Introduction

Recreational "Drugs"

Recreational drugs include a wide variety of compounds used to impart desired behavioral effects. The major source is botanical including concentrated products (e.g., hashish), also includes synthesized chemicals, industrial materials (e.g., solvents, glues), and therapeutic drugs (Table 1). Animals are exposed to these compounds primarily because of accidental ingestion, but intent (recreational or therapeutic) and malicious poisoning also play a role. Emergency clinics and selected veterinary diagnostic laboratories have quick screening tests that can detect the most commonly abused drugs (including metabolites) in body fluids (e.g., amphetamines, barbiturates, benzodiazepines, cocaine, marijuana, and opiates). Over-the-counter tests may also be useful. The pet poison help line (www.petpoisonhelpline.com), animal poison control center of the ASPCA (www.aspca.org/pet-care/animal-poison-control; VIN editor: link was modified as of 10-17-15) can provide support. Local police and related energies should be contacted for help with street names.

Table 1 lists recreational drugs, the most common affecting dogs (*) and in order, the top 10 abused by humans and thus at risk for harm in animals. These are, in reverse order of use:

 10. Solvents

 9. Psychedelic mushrooms: Over 180 different species contain psilocybin, a hallucinogenic compound similar to but shorter acting than LSD. Some may also contain non-hallucinogenic poisons. Clinical signs: disorientation, stumbling gait, vocalization, dilated pupils. Therapy is supportive; signs may last 8 h or more. Their possession is legal in some countries (e.g., UK).

 8. Opium-opioids: From the sap of the opium poppy (laudanum is prepared in alcohol), its seeds are also a food source. Toxicities to morphine derivatives are included. Clinical signs are typical of opioid overdose; treatment involves narcotic antagonists and supportive therapy. Diazepam (phenothiazine derivatives) can be used to treat dysphoria.

 7. Lysergic acid diethylamide: The most powerful hallucinogenic known (intended purpose was to cure the cold). Heightens visual and auditory awareness; enhances emotional and physical sensations. Risk of paranoia, confusion, panic.

 6. Barbiturates, benzodiazepines: (refer to therapeutic sources).

 5. Amphetamines. CNS stimulants (norepinephrine release targeting alpha and beta receptors; dopamine and serotonin also impacted). Used medically as appetite suppressants and treatment of ADHD in children. Induce euphoria, enhance metal focus and resilience against physical fatigue. Toxicity may be medically indistinguishable from cocaine. Generally detected based on stomach content. Treatment includes phenothiazine tranquilizers (chlorpromazine, phenothiazine), anticonvulsants, and beta-blockers as needed along with supportive therapy.

 4. MDMA: Ecstasy. Similar to amphetamines, induces euphoria, decreases fear and anxiety and physically and sensationally stimulates, presumably due to excessive release of serotonin; norepinephrine and dopamine also are released. Bad reactions are common particularly with first time users, particularly in the face of physical exertion. Risk of dehydration and harm due to unclean processes. Pet toxicosis generally reflects accidental ingestion. Treatment is as with amphetamines, but antiserotonergic drugs (e.g., cyproheptadine) may be necessary.

 3. Cocaine. Derived from the coca plant; CNS stimulant, appetite suppressant, and local anesthetic. Crack cocaine is the cheaper street form. See amphetamines for more information. Cocaine is likely to contain adulterants (anesthetics, decongestants). Twelve to 13 mg/kg may be lethal (IV); the oral lethal dose is generally 2 to 4 times higher. Decontamination (emesis and cathartic) should be followed by treatment as described for amphetamines.

 2. Heroin. A derivative of morphine (thought to be less addictive than morphine but effective as an analgesic). Induces exhilaration, euphoria and sense of well being. Intensive withdrawal (physical pain, nausea, cramping, diarrhea, shaking, twitching, addiction).

 1. Cannabis. Because cannabis is the number one recreational drug, the remainder of this session will focus on its role in both toxicity and medical use.

Table 1. Recreational drugs

Cannabis

Source

Marijuana is formed from the dried leaves and tops of the hemp plant (Cannabis sativa). Marijuana has been a part of recreational, religious, and medical activities of a variety of cultures for over 5000 years. Indeed, it was among the most commonly prescribed medications in the United States Pharmacopeia until declared illegal in the 1930s. It has been subsequently declared a controlled substance (Class II: High potential for abuse, but significant clinical indication). The potential efficacy of marijuana for control of pain has led to a passage of laws allowing medical use in several states. This, in turn, has stimulated a flurry of scientific activity in an attempt to provide evidence for medical use of marijuana. Not surprisingly, pet owners have also been engaged in the conversation, with a potentially legitimate reason for administering marijuana. Most scientific information generated as evidence is intended to support human, rather than veterinary use. To understand the allure of marijuana, and specifically if its promise of relief from what ails our pets is hype or hope, one must understand the plant.

Marijuana Ingredients

Marijuana is a pharmacologically (and toxicologically) diverse herb. Cannabis contains at least 480 unique compounds, with their presence varying with the plant product. Plant products include, in addition to marijuana, hashish and hashish oil, formed from the resin secreted by the plant. It is important to note that the amount of any one compound in the hemp plant can vary markedly, depending on the plant part. The most well known of the compounds in the hemp plant are the cannabinoids, a term used to refer to a terpene phenolic compound. The discovery of cannabinoids led to the recognition of the endocannabinoid system with endogenous cannabinoids. Since their discovery, both pharmaceutical companies and substance abusers have synthesized synthetic compounds. "Phytocannabinoids" is thus used to refer to those occurring in the plant whereas "endocannabinoids" refers to endogenous and synthetic chemicals. Endocannabinoids also appear to be important as neuroprotectants (e.g., antioxidants, inhibition of calcium influx and excessive glutamate production), for example, that associated with CNS ischemia or hypoxia, or the presence of neurotoxicants. These effects appear to be mediated predominantly by CB1 (located particularly in the dorsal horn of the spinal cord) although CB2 also plays a role, depending on the tissue (Svizenska 2008). Cannabinoids also inhibit neuroinflammation (see therapeutic indications).

Close to 70 phytocannabinoids, divided into 10 classes, have been identified in the hemp plant, and particularly marijuana. Table 1 lists those associated with presumed therapeutic use (Brenneisen Ch. 2). Among the cannabinoid compounds found in marijuana, THC is the most pharmacologically and toxicologically relevant, and the most understood. It is THC that is responsible for most of the natural effects of the Cannabis plant. It acts by binding to the CB1 receptor. CBD is the next "best" phytocannabinoid. In addition to its anxiolytic effects, it also reduces unpleasant side effects, primarily due to potent inhibition of cytochrome P450 3A11 which otherwise would metabolize THC to much more potent psychoactive compounds.

In addition to the cannabinoids, marijuana contains approximately 140 different terpenoids which are responsible for its scent. The terpenoids yielded from a marijuana plant depend on the type of Cannabis (based on drug or fiber content), the part of the plant, its sex and age, whether or not it is cultivated in or outdoors, when it is harvested and the conditions at harvest, and how it is dried and stored. The serotonergic effects of marijuana (5-HT1A and 2A) may reflect the impact of these essential oils, contributing to analgesia and mood modification. Other components in the plant include nitrogen-containing compounds (n = 70: alkaloids, amines); carbohydrates, including common monosaccharides (n = 13: fructose, glucose, mannose), selected disaccharides (sucrose, maltose), and several polysaccharides (e.g., cellulose, pectin) as well as several sugar alcohols (n = 12; mannitol, sorbitol, glycerol). A number of flavonoids also are present (n = 23); among them, apigenin has a wide variety of effects, including interaction with benzodiazepine receptors, resulting in an anxiolytic effect. Other ingredients include fatty acids (n = 33) and others.

The Target: Cannabinoid Receptors

The endocannabinoid system is comprised of eicosanoid cannabinoid [CB; protein G coupled, negative to adenylyl cyclase] receptors [CBr], their endogenous ligands and the enzymes responsible for their synthesis and degradation. This system as a known contributor to physiology has been recognized for only about 25 years old. At least two CBr have been identified in many species, including the dog. CB1r occurs in the brain but also occurs in some peripheral tissues (cardiovascular, reproductive, gastrointestinal). They are responsible, in part, for central and peripheral regulation of food intake, fat accumulation, and lipid and glucose metabolism. The dopaminergic reward pathway is stimulated by CB1 receptors, motivating eating, smoking and substance abuse. CB2r are located principally on immune cells, but this includes microglia. CB2 is also located on neurons where it may be associated with cell differentiation (Svizenska 2008). In the CNS, CBr are suggested to influence neurotransmitter release. At least 5 endogenous cannabinoids have been described, with anandamide (CB1 and 2 agonist, but higher affinity for CB1) being the most thoroughly studied. It is synthesized by postsynaptic neurons, acting as a retrograde messenger to influence neurotransmitter release. It is extremely unstable, being rapidly hydrolyzed to ethanolamine (an antihistamine) and arachidonic acid. Cannabinoids are able to disrupt short-term memory, impair cognition and time perception, alter mood while enhancing body awareness, discoordination, sleepiness, and reduce attention focus and the ability to "filter" irrelevant information.

As with many CNS active and recreational drugs, marijuana is associated with both tolerance (higher concentration needed to impart a similar pharmacologic effect) and withdrawal (a clinical syndrome of nervousness, tension, restlessness, sleep disturbance, and anxiety). However, the long elimination half-life of the most active ingredient THC (and others) appears to preclude a clear-cut abstinence syndrome (Svizenska 2008). As with other addictive agents, laboratory rodents have been demonstrated to self-medicate, suggesting an addictive component. It is important to note that although interaction with cannabinoid receptors is unique among plants to hemp, other receptors are also targeted (as noted above: benzodiazepines, serotonin, others).

Medicinal Marijuana

The proposed indications for medical marijuana have included, but are not limited to, behavioral, sleep and gastrointestinal disorders, neuroprotection, antispasmodic but prokinetic, anorexia, nausea, glaucoma, diabetes, immunosuppression, malaria, anti-inflammatory and, of course, pain (Table 2) However, other potential indications have included a proposed advantage of medical marijuana compared to a single drug (e.g., dronabinol, a synthetic THC [Marinol®]), is the multiple compounds contained in the plant. Two advantages are offered: 1) The compounds might act synergistically (a "synergistic" shotgun) to provide an enhanced desired pharmacologic effect, while 2) at the same time, mitigating (one compound acting on another) undesirable effects. However, evidence for a synergistic benefit is lacking based on the lack of differences when THC is consumed as marijuana, versus Marinol® (humans). Presumably, because marijuana contains so much THC, it may not be the most effective portion of the plant and it may contribute to more side effects (hence the question mark for this section; see also Marijuana and pets). Hybrids (www.leafly.com) contain more or less of a specific target compound.

Table 2

Marijuana and Pets

Most of the information surrounding marijuana and pets is from a toxicologic standpoint. THC is among the compounds cited as a toxicologic hazard in detection (police) dogs (Llera 2008). It is the most common drug to which detection dogs are exposed. Both dogs and cats may become intoxicated with smoke inhalation as well as ingestion of food-containing marijuana (or hashish). It is absorbed rapidly following either oral or inhalant administration with clinical signs evident within 30 to 60 minutes of ingestion, although one reference indicates onset as long as 12 hours after exposure. The drug is eliminated by hepatic metabolism and biliary excretion with elimination being complete in 5 days in dogs; duration of toxicity ranges from 30 minutes to 3 days, but 18–24 is the average. Enterohepatic circulation contributes to the prolonged half-life. The most common signs of toxicity following ingestion in dogs include tachycardia, hypotension, depression, ataxia, vomiting (inducing emesis is not recommended in clinically depressed dogs because of the risk of aspiration), altered behavior, bradycardia, hypersalivation, weakness, hypothermia and seizures. Toxicity might be confused with ethylene glycol toxicity. Legalization of marijuana may be associated with an increased incidence of toxicity, with a 4-fold increase cited in one study (Meola J Vet Emerg Crit Care. 2012). Treatment is largely supportive, with sedation with benzodiazepines or phenothiazines as needed. Antiemetic therapy may be indicated. No data exist regarding the efficacy of any portion of the hemp plant as an analgesic or for other therapeutic indications. A commercially available dietary supplement purportedly consisting primarily of hemp stem is being marketed for dogs. Because the stem contains very little THC but a high proportion of CBD and other non-psychotropic cannabinoids, its claim is that it is an effective analgesic without psychotropic effects. While such a product is more appealing than marijuana as an analgesic, neither data supporting efficacy nor safety nor quality assurance data could be obtained.

Synthetic Cannabinoids

An increasing problematic issue is the synthesis of cannabinoids. Modification of an R group on the cannabinoids that does not alter the psychotropic effects results in a compound that is not in the list of illegal drugs. Such products are sold in a variety of stores as "non-illegal substances" under names such as "spice" and other names. The DEA has passed emergency laws that are intended to make illegal the sale of any compound that is based on modification of cannabinoids. However, testing of such products is difficult because of the ease with which chemical modifications are made. Selected governments have begun to implement studies intended to determine the LD 50 (lethal dose 50) for selected synthetic cannabinoids.