current chemotherapy regimens and newer anti-emetic drugs is likely to modify these conclusions. PMID:
37 2015 Systematic Review and Meta AnalysisJAMA Jun Cannabinoids for Medical Use: A Systematic Review and Meta-analysis.Whiting PF et al. To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. RCTs of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. RESULTS: 79 trials (6462 participants) were included. Most trials showed improvement in sxs associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%, 3 trials), reduction in pain, and spasticity. Common Aes: dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs. PMID:
38 Dronabinol (Marinol) Synthetic delta-9-tetrahydrocannabinol (delta-9-THC) The mechanism of action is not completely understood. Central cannabinoid receptors may mediate the effects of dronabinol and other cannabinoid compounds. Animal studies with other cannabinoids suggest that antiemetic effects may be due to inhibition of the vomiting control mechanism in the medulla oblongata. Dronabinol has an onset of action of approximately 30 to 60 minutes following oral dosing Peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4-6 hours, but appetite effects may continue for 24+ hours.
39 Cannabinoid Hyperemesis SyndromeBased on the known antiemetic effect of Δ9-THC, the mechanism of hyperemesis that occurs in some people is not well understood. CB1 receptors have a neuromodulatory function in the gut. Cannabinoids slow gastric emptying and peristalsis. In patients with CHS, this activity is thought to override the central CB1 antiemetic effect. Some components of cannabis have a long half-life and may accumulate in the brain. Buildup may also downregulate cannabinoid receptors. Classic triad of: 1. Chronic use. 2. Cyclical N/V. 3. Hot bathing (pathognomonic).
40 Case #3 61 y/o male with a hx of heavy tobacco and alcohol use and episode of pancreatitis in 2010. 2011: presented with abdominal pain and was found to have a low grade neuroendocrine pancreatic cancer with metastases to the liver. Neuroendocrine cells have a diffuse distribution Neuronal structure Hormone production In the GI tract, neuroendocrine cells regulate peristalsis and the release of digestive enzymes. Approximately 8000 cases per year in US (GI NET) Serotonin secretion Diarrhea and flushing
41 Case #3 Following dx he underwent distal pancreatectomy/ splenectomy, omentectomy and wedge resection liver revealing multifocal liver metastasis. He then underwent TheraSphere (Yttrium-90) treatment. He was stable on observation till 2014
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43 Case #4 Initial stage IIIa T3N1M0 ER/PR negative Her2 positive cancer of the right breast. Started neoadjuvant therapy and initially had a good response but developed inflammatory recurrence in the breast. Various chemos were tried and then went for bilat mastectomy. Her2 blockade for 2 years Chest wall and LN recurrence with subcutaneous tumor nodules Herceptin/Perjeta/Tykerb Topical use of Cannabis salve
44 Case #5 22 y/o male who began using recreational Cannabis 3 years prior. Increased use in 4 months immediately prior, approx 10x/day. No other substance abuse hx Began skipping classes and missing planned events with friends. Increasing anxiety and began to have some paranoid features, followed by an acute psychotic break. First inpatient stay was approx 2 months.
45 Schizophrenia: Diagnostic criteriaA. 2 or more characteristic symptoms below are present for a significant portion of time during a one-month period (or less if successfully treated): •1. Delusions- strongly held false beliefs that are not typical of cultural or religious background •2. Hallucinations- wakeful sensory experiences of content that is not actually present •3. Disorganized speech (eg, frequent derailment or incoherence) •4. Grossly disorganized or catatonic behavior •5. Negative symptoms, ie, affective flattening, alogia, or avolition B. Affects one or more functional areas: Work, interpersonal relations, or self-care. Failure to achieve expected level of academic or occupational achievement. C. Signs of the disturbance persist for at least six months. The six-month period must include at least one month of active-phase symptoms and may include periods of prodromal or residual symptoms. During these prodromal/residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A that present in an attenuated form (eg, odd beliefs, unusual perceptual experiences). D. Schizoaffective disorder and mood disorder with psychotic features have been ruled out E. Disturbance not due to the direct physiological effects of a substance (eg, a drug of abuse or medication) or a general medical condition. F. If the patient has a history of autistic disorder or developmental disorder, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations are also present for at least a month.
46 Moore 2007 Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Moore TH et al. Lancet. 2007;370(9584):319. BACKGROUND: 35 studies from 4804 references were included. FINDINGS: There was an increased risk of any psychotic outcome in individuals who had ever used cannabis (pooled adjusted odds ratio=1.41, 95% CI ). Findings were consistent with a dose-response effect: 2 fold increase in risk of psychosis for people who used cannabis most frequently Evidence was consistent with the view that cannabis increases risk of psychotic outcomes independently of confounding and transient intoxication effects, although evidence for affective outcomes is less strong. The uncertainty about whether cannabis causes psychosis is unlikely to be resolved by further longitudinal studies such as those reviewed here. However, we conclude that there is now sufficient evidence to warn young people that using cannabis could increase their risk of developing a psychotic illness later in life. PMID
47 Large et al 2011 Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Large M et al. Arch Gen Psychiatry. 2011;68(6):555. To establish the extent to which use of cannabis, alcohol, and other psychoactive substances affects the age at onset of psychosis by meta-analysis. 83 studies met the inclusion criteria. Age at onset of psychosis for cannabis users was 2.7 years earlier than for nonusers, and was 2.0 years earlier for other substance abuse than nonusers. Alcohol use was not associated with a significantly earlier age at onset of psychosis. “Provides evidence for a relationship between cannabis use and earlier onset of psychotic illness, and support the hypothesis that cannabis use plays a causal role in the development of psychosis in some patients. The results suggest the need for renewed warnings about the potentially harmful effects of cannabis.” PMID
48 Marconi 2016 Schizophr Bull Feb 15. Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis. Marconi et al. Systematic review of studies that investigate the association between the degree of cannabis consumption and psychosis and a meta-analysis to quantify the magnitude of effect. 18 studies met inclusion criteria for the systematic review and 10 were inserted in the meta-analysis, for a total of individuals. Higher levels of cannabis use were associated with increased risk for psychosis in all the included studies. A logistic regression model gave an OR of 3.90 (95% CI 2.84 to 5.34) for the risk of schizophrenia and other psychosis-related outcomes among the heaviest cannabis users compared to the nonusers. Current evidence shows that high levels of cannabis use increase the risk of psychotic outcomes and confirms a dose-response relationship between the level of use and the risk for psychosis. Although a causal link cannot be unequivocally established, there is sufficient evidence to justify harm reduction prevention programs. PMID:
49 Ksir and Hart 2016 Curr Psychiatry Rep Feb;18(2):12. Cannabis and Psychosis: a Critical Overview of the Relationship. Ksir C, Hart CL. “Shared vulnerability” Is early or heavy Cannabis use a prodromal sign for the appearance of psychosis?
50 Are some people more susceptible?Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Caspi et al. Biol Psychiatry. 2005;57(10):1117. Longitudinal study: Functional polymorphism in COMT gene moderated influence of adolescent cannabis use on developing adult psychosis. Carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis. Cannabis use had no such adverse influence on individuals with two copies of the methionine allele. PMID COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life. Henquet et al. Acta Psychiatr Scand. 2009;119(2):156. Data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Carriers of the COMT Val(158)Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure. PMID
51 Case #5 Cannabis cessation CBT Abilify (Aripiprazole)IgG Mediated food allergy testing Glycemic balance High dose fish oil Volunteering
52 Questions and discussionAcknowledgments: Shelly Smekens, N.D., FABNO Contact information: